Mg, mcg, units, mL: How will Symlin's safety measure up?

From the June 2005 issue

Amylin Pharmaceuticals recently released SYMLIN (pramlintide acetate), a subcutaneous injection indicated as an adjunct treatment in both type 1 and type 2 diabetics who use mealtime insulin therapy and have failed to achieve desired glucose control despite optimal therapy.
Unfortunately, we can envision a host of opportunities for dose confusion and highly recommend that practitioners become familiar with the variety of warnings and precautions associated with Symlin therapy. After a careful review of the product information and consideration of how the medication will be used, ISMP has identified several issues that, we believe, will increase the potential for patient and practitioner
error with this medication. We are concerned that these risks may preclude its safe use. Symlin is a synthetic analog of human amylin, a hormone manufactured by pancreatic beta cells that contributes to postprandial glucose control through several mechanisms.

For example, it slows gastric emptying, decreases postprandial glucagon concentrations, and regulates food intake due to centrally mediated modulation of appetite. While many other advances have been made in the treatment of type 2 diabetes, Symlin represents a novel advance in the treatment of type 1 diabetes since the only other treatment option for these patients is insulin. According to the product information, Symlin should only be used in patients who: use their insulin as prescribed, but still need better blood glucose control; will follow their doctor’s instructions exactly; will follow up with their doctor often; will test their blood glucose levels before and after every meal and at bedtime; and understand how to adjust Symlin and insulin doses. Also, the prescribing information contains a boxed warning that highlights the risk of insulin-induced severe hypoglycemia, especially in type 1 patients. It also stresses the explicit need for appropriate patient selection. Due to the risk of hypoglycemia, all patients treated with Symlin should be instructed to initially reduce preprandial rapid- or short-acting insulin dosages, including fixed-mixture insulins (e.g., 70/30) by 50%.

Please consider the following before prescribing, dispensing, administering, or adding Symlin to your inventory:

How the dosage will be expressed and measured. Symlin is available in 5 mL vials labeled with a concentration of 0.6 mg/mL. However, dosages are expressed throughout the prescribing information and the Medication Guide for patients in micrograms (as “µg,” an error-prone abbreviation). Doses range from 15 to 120 micrograms (in 15 microgram increments). In order to administer Symlin, the manufacturer recommends using U-100 insulin syringes (preferably the 0.3 mL size) for optimal accuracy even though the medication is not dosed in units. Unfortunately, for measurement with a U-100 syringe, the dose must be
converted into insulin unit equivalents (see chart below that appears in prescribing information). As a result, several problems could arise:

1) Practitioners and patients will need to have the chart available or commit it to memory in order to “convert” a dose into units. 2) The prescribing information contains the chart above, which includes the volumetric measurement (cc or mL) for each dose. However, the chart that appears in the patient information contains only the conversion to units, not volume. This presents a serious issue in that prescribers may recognize that the volumes can be measured in a tuberculin syringe and subsequently order these syringes in an effort to reduce confusion with patients’ insulin syringes. However, because the chart in the patient information does not contain the volumetric measure, patients may be unable to measure the correct dose. Also, the Medication Guide for patients states, “Use a U-100 insulin syringe (best to use 0.3 mL [0.3 cc] size) to draw up and inject Symlin.” 3) The dangerous abbreviations or dose designations that could be used to express Symlin doses (µg, u, cc, trailing zeros) could cause misinterpretations.

For example, ISMP has received reports where the abbreviation “u” for units has been read as “cc” or vice versa. It’s also possible that patients could misinterpret “µg” as “units.” Because patients may be unfamiliar with the mu (µ) symbol used throughout the Medication Guide and patient education materials) and it resembles a “u,” an abbreviation that these patients are likely familiar with due to insulin dosing, they may accidentally administer more Symlin than required. With this in mind, a patient could easily confuse “30 µg” for “30 u” and administer a six-fold overdose! Also, the use of trailing zeros (e.g., 5.0 instead of 5) in the column for units could contribute to errors. Practitioners and patients (especially those with diabetic retinopathy) may overlook the decimal point and accidentally administer a ten-fold overdose. For clarity, Symlin dosages should be expressed as micrograms (mcg), and avoid using “µg” in communications. Also, unless the manufacturer begins to promote volumetric dosing, it would be best that any reference to volumetric dose measurement (mL or cc) be eliminated from both practitioner and patient information.

Potential for confusion with insulin products. Many similarities exist between Symlin and insulin products. Patients treated with Symlin will also be receiving mealtime insulin so the two medications, each measured in units, will be administered around the same time, by the same route, in the same physical location with the same type of syringe. There is an increased likelihood that a Symlin dose could be confused for an insulin dose and vice versa. Symlin should be administered only in the abdomen or thigh, not the arm, and at least 2 inches from an insulin injection. Symlin and insulin should not be mixed in the same syringe. Also, like many other insulins, Symlin is a clear solution that may be stored in the refrigerator, but remains stable at room temperature for 28 days when in use. Patients with impaired
vision may also have trouble differentiating between multiple Symlin and insulin doses that have been prefilled in syringes for them and stored in the refrigerator.

Assessing the appropriateness of therapy. As mentioned previously, the prescribing information warns about proper patient selection and provides criteria that should be met before initiating therapy. However, none of the criteria mention a patient’s literacy level, which may affect their ability to read and comprehend the lengthy Medication guide, how to “convert” their dose from micrograms into units, as well as how to follow the appropriate titration schedule. A dose titration of Symlin is used to reduce the incidence and severity of nausea. After a dose has been tolerated for 3 to 7 days without nausea, a dose adjustment may be made. Different starting and maintenance doses are used for type 1 and type 2 diabetics; therefore, it’s important for prescribers to indicate the specific diagnosis on Symlin prescriptions. If this information is not provided, pharmacists and nurses should ask the patient or physician in order to verify that the dosage is appropriate. Patients must be aware of their specific diagnosis since both type 1 and type titration schedules appear in the MedicationGuide.

Practitioners must also consider and discuss the increased financial burden and demands of this therapy with patients. In addition to the cost of the medication, patients will require up to 3 additional syringes per day and be required to test their blood glucose 7 times daily.
Necessary in-depth patient education. As evidenced by the multiple opportunities for error mentioned thus far, extensive patient education is a vital component of this therapy for every practitioner involved in the patient’s care. For example, prescribers must realize that the instructions for the titration schedule and insulin dose adjustments are not likely to fit on the pharmacy label, so the patient will need some other form of written instructions.

Knowing this, pharmacists who are presented with prescriptions for Symlin, (especially those indicating, “as directed”) must ensure that patients have been provided with adequate printed instructions that include both Symlin dosages and reduced insulin dosages. Patients should, at minimum, be asked about their dose, how and when they will adjust the dose, demonstrate how to measure the dose using a U-100 syringe, discuss where and when it will be administered, and how they will monitor and keep track of their blood sugar levels. Although practitioner and patient dosing guides specific for type 1 or type 2 patients are available through the Symlin website (www.symlin.com), they offer, in our opinion, little help as far as assisting patients with monitoring their response to therapy on a daily basis. Patients will likely need a comprehensive monitoring form that includes space for recording, for example: blood sugar levels before and after every meal and at bedtime, administered doses of insulin and Symlin, and whether nausea was present.