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

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Abstract

Introduction

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.

Objective

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?

Methods

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.

Results

The search found nine drugs (methadone, epinephrine, papaverine, oxytocin, vasopressin, testosterone, estradiol, isoniazid, and desmopressin) that contain chlorobutanol 2.5 (n = 1) or 5.0 mg/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.

Conclusion

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.

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Acknowledgements

The authors gratefully acknowledge the contributions of Kristin Black and Marius Petriu for technical maintenance of the http://www.CredibleMeds.org website and the QTdrugs knowledge base.

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  1. AZCERT, 1822 E. Innovation Park Dr., Oro Valley, AZ, 85755, USA

    R. David Woosley, Klaus Romero & Raymond L. Woosley

  2. Critical Path Institute, 1730 E. River Road, Tucson, AZ, 85705, USA

    Klaus Romero

  3. University of Arizona College of Medicine-Phoenix, 550 E. Van Buren St., Phoenix, AZ, 85004, USA

    Craig W. Heise, Tyler Gallo & Raymond L. Woosley

  4. University of Arizona, College of Pharmacy, 1295 N. Martin Ave, Tucson, AZ, 85721, USA

    Jared Tate

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The authors, R. David Woosley, Klaus Romero, Craig W. Heise, Tyler Gallo, Jared Tate, and Raymond L. Woosley have no conflicts of interest that are directly relevant to the content of this work.

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This research was supported by award number HHSF223201400189C from the Safe Use Initiative of the US Food and Drug Administration and the Bert W. Martin Foundation.

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Woosley, R.D., Romero, K., Heise, C.W. et al. Summary of Torsades de Pointes (TdP) Reports Associated with Intravenous Drug Formulations Containing the Preservative Chlorobutanol. Drug Saf 42, 907–913 (2019). https://doi.org/10.1007/s40264-019-00804-7

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