For AMI, tenecteplase is given as a single intravenous bolus for 5 s (“TNKase (tenecteplase),” 2017), with the recommended dose based on patient weight (“TNKase (tenecteplase),” 2017). The maximum recommended dose for alteplase (90 mg; “Activase (alteplase),” 2017) in AIS is higher than the maximum labeled dose for tenecteplase (50 mg; “TNKase (tenecteplase),” 2017); thus, tenecteplase overdose may occur if a patient inadvertently receives tenecteplase instead of alteplase using the alteplase weight-based dosing regimen (i.e., administering tenecteplase at the alteplase dose would be almost double the highest recommended tenecteplase dose).
Reteplase is administered by intravenous bolus injection as two 10-unit doses 30 min apart, which should be started quickly after onset of AMI symptoms (“Retavase (reteplase),” 2017). Accidentally administering 100 units of reteplase instead of alteplase would be less likely to occur than accidentally administering 100 mg of tenecteplase, given that the reteplase and alteplase dosing units are different and the reteplase vial size (each vial contains 10 units = 34.8 mg) would require 2.9 vials to be administered for a single-bolus injection.
Alteplase is provided as a preservative-free, sterile, lyophilized powder in 50-mg vials with a vacuum or 100-mg vials without a vacuum (see Table 1). To make the solution for injection, each vial is packaged with a 50- or 100-ml vial, respectively, of sterile water USP; 100-mg vials are also accompanied by a transfer device for reconstitution and a clear plastic hanger to facilitate infusion from the vial. After reconstitution, each vial will contain alteplase 1 mg/ml; if necessary, the alteplase solution can be further diluted with an equivalent amount of 0.9% sterile saline injection, USP, or 5% dextrose injection, USP.
Tenecteplase is provided as a preservative-free, sterile, lyophilized powder in 50-mg vials under partial vacuum, with a 10-ml vial of sterile water for making the solution for injection, USP, a 10-ml syringe with Twinpak dual-cannula device (Becton Dickinson, Franklin Lakes, NJ) for reconstitution and administration, and three alcohol preparation pads (see Table 1). Tenecteplase should be administered as a reconstituted 5-mg/ml solution.
Reteplase is supplied in a full- or half-kit configuration with preservative-free, sterile, lyophilized powder in 10-unit vials without a vacuum with components for reconstitution and delivery (see Table 1). The full kit contains the components for a single dosing regimen (i.e., two 10-unit bolus injections), including two 10-unit vials of reteplase, two 10-ml prefilled syringes of sterile water for injection, USP, two syringe plungers, two 10-ml graduated syringes, and two sterile reconstitution spikes, whereas each half kit contains one of each component. After reconstitution, each reteplase vial contains 10 ml of reteplase 1 unit/ml (i.e., one 10-unit bolus injection) plus a small amount of extra solution to ensure sufficient drug for administration.
A primary contributing factor to tissue plasminogen activator drug errors is use of the abbreviation “TPA” (ISMP, 2015; Scott & Davis, 2001; Tu, 2015). “TPA” (or “tPA”) is the abbreviation commonly used for “tissue plasminogen activator.” However, health care professionals often use “TPA” to refer specifically to alteplase because it was the first FDA-approved recombinant human tissue plasminogen activator; in addition, alteplase is often referred to as “TPA” in published literature. Because “TPA” is the abbreviation used for the drug class that encompasses all tissue plasminogen activators, use of “TPA” in written or verbal prescriptions may lead to confusion regarding the intended agent. In addition, health care professionals may refer to tenecteplase as “TNK,” an abbreviation of the tenecteplase brand name TNKase (Genentech, Inc., South San Francisco, CA); however, “TNK” has been frequently confused with “TPA,” further increasing the potential for medication error (Tu, 2015). “TPA,” “tPA,” and “TNK” are listed in the ISMP list of error-prone abbreviations, symbols, and dose designations and the list of high-alert medications in acute care settings (ISMP, 2018a, 2018b).
Both the FDA and the ISMP recommend using full brand or generic names for the approved tissue plasminogen activators in prescriptions, order sets, treatment protocols, and published literature (see Table 2; ISMP, 2015; Tu, 2015). The abbreviation “TPA” should not be used for written prescriptions or verbal orders for alteplase. Similarly, the abbreviation “TNK” should not be used to prescribe tenecteplase; the full brand name TNKase or full generic name tenecteplase should be used in written prescriptions and verbal orders. The ISMP also recommends including the indication on written prescriptions (ISMP, 2015). Because alteplase is the only tissue plasminogen activator approved for management of AIS and PE, including the indication may help reduce confusion in prescriptions for patients with these conditions. Separate order sets can be established for each indication (i.e., AIS, AMI, and PE). In addition, hospital pharmacy formularies could be limited to one fibrinolytic agent if possible. If more than one agent is available, using a pocket in an automated dispensing machine that is sized to fit only one treatment dose of a fibrinolytic could be a possibility. Similarly, for institutions that use smart pumps for dosing, the indication can be used for correct selection.
Both the FDA and the ISMP require participating hospitals to have “look-alike–sound-alike” medication lists to raise awareness of confusing medication names. They recommend using bolded tall man letters to draw attention to dissimilarities with look-alike names (e.g., predniSONE vs. prednisoLONE; ISMP, 2018c). Additional warning labels could be included to alert staff to look-alike or sound-alike drugs, particularly in hospitals that have limited technology. For hospitals with computerized physician order entry systems, written orders could be discouraged in general to prevent confusion. If door-to-needle times will not be compromised, entering an order and bar code scanning the medication before administration can be considered. If the medication is stored in an automated dispensing machine, an alert can be activated to ensure that the correct medication is being acquired.
Other factors contributing to drug errors among tissue plasminogen activators may include similar settings of use, such as emergency departments and critical care areas; approval of alteplase, tenecteplase, and reteplase for treatment of AMI; inadequate knowledge of or experience with multiple tissue plasminogen activators; lack of understanding of the differences among tissue plasminogen activators; stocking of a single tissue plasminogen activator for cardiac use in emergency departments; and/or use of automated drug-dispensing systems that may or may not recognize “TPA” or “tPA” (Cohen & Smetzer, 2015; ISMP, 2015; Scott & Davis, 2001). Additional steps to reduce errors may include revision of stroke treatment protocols to reduce the chance of drug substitutions, increased physician and staff education on the differences among tissue plasminogen activators, and addition of alerts in electronic prescriber order entry systems or automated medication-dispensing systems to ensure selection of the correct agent (Cohen & Smetzer, 2015; ISMP, 2015; Scott & Davis, 2001). Several strategies to prevent medication errors are summarized in Table 2.
Three tissue plasminogen activators are FDA approved for treatment of AMI: alteplase, tenecteplase, and reteplase; among these, only alteplase is also approved for management of AIS. Because of different indications and dosing regimens among these tissue plasminogen activators, accidental administration of tenecteplase or reteplase instead of alteplase in patients with AIS can result in failure to administer the most effective treatment and increase the risk of overdose. To avoid confusion and reduce the likelihood of errors, full brand or generic names should be used in written prescriptions, verbal orders, and publications and the abbreviations “TPA” and “TNK” should be avoided. Additional steps to reduce wrongful administration of tissue plasminogen activators include increased physician and staff education and use of alerts in electronic prescriber order entry systems or automated medication-dispensing systems.
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Keywords:Copyright © Wolters Kluwer Health, Inc. All rights reserved.
acute ischemic stroke; alteplase; reteplase; tenecteplase