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Symlin insulin adjunct presents safety issues


From the June 16, 2005
issue

Problem: In May, Amylin Pharmaceuticals released SYMLIN (pramlintide acetate), which is indicated as adjunctive therapy for type 1 and type 2 diabetics who use mealtime insulin and have failed to achieve desired glucose control despite optimal therapy. 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 advances have been made in the treatment of type 2 diabetes, Symlin represents a novel advance for type 1 diabetes since it provides a new treatment option for use with insulin. Unfortunately, we envision a host of opportunities for dose confusion and user errors that may preclude the safe use of this drug.

Dose confusion. One serious problem with Symlin is the manufacturer-recommended method for measuring doses. Symlin is available in 5 mL vials labeled as 0.6 mg/mL (photo appears in the PDF version of the newsletter). The usual dose is between 15 and 120 mcg. For a 30 mcg dose, for example, 0.05 mL of medication would be administered. The manufacturer recommends using a U-100 insulin syringe to measure the dose and provides the following chart in the package insert. Thus, users who require a 30 mcg dose, for instance, would withdraw Symlin to the 5 unit level of an insulin syringe. But, despite education, it's predictable that a patient or practitioner will use an insulin syringe and withdraw 30 units when 30 mcg is intended. This would result in a 6-fold overdose that is likely to cause serious harm, perhaps even death, since the drug is given to enhance insulin's effect. Incidentally, no information was available from Amylin about the effects of administering a 6-fold overdose of Symlin to a diabetic patient.

Underdoses are also possible. Last week, we received a report about a patient who had been on Symlin for about a week before she was admitted to a hospital for an unrelated condition. An endocrinologist called in an order for "Symlin 20 units" (equal to 120 mcg). Unfamiliar with the new drug, the pharmacist who reviewed the order was confused by the dose expressed in units since the drug monograph in Micromedex expressed the dose in mcg under the dosing information section. The package insert was not available in the pharmacy as the patient's vial from home was being used during hospitalization. These factors led the pharmacist to believe that the endocrinologist must have meant to order 20 mcg. After discussion with the nurse, the pharmacist entered the dose as 20 mcg (not 120 mcg as intended), and for several days, the patient received an underdose and experienced loss of glycemic control requiring insulin dose adjustments. Later, a clinical coordinator discovered the error while reviewing the order.

Another potential problem is that the dosing chart in the patient's Medication Guide contains only two columns: the dosage prescribed and the increment using a U-100 syringe. The column listing volume is only in the prescriber's package insert. This could lead to errors if prescribers recognize that Symlin doses can be measured in a tuberculin syringe and subsequently order these syringes to reduce confusion with the patient's insulin syringes. However, because the patient's chart does not contain the volumetric measure, patients may be unable to measure the correct dose.

Risk of 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 will be administered around the same time, by the same route, in the same physical location, with the same type of syringe. Thus, the risk of confusing a dose of Symlin with an insulin dose, or vice versa, is heightened. 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 also should not be mixed in the same syringe. Additionally, like many other insulins, Symlin is a clear solution that may be stored in the refrigerator (but is stable at room temperature for 28 days when in use). Patients with impaired vision may have trouble differentiating Symlin and insulin vials, as well as individual doses that have been prefilled in syringes and refrigerated.

Assessing the appropriateness of therapy. Symlin prescribing information contains a boxed warning that highlights the risk of insulin-induced severe hypoglycemia. The prescribing information also warns that Symlin should only be used in patients who: (1) use insulin as prescribed, but still need better blood glucose control; (2) will follow their doctor's instructions exactly; (3) will keep follow-up appointments with their doctor; (4) will test their blood glucose levels before and after every meal and at bedtime; and (5) can understand how to adjust Symlin and insulin doses. The patient's literacy level is not considered, though, which may affect his or her ability to read the lengthy Medication Guide and comprehend how to "convert" their dose from mcg into units and follow the titration schedule

A dose titration schedule is used to reduce the incidence and severity of nausea, a known side effect. After tolerating a dose for 3-7 days without nausea, doses may be adjusted accordingly. But patients must be aware of their diagnosis since both type 1 and type 2 titration schedules appear in the Medication Guide.

Abbreviations and dose designations. The dangerous abbreviations or dose designations that are included in the packaging and dosing chart, or might be used to express Symlin doses (µg, u, cc, trailing zeros), could lead to errors. Patients could misinterpret "µg" as "units." Since they may be unfamiliar with the mu (µ) symbol, which is used in the Medication Guide and other patient education materials, they might misinterpret it as a "u" for units-a more familiar abbreviation to diabetic patients. Thus, a patient could confuse "30 µg" for "30 u," for example, and administer a 6-fold overdose. Also, error-prone trailing zeros (e.g., 5.0 instead of 5) are used in the dosing chart. Thus, practitioners and patients (especially those with diabetic retinopathy) may overlook the decimal point and administer an overdose.

Safe Practice Recommendation: Patient education is a vital component of Symlin therapy, and this responsibility involves every practitioner who provides care to the patient. Before prescribing Symlin, physicians should talk to patients about the increased financial burden and demands of this therapy. In addition to the medication cost, patients will require up to three additional syringes per day and need to test their blood glucose levels 7 times daily. Due to the risk of hypoglycemia, all patients treated with Symlin must be instructed to initially reduce preprandial rapid- or short-acting insulin dosages, including fixed-mixture insulins (e.g., 70/30), by 50%, as indicated in the dosing instructions. 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 and ensure that the patient knows his or her diagnosis. If this information is not provided, pharmacists and nurses will need to ask the patient or physician to verify that the dosage is appropriate.

Prescribers must realize that the instructions for the titration schedule and insulin dose adjustments will not fit on the pharmacy label, so patients will need some other form of written instructions. Knowing this, pharmacists who receive Symlin prescriptions must ensure that patients have been given printed instructions that include Symlin doses and reduced insulin doses. Patients should be asked about their dose and how and when to adjust it, demonstrate how to measure the dose using a syringe, and be able to explain where it will be administered and how to monitor their blood sugars.

Although practitioner and patient dosing guides specific to type 1 or type 2 diabetes are available on the Symlin website (www.symlin.com), they offer, in our opinion, little help to assist patients with monitoring their daily response to therapy. Patients will likely need a comprehensive monitoring form that includes space for recording blood sugars, doses of insulin and Symlin, and other pertinent information. A consult to home care services is also advisable for new patients on Symlin.

ISMP notified Amylin about these concerns, including the use of error-prone abbreviations and dose designations on the dosing chart. We recommended expressing Symlin doses in micrograms (mcg, not µg) in the package insert, Medication Guide, and on the vial label (which lists the concentration in mg). We also suggested providing Symlin in its own delivery device, such as a pen injector, that is capable of delivering 15 to 120 mcg per dose with 15 mcg dosing increments. Another option is a making the product less concentrated so tuberculin syringes can be easily used to measure doses.

Please contact usf if you have additional concerns or to report errors with Symlin.

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