Two new fixed-ratio combination insulin/glucagon-like peptide-1 (GLP-1) receptor agonists were approved by the U.S. Food and Drug Administration (FDA). They each combine a basal insulin with a GLP-1 agonist and are administered once daily. SOLIQUA 100/33, a Sanofi product, provides 100 units of insulin glargine per mL and 33 mcg of lixisenatide per mL in a 3 mL single-patient-use pen. Novo Nordisk's XULTOPHY 100/3.6 provides 100 units of insulin degludec per mL and 3.6 mg of liraglutide per mL, also in a 3 mL single-patient-use pen. Soliqua 100/33 and Xultophy 100/3.6 differ from other insulin-containing products and present new potential safety issues.
One potential safety issue is that practitioners may mistakenly think these products contain only insulin. This is one reason why computer system drop-down lists and pharmacy communications about these products should use the ratio expressions (i.e., Xultophy 100/3.6 and Soliqua 100/33), which hopefully tell users the product contains two different ingredients. In contrast to the ratios used for insulin-insulin combination products such as NOVOLOG MIX 70/30 (insulin aspart protamine, insulin aspart) or HUMALOG MIX 50/50 (insulin lispro protamine, insulin lispro), the ratio expressions for Soliqua 100/33 and Xultophy 100/3.6 do not sum up to 100%, which should also help practitioners differentiate them from insulin-only products.
If your computer system or electronic medication administration record uses generic names, make sure both ingredients are displayed and not truncated. However, keep in mind, the first name practitioners will see is "insulin." That may contribute to practitioners mistaking these as insulin-only products. Using the brand names could reduce the risk of an error. Also, counsel patients when initiating Soliqua 100/33 and Xultophy 100/3.6 so they understand the products contain both insulin and a GLP-1 agonist.
Dosing of these products is expressed based on the number of insulin units (the pen dials the dose in insulin units only). The package insert for each product has a table that indicates the amount of GLP-1 agonist per insulin unit, but including the GLP-1 agonist dose is not recommended when prescribing these products. If an order is communicated without the ratio expression ("Soliqua 40 units" or "Xultophy 35 units"), practitioners could think it's a new insulin product and not recognize there is a GLP-1 agonist contained within. This could lead someone to prescribe a separate GLP-1 agonist (e.g., albiglutide [TANZEUM], dulaglutide [TRULICITY], exenatide [BYETTA/BYDUREON], liraglutide [VICTOZA], lixisenatide [ADLYXIN]) to go along with what is thought to be the patient's only insulin dose.
These products are not recommended for use in combination with any other product containing a GLP-1 agonist because of the risk of overdose. The package insert recommends using alternative antidiabetic products if patients require a Soliqua 100/33 daily dosage below 15 units or over 60 units. For Xultophy 100/3.6, alternative antidiabetic products should be used if patients persistently require less than 16 units or more than 50 units.
ISMP thanks Ariane O. Conrad, PharmD, BCACP, CDE, FISMP, at the US Food and Drug Administration (FDA) Division of Medication Error Prevention and Analysis, and Steven Meisel, PharmD, CPPS, at Fairview Health Services in Minneapolis, MN, for their assistance in preparing this article for publication.
Educate Fluorouracil Home Infusion Patients About Accidental Overinfusion
We received a call from a family member of a patient with cancer who was to receive a 7-day infusion of fluorouracil at home via an ambulatory infusion pump. For an unknown reason, the entire infusion ran in over 4 days. The patient was very sleepy for the next 2 days and had "terrible diarrhea." Even though the infusion was empty, they waited until the patient's scheduled appointment 4 days later to report the mishap. The doctor hospitalized the patient and treated her with IV hydration. It's unclear why the antidote uridine triacetate was not administered, but the safety and efficacy of uridine triacetate initiated more than 96 hours following the end of fluorouracil or capecitabine administration has not been established. The patient was discharged after 7 days of hospitalization.
We are learning more about the pump issue that occurred, but this incident points to the need to educate patients with ambulatory infusion pumps about specific details in regard to how the pump works, infusion rates, how long the infusion should last, how much should be left in the container each day, and the need to immediately report any incident to their care team should the container empty sooner than anticipated.
Dangerous delays have been known to occur because patients are often asymptomatic in the first few hours and days. Rapid identification of a fluorouracil overdose allows prompt treatment with the antidote to minimize serious side effects and the risk of a harmful or fatal outcome. Patients need to be educated about rapidly reporting events to their healthcare team.
Are Divided