1. Shastay, Ann MSN, RN, AOCN

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A patient with a history of bipolar disorder presented to a hospital with agitation and confusion. He had been prescribed (off-label) the antipsychotic cloZAPine (CLOZARIL). However, he had not been taking the cloZAPine for several weeks. Upon admission, the patient was restarted on his home dosage of cloZAPine (the target maintenance dose of cloZAPine for bipolar disorder is 100 to 300 mg daily and for schizophrenia it is 300 to 450 mg daily administered in divided doses). The patient was later found unconscious and without a palpable pulse. He was successfully resuscitated. When restarting cloZAPine in patients who have not been taking it for 2 days or more, the manufacturer recommends administering 12.5 mg once daily or twice daily. This is necessary to minimize the risk of hypotension, bradycardia, and syncope, all of which are mentioned in the product's Boxed Warning. If that dose is well tolerated, the dose may be increased to the previously therapeutic dose more quickly than recommended for initial treatment.


cloZAPine is well known to be associated with severe neutropenia (absolute neutrophil count less than 500/[mu]L), which can lead to serious and fatal infections. The U.S. Food and Drug Administration (FDA) requires a Risk Evaluation and Mitigation Strategy (REMS) program ( to help manage this risk. However, the patient safety risks posed by rapid reinitiation of the drug when the patient has not taken a dose for even short periods of time (e.g., 2 days) may not be as widely known as illustrated by the case above. Prescribers, pharmacists, and nurses need to be aware of this issue and restart cloZAPine treatment at 12.5 mg once or twice daily when there has been a break in therapy for 2 days or longer. We have asked the commercial drug information vendors and FDA to explore ways to make this information more prominent in product monographs and labeling.


Diastat AcuDial-Set and Lock the Dose

The DIASTAT ACUDIAL delivery system is a gel formulation of diazePAM intended for rectal administration. It is used to manage select refractory epilepsy in patients on stable antiepileptic drugs who require intermittent use of diazePAM to control bouts of increased seizure activity. The product is available in 10 mg or 20 mg rectal syringes designed to deliver minimum dosages of 5 mg or 12.5 mg respectively, with dosage increments of 2.5 mg up to a maximum of either 10 mg or 20 mg. A 2.5 mg syringe is available for pediatrics. Each package contains 2 unlocked rectal syringes.


Before the product is dispensed, pharmacists must dial, set, and lock the syringe according to the prescribed dose, even when the maximum dose has been prescribed. Once dialed and locked, the prescribed dose will appear in the dose display window, and the locking ring, designated with a green "ready" band, will be engaged (Figure 1). This helps to prevent the wrong dose from being administered by the caregiver. However, since the introduction of the device in 2005, errors have been reported because the device was not dialed and locked to the proper dose prior to dispensing and administration. Pharmacists, nurses, patients, and caregivers should be educated about how to use the device, including confirming that the prescribed dose is visible in the display window and the green "ready" band is visible. A useful video is available at:

Figure 1 - Click to enlarge in new windowFigure 1. After setting the dose of 7.5 mg, for example, and locking the syringe, a green band appears to indicate it is ready for administration.

ISMP recognizes that the use of diazePAM rectal gel may decrease as products are developed to take advantage of intranasal administration. As more clinical trials are published and familiarity with intranasal benzodiazepines-particularly midazolam-increases, diazePAM rectal gel use and accompanying errors may subsequently decline.


Nearly Identical Methotrexate and Folic Acid Tablets

We do not usually highlight errors due to the look-alike color of the tablets, but in the case of methotrexate and folic acid, which are often used together to lessen toxicity of the former, there is reason to do so. We received a report involving an accidental mix-up between these two medications. The mix-up resulted in the patient taking methotrexate daily for 6 days of the week and only taking folic acid once a week. It should have been the opposite.


The prescriber had reminded the patient to take the methotrexate once weekly using the mnemonic, "Take methotrexate on Monday." However, in this case, a friend helped set up the patient's medications in a weekly pill container. The friend did not realize the difference between the methotrexate and folic acid because both tablets looked similar; both were round and yellow (Figure 2). The friend accidentally interchanged the days the patient was supposed to take the methotrexate and folic acid. That led the patient to take the folic acid on Mondays and the methotrexate tablets daily. The error continued until the patient presented to an emergency department with severe thrombocytopenia. The patient was hospitalized for treatment and monitoring and was later discharged. Google image searches show that many methotrexate and folic acid tablets are various shades of yellow, with some looking essentially identical.

Figure 2 - Click to enlarge in new windowFigure 2. Methotrexate 2.5 mg tablets (left) and folic acid 1 mg tablets (right) may look almost identical.

It is critical to provide clear instructions for weekly dosing of methotrexate, utilizing auxiliary labels to draw attention to the once-weekly frequency. Practitioners should provide all patients with a copy of ISMP's free high-alert medication consumer leaflet on oral methotrexate ( Dispensed quantities should always be limited to a 4-week supply, and patients should be encouraged to keep methotrexate tablets in their original packaging rather than combining them with daily medications in pill containers. If patients are taking concurrent folic acid, additional education about the purpose of folic acid and the differences between the medications is necessary. Practitioners should also be aware of the potential for errors where patients confuse "Monday" with "morning." That may lead patients to take a dose of methotrexate every morning if written as an abbreviation (e.g., "q Mon" may be seen as "q Morn" [or q month]).