Drug Risk Update

Drug labels, QT prolongation and ECG recommendations

CredibleMeds, a valuable resource for prescribing physicians, now includes information from FDA drug labels to inform prescribers of any ECG monitoring recommendations, warnings for use in congenital long QT and any contraindicated concomitant drugs.

Figure 1. Screenshot for CredibleMeds.org with red circle to denote the tab linking to the portal “For Healthcare Providers.”
Source: Figures provided by authors
Raymond L. Woosley, MD, PhD
Raymond L. Woosley

The CredibleMeds.org website is regularly cited in scientific publications and clinical practice guidelines as a reliable source of drug information, especially for the QTdrugs.org lists of drugs that have a risk for QT prolongation and torsades de pointes (TdP) arrhythmia. Each month, more than 25,000 people visit the website and more than 70,000 health care providers are registered to receive email notification when the QTdrugs lists are revised. To date, more than 69,000 people have installed the CredibleMeds app on their smartphone, tablet or desktop to gain instant access and search for drugs on the lists. The CredibleMeds website has three portals, and in 2018 the portal “For Healthcare Providers” (Figure 1) was accessed more than 103,000 times.

C. Will Heise, MD
C. Will Heise

Increasingly, prescribers rely on CredibleMeds.org when making clinical decisions on medications. CredibleMeds recently added new features to specifically meet the needs of practicing physicians by providing critical information they need at their fingertips when prescribing drugs that are on the QTdrugs lists. The new features provide immediate answers to the following questions:

  • Does the manufacturer’s label (package insert) recommend obtaining an ECG before prescribing this drug?
  • Is routine QT monitoring during therapy recommended in the manufacturers drug label?
  • Is ECG monitoring recommended in the drug label for specific subsets of patients?
  • Are there warnings in the package insert about prescribing this drug to patients with congenital long QT syndrome?
  • What drugs are contraindicated when a specific QT-prolonging drug is prescribed?

Limitations of drug labels as an information resource

Jared Tate, PharmD
Jared Tate
Tyler Gallo, PharmD
Tyler Gallo

In the United States and most developed countries, the official label for a marketed drug contains the information that the manufacturer and the FDA, or other regulatory agency, agree is needed by prescribers and other health care professionals to use the medication safely and optimally. Because of the complexity of modern therapeutics and the sheer number of medicines taken by the average patient, the amount of information can be overwhelming. Figure 2 shows the label for the antibiotic azithromycin — one of the most commonly prescribed drugs. The azithromycin label contains more than 14,000 words in 29 pages and includes more than 500 facts about azithromycin and instructions to prescribe it safely. Embedded deep in the label’s text is one fact that can be especially important to practicing cardiologists: “Prolongation of QT interval and cases of TdP have been reported. This risk, which can be fatal ...”. This is only one of many examples of important information in the drug label that is needed for the safe use of a medicine, but which can be difficult for health care providers to find.

CredibleMeds drug classification of TdP risk

Azithromycin is one of 49 drugs on the market that CredibleMeds has placed in the “Known Risk of TdP” category. The “Possible Risk of TdP” category includes 128 drugs that are known to prolong QT interval during clinical use and are being closely monitored for evidence of TdP that would support their move to the “Known Risk of TdP” category. Another 50 drugs are in the “Conditional Risk of TdP” category because they have been associated with TdP under certain conditions such as drug-drug interactions or they createconditions that favor TdP development (eg, loop diuretics and hypokalemia).

Figure 2. Official label (package insert) for azithromycin highlighting the section with a warning of QT interval prolongation and torsades de pointes.
David Woosley, MPH
David Woosley
Klaus Romero, MS, MD
Klaus Romero

