1. Shastay, Ann MSN, RN, AOCN

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A string of errors associated with tacrolimus, an immunosuppressant used primarily to prevent rejection in transplant recipients, prompted a literature review and analysis of related events reported to the U.S. Food and Drug Administration Adverse Event Reporting System and the ISMP National Medication Errors Reporting Program. We found that tacrolimus has been involved in many reported errors during the past decade that have been caused by a wide variety of factors:


Tacrolimus is commercially available for oral use in the United States in 0.5 mg, 1 mg, and 5 mg capsules (immediate-release PROGRAF and generics, extended-release ASTAGRAF XL), and 0.75 mg, 1 mg, and 4 mg tablets (extended-release ENVARSUS XR).


Types and Causes of Errors

Drug strengths that differ by a factor of 10. Mix-ups between drug strengths that differ by a factor of 10 are a common type of dosing error among products available in 10-fold increments. So, it is not surprising that mix-ups have been reported between the 0.5 mg and 5 mg strengths of tacrolimus. Most errors involved dispensing and administration of the 5 mg strength instead of the 0.5 mg strength. These may have been precipitated by the unsafe practice of not including a leading zero (i.e., .5 mg rather than 0.5 mg).


Various release formulations. Mix-ups between regular-release and extended-release tacrolimus formulations were another frequently observed theme, again reflecting a common error type among the many drugs available in both conventional (immediate-release, regular-release) and modified (e.g., delayed-release, extended-release) formulations.


Look-alike medication names. We have recently been asked to consider including on our list of confused drug names tacrolimus and tamsulosin, an alpha1-blocker used to treat benign prostatic hyperplasia. Although the available strengths differ, we discovered that several mix-ups between tacrolimus 0.5 mg and tamsulosin 0.4 mg have been reported, some leading to patient harm.


A liver transplant coordinator reported two incidences where outpatient pharmacies had dispensed tamsulosin 0.4 mg to patients who had been prescribed tacrolimus 0.5 mg. Tragically, both reported cases were believed to have contributed to the rejection of the transplanted liver. In another case, a patient had been hospitalized with symptoms of organ transplant rejection. During collection of a home medication list, a nurse noticed that the capsules in the patient's vial of medication labeled as tacrolimus 0.5 mg were quite different in color than she expected. She contacted a pharmacist, who identified the capsules as tamsulosin 0.4 mg.


Confusion among brand names has been reported less frequently. In one case, it was discovered that a patient with a high tacrolimus serum level had been given Prograf 5 mg capsules, intended for another family member, instead of his prescribed PROSCAR (finasteride) 5 mg. Apparently, the Prograf had been placed in the patient's dosing pill box by a family member in error instead of Proscar.


Confusion when dispensing and administering more than one strength for the patient's dose. With variable tacrolimus dosing based on the patient's weight, type of organ transplant, response to therapy, adjuvant immunosuppressants, and other factors, any of the available capsule or tablet strengths might be needed to fill a prescription. However, the pharmacy may not stock all strengths, and/or several strengths of the drug may be needed to accommodate the patient's total daily dose. This can lead to dosing confusion, particularly during the dispensing and administration phases of the medication-use process. For example, a post renal transplant patient was prescribed tacrolimus 6 mg orally every 12 hours. The initial prescription was partially filled with 1 mg capsules, with directions to take 6 capsules for each dose every 12 hours, until a supply of 5 mg capsules could be ordered to lower the cost of the prescription medication. Once the 5 mg capsules arrived in the pharmacy, the remainder of the prescription was filled using 5 mg capsules along with 1 mg capsules to achieve each 6 mg dose. A pharmacist had placed a note on the bag containing the medication in the will-call area as a reminder to talk to the patient about the change in capsule strength and the new directions for use. However, the note was not noticed, and patient counseling never occurred.


Although new directions had been provided on the labels of the two newly dispensed vials, the patient combined all the capsules into the initial prescription vial. The patient then took 6 capsules in the morning and 6 at night, as indicated on the label instructions. A month later, a very high serum tacrolimus level was obtained. Inspection of the patient's supply of tacrolimus showed the two strengths commingled in the vial, with the 1 mg capsules predominantly on the bottom (meaning the patient took mostly the 5 mg capsules each day, up to 60 mg daily).


Manufacturer's label confusion. One of the extended-release formulations of tacrolimus, Astagraf XL, comes in a bottle with a label that has occasionally confused patients who were dispensed the product in the sealed manufacturer's (Astellas Pharma US) container. In one case, a patient who was previously taking immediate-release tacrolimus 3 mg every 12 hours had just been converted to 6 mg of the extended-release product Astagraf XL daily. The new prescription for Astagraf XL had been filled using sealed manufacturers' bottles of the 1 mg capsules, onto which pharmacy labels had been applied, directing the patient to take 6 capsules daily. However, 1 week later, lab work showed the tacrolimus trough had dropped to an undetectable level. The patient had been taking only 1 mg of the drug daily, not the 6 mg dose. Instead of following the correct directions on the pharmacy label, the patient had been following what she thought were directions for use on the manufacturer's label that stated, "ONCE-DAILY," listed right below the drug name and dose.


Safe Practice Recommendations

Avoid leading decimal point doses. Always include a leading zero when expressing tacrolimus doses less than 1 mg. Whenever possible, avoid fraction doses greater than 1 mg by rounding the dose to the nearest whole number.


Monitor patients frequently. Tacrolimus has a narrow therapeutic index, so trough levels should be obtained for monitoring to prevent organ rejection (from levels that are subtherapeutic) and nephrotoxicity (from supratherapeutic levels).


Use brand names. Display the brand name of tacrolimus extended-release formulations (i.e., Astagraf XL, Envarsus XR) on drug ordering and verification screens to help differentiate these formulations from regular-release tacrolimus (i.e., Prograf, generics). When prescribing regular-release tacrolimus, use only the brand or generic name, without any modifiers such as "IR" for immediate-release.


Add to look-alike list. Consider including tacrolimus and tamsulosin on your organization's look-alike drug name list, and increase the situational awareness of staff regarding the risk of potential mix-ups. (The drug name pair will be added to ISMP's List of Confused Drug Names with the next update.)


Educate patients about correct dose. Educate patients regarding the directions for taking the correct dose of tacrolimus, how to manage dose changes, and the importance of monitoring drug levels. Ensure that patients can repeat back the specific directions for taking each prescribed dose. Provide patients with information about the common types of errors that may happen with tacrolimus and how to prevent and detect these errors.