Error Alert
Institute for Safe Medication Practices, Horsham, PA
A string of errors associated with the high-alert drug tacrolimus, an immunosuppressant used primarily to prevent rejection in transplant recipients, prompted the Institute for Safe Medication Practices (ISMP) to review the literature and analyze related events reported to FDA’s Adverse Event Reporting System (FAERS) and the ISMP National Medication Errors Reporting Program (MERP). ISMP found that tacrolimus has been involved in many reported errors during the past decade that have been caused by a wide variety of factors. Below are some of the most common.
Tacrolimus availability
Tacrolimus is commercially available for oral use in 0.5-, 1-, and 5-mg capsules as immediate-release Prograf (Astellas Pharma) and generics and as extended-release Astagraf XL (Astellas Pharma), and in 0.75-, 1-, and 4-mg tablets as extended-release Envarsus XR (Veloxis Pharmaceuticals). The drug is also available in 1-mL ampules containing 5 mg/mL (Prograf) for I.V. use after dilution only in patients who are unable to take oral medications. If an oral liquid formulation is needed, it must be compounded.
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 (e.g., aripiprazole, 2 mg and 20 mg; buprenorphine 75 mcg and 750 mcg). So, it is not surprising that a number of mix-ups have been reported between the 0.5-mg and 5-mg strengths of tacrolimus.
Most of the reported errors involved dispensing and administering 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) when prescribing or displaying the 0.5-mg strength.
Some of the errors resulted in patient harm. For example, a patient was hospitalized with an acute kidney injury due to a tacrolimus overdose. The overdose was caused by dispensing 5-mg capsules instead of 0.5-mg capsules. The patient had been taking 5 mg twice daily (10 mg) instead of 0.5 mg twice daily (1 mg) for approximately 1 month before hospitalization.
Confused generic medication names. Confusion between tacrolimus and tamsulosin, an alpha-1 blocker used to treat benign prostatic hyperplasia, has been reported. Although the available strengths differ, ISMP discovered that several mix-ups between tacrolimus 0.5 mg and tamsulosin 0.4 mg have been reported, some leading to patient harm. For example, a liver transplant coordinator reported two incidences in which 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.
Confusion when dispensing more than one strength for the patient’s dose. With variable tacrolimus dosing, any of the available capsule or tablet strengths might be needed to fill a prescription. As a result, several strengths of the drug may be needed to accommodate the patient’s total daily dose. This can lead to confusion and medication errors.
For example, a postrenal 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 six capsules for each dose every 12 hours, until a supply of 5-mg capsules could be ordered. 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. 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 six capsules twice a day. 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).
Compounding errors. Errors during compounding of tacrolimus oral liquid formulations were also reported, including 10-fold overdoses and underdoses when the incorrect capsule strength was used for preparation (i.e., 0.5 mg instead of 5 mg), inappropriate substitution of a generic for a brand-name product, incorrect preparation of the suspension, and incorrect storage conditions.
In two of the cases, a tacrolimus suspension was created using the wrong suspending agent. Tacrolimus is poorly soluble in water, so it is recommended to compound an oral suspension using Ora-Plus and Simple Syrup.1 Ora-Plus contains suspending agents, which prevent drug particles from aggregating and settling. This allows for the creation of a homogenous suspension and uniform concentration.
One of the patients who received an incorrectly compounded suspension for which Ora-Plus was not used experienced problems with extreme fluctuations in his tacrolimus levels. The outcome for the second patient is unknown.
Safe practice recommendations
Standardize compounding concentrations and recipes. If oral liquid formulations must be compounded, establish a standard concentration for pediatrics and adults, and provide staff with clear recipes that include the oral suspension vehicle (e.g., Ora-Plus and Simple Syrup, not water) to use along with detailed directions for preparing the suspension. The Standardize 4 Safety Initiative of the American Society for Health-System Pharmacists recommends a standard concentration of 1 mg/mL to be consistent with the concentration of sirolimus oral solution and for ease of measurement.2
Avoid leading decimal point doses. Always include a leading zero when expressing tacrolimus doses less than 1 mg on computer screens, device screens, pharmacy labels, shelf markers, and other paper and electronic formats. 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.
Stock needed strengths. Stock all available tacrolimus strengths that might be prescribed, and use the simplest single strength or combination of strengths to match the patient’s prescribed dose when dispensing the product.
Educate patients. Establish a fail-safe mechanism to ensure that patients are counseled when picking up prescriptions for tacrolimus, particularly for the first prescription and whenever the dose, dosage strength, or formulation are changed. Educate patients about the directions for taking the correct dose, 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 information to patients about the common types of errors that may happen with tacrolimus and how to prevent and detect these errors.
References
1. Han J, Beeton A, Long PF, et al. J Clin Pharm Ther. 2006;31(2):167–72
2. www.ashp.org/-/media/assets/pharmacy-practice/s4s/docs/s4s-ashp-oral-compound-liquids.ashx