Knowing which of the many drugs taken by patients are in any of these categories is a challenge that requires awareness by prescribers, ready access to trusted and reliable information, and, increasingly, decision support systems embedded in the electronic medical record. Michael J. Ackerman, MD, PhD, and colleagues at Mayo Clinic used the QTdrugs lists and QT risk factors to calculate a “pro-QTc score” that can identify patients at risk for increased mortality; the results were published in Mayo Clinic Proceedings in 2013. James E. Tisdale, PharmD, BCPS, and colleagues used the list of drugs in the Known Risk of TdP to develop and validate a QT risk score for use in the cardiac care unit of a tertiary care hospital; the findings were published in Circulation: Cardiovascular Quality and Outcomes in 2013. The score identifies patients at highest risk for developing QTc greater than 500 milliseconds, a magnitude of change associated with TdP. Similar decision support systems that employ the QTdrugs lists to calculate a QT risk score have been developed in health care systems in the Netherlands and Belgium. However, even after these smart decision support systems are implemented widely, it will remain essential that prescribers maintain access to readily available and reliable information when prescribing.

New features in QTdrugs lists

To make difficult-to-find information in drug labels more readily available to prescribers, CredibleMeds has recently installed new features on its website and in the apps it provides for smartphones and tablets. When the user accesses the QTdrugs lists and selects a drug that is in one of the TdP risk categories, a pop-up such as the one shown in Figure 3 appears and provides the following drug label information:

  • when reports of QT prolongation or TdP are mentioned in the drug label;
  • when an ECG is recommended or is required before prescription of a drug;
  • when intermittent ECG monitoring is recommended during therapy;
  • when ECG monitoring is recommended for specific subsets of patients;
  • any warning for prescribing the drug for patients with congenital long QT syndrome; and
  • any mention of contraindicated concomitant medicines.

Info in drug label: Recommendations for ECG monitoring

For 95 of the drugs known to prolong QT, the labels recommend ECG monitoring of QT intervals and for 22 drugs the QT should be checked before the drug is prescribed. For 60 drugs, QT monitoring is recommended in the following clinical categories of patients and conditions:

  • drug overdose: 40 drugs;
  • high-risk patients (heart, liver or kidney disease): 19;
  • concomitant prescription with a QT-prolonging drug: 14;
  • prescription of a higher than usual dosage: 3; and
  • patients diagnosed as “poor metabolizers”: 1.

Info in drug label: Warnings for use in congenital long QT syndrome

Because patients with congenital long QT syndrome are at high risk for drug-induced TdP, the labeling for 70 drugs includes warnings or recommendations that the drugs either should be avoided (n = 34), should be used with caution (n = 35), have a box warning against use (n = 2) or are contraindicated (n = 7). This information and the risk category “Drugs to Avoid in Congenital Long QT” are shown in the pop-up and should be helpful in managing these patients.

Drug label warning for contraindicated concomitant drugs

Finally, for 77 drugs, the “Info in Drug Label” section of the pop-up includes a list of any drugs that are “contraindicated” for use with the drug that has been selected. For example, as shown in Figure 3, there are 21 drugs listed in the dofetilide label that are classified as contraindicated and should never be prescribed with dofetilide. The other often contraindicated drugs include monoamine oxidase inhibitors, ergot alkaloids, metabolic inhibitors or psychotropics. In many cases, drug-interaction checkers fail to inform the prescriber of these drug contraindications.

Figure 3. Screenshot of CredibleMeds.org/new-drug-list for the dofetilide pop-up. The pop-up now includes a section labeled “Info in Drug Label” and is available for all drugs marketed in the U.S.

CredibleMeds mission and analysis of evidence

The CredibleMeds website and the QTdrugs lists are maintained by the nonprofit Arizona Center for Education and Research on Therapeutics (AzCERT), which provides free access to the website and apps for clinical and scientific applications. An application programming interface, or API, is available for health care systems that wish to electronically link the QTdrugs lists to their information technology system or EMR. The process AzCERT uses to evaluate evidence and place drugs in TdP risk categories has been described in peer-reviewed publications and on the website. AzCERT’s drug review process is overseen by an internationally respected advisory board of 38 expert cardiovascular scientists and cardiologists. AzCERT welcomes feedback from health care providers; such feedback has previously resulted in modifications and improvements to CredibleMeds.org such as the changes described above.

Disclosures: Raymond L. Woosley is president of AzCERT, the nonprofit sponsor of the CredibleMeds website. The other authors report no relevant financial disclosures.

CredibleMeds, a valuable resource for prescribing physicians, now includes information from FDA drug labels to inform prescribers of any ECG monitoring recommendations, warnings for use in congenital long QT and any contraindicated concomitant drugs.

Figure 1. Screenshot for CredibleMeds.org with red circle to denote the tab linking to the portal “For Healthcare Providers.”
Source: Figures provided by authors
Raymond L. Woosley, MD, PhD
Raymond L. Woosley

The CredibleMeds.org website is regularly cited in scientific publications and clinical practice guidelines as a reliable source of drug information, especially for the QTdrugs.org lists of drugs that have a risk for QT prolongation and torsades de pointes (TdP) arrhythmia. Each month, more than 25,000 people visit the website and more than 70,000 health care providers are registered to receive email notification when the QTdrugs lists are revised. To date, more than 69,000 people have installed the CredibleMeds app on their smartphone, tablet or desktop to gain instant access and search for drugs on the lists. The CredibleMeds website has three portals, and in 2018 the portal “For Healthcare Providers” (Figure 1) was accessed more than 103,000 times.

C. Will Heise, MD
C. Will Heise

Increasingly, prescribers rely on CredibleMeds.org when making clinical decisions on medications. CredibleMeds recently added new features to specifically meet the needs of practicing physicians by providing critical information they need at their fingertips when prescribing drugs that are on the QTdrugs lists. The new features provide immediate answers to the following questions:

  • Does the manufacturer’s label (package insert) recommend obtaining an ECG before prescribing this drug?
  • Is routine QT monitoring during therapy recommended in the manufacturers drug label?
  • Is ECG monitoring recommended in the drug label for specific subsets of patients?
  • Are there warnings in the package insert about prescribing this drug to patients with congenital long QT syndrome?
  • What drugs are contraindicated when a specific QT-prolonging drug is prescribed?
PAGE BREAK

Limitations of drug labels as an information resource

Jared Tate, PharmD
Jared Tate
Tyler Gallo, PharmD
Tyler Gallo

In the United States and most developed countries, the official label for a marketed drug contains the information that the manufacturer and the FDA, or other regulatory agency, agree is needed by prescribers and other health care professionals to use the medication safely and optimally. Because of the complexity of modern therapeutics and the sheer number of medicines taken by the average patient, the amount of information can be overwhelming. Figure 2 shows the label for the antibiotic azithromycin — one of the most commonly prescribed drugs. The azithromycin label contains more than 14,000 words in 29 pages and includes more than 500 facts about azithromycin and instructions to prescribe it safely. Embedded deep in the label’s text is one fact that can be especially important to practicing cardiologists: “Prolongation of QT interval and cases of TdP have been reported. This risk, which can be fatal ...”. This is only one of many examples of important information in the drug label that is needed for the safe use of a medicine, but which can be difficult for health care providers to find.

CredibleMeds drug classification of TdP risk

Azithromycin is one of 49 drugs on the market that CredibleMeds has placed in the “Known Risk of TdP” category. The “Possible Risk of TdP” category includes 128 drugs that are known to prolong QT interval during clinical use and are being closely monitored for evidence of TdP that would support their move to the “Known Risk of TdP” category. Another 50 drugs are in the “Conditional Risk of TdP” category because they have been associated with TdP under certain conditions such as drug-drug interactions or they createconditions that favor TdP development (eg, loop diuretics and hypokalemia).

Figure 2. Official label (package insert) for azithromycin highlighting the section with a warning of QT interval prolongation and torsades de pointes.
PAGE BREAK
David Woosley, MPH
David Woosley
Klaus Romero, MS, MD
Klaus Romero

Knowing which of the many drugs taken by patients are in any of these categories is a challenge that requires awareness by prescribers, ready access to trusted and reliable information, and, increasingly, decision support systems embedded in the electronic medical record. Michael J. Ackerman, MD, PhD, and colleagues at Mayo Clinic used the QTdrugs lists and QT risk factors to calculate a “pro-QTc score” that can identify patients at risk for increased mortality; the results were published in Mayo Clinic Proceedings in 2013. James E. Tisdale, PharmD, BCPS, and colleagues used the list of drugs in the Known Risk of TdP to develop and validate a QT risk score for use in the cardiac care unit of a tertiary care hospital; the findings were published in Circulation: Cardiovascular Quality and Outcomes in 2013. The score identifies patients at highest risk for developing QTc greater than 500 milliseconds, a magnitude of change associated with TdP. Similar decision support systems that employ the QTdrugs lists to calculate a QT risk score have been developed in health care systems in the Netherlands and Belgium. However, even after these smart decision support systems are implemented widely, it will remain essential that prescribers maintain access to readily available and reliable information when prescribing.

New features in QTdrugs lists

To make difficult-to-find information in drug labels more readily available to prescribers, CredibleMeds has recently installed new features on its website and in the apps it provides for smartphones and tablets. When the user accesses the QTdrugs lists and selects a drug that is in one of the TdP risk categories, a pop-up such as the one shown in Figure 3 appears and provides the following drug label information:

  • when reports of QT prolongation or TdP are mentioned in the drug label;
  • when an ECG is recommended or is required before prescription of a drug;
  • when intermittent ECG monitoring is recommended during therapy;
  • when ECG monitoring is recommended for specific subsets of patients;
  • any warning for prescribing the drug for patients with congenital long QT syndrome; and
  • any mention of contraindicated concomitant medicines.
PAGE BREAK

Info in drug label: Recommendations for ECG monitoring

For 95 of the drugs known to prolong QT, the labels recommend ECG monitoring of QT intervals and for 22 drugs the QT should be checked before the drug is prescribed. For 60 drugs, QT monitoring is recommended in the following clinical categories of patients and conditions:

  • drug overdose: 40 drugs;
  • high-risk patients (heart, liver or kidney disease): 19;
  • concomitant prescription with a QT-prolonging drug: 14;
  • prescription of a higher than usual dosage: 3; and
  • patients diagnosed as “poor metabolizers”: 1.

Info in drug label: Warnings for use in congenital long QT syndrome

Because patients with congenital long QT syndrome are at high risk for drug-induced TdP, the labeling for 70 drugs includes warnings or recommendations that the drugs either should be avoided (n = 34), should be used with caution (n = 35), have a box warning against use (n = 2) or are contraindicated (n = 7). This information and the risk category “Drugs to Avoid in Congenital Long QT” are shown in the pop-up and should be helpful in managing these patients.

Drug label warning for contraindicated concomitant drugs

Finally, for 77 drugs, the “Info in Drug Label” section of the pop-up includes a list of any drugs that are “contraindicated” for use with the drug that has been selected. For example, as shown in Figure 3, there are 21 drugs listed in the dofetilide label that are classified as contraindicated and should never be prescribed with dofetilide. The other often contraindicated drugs include monoamine oxidase inhibitors, ergot alkaloids, metabolic inhibitors or psychotropics. In many cases, drug-interaction checkers fail to inform the prescriber of these drug contraindications.

Figure 3. Screenshot of CredibleMeds.org/new-drug-list for the dofetilide pop-up. The pop-up now includes a section labeled “Info in Drug Label” and is available for all drugs marketed in the U.S.
PAGE BREAK

CredibleMeds mission and analysis of evidence

The CredibleMeds website and the QTdrugs lists are maintained by the nonprofit Arizona Center for Education and Research on Therapeutics (AzCERT), which provides free access to the website and apps for clinical and scientific applications. An application programming interface, or API, is available for health care systems that wish to electronically link the QTdrugs lists to their information technology system or EMR. The process AzCERT uses to evaluate evidence and place drugs in TdP risk categories has been described in peer-reviewed publications and on the website. AzCERT’s drug review process is overseen by an internationally respected advisory board of 38 expert cardiovascular scientists and cardiologists. AzCERT welcomes feedback from health care providers; such feedback has previously resulted in modifications and improvements to CredibleMeds.org such as the changes described above.

Disclosures: Raymond L. Woosley is president of AzCERT, the nonprofit sponsor of the CredibleMeds website. The other authors report no relevant financial disclosures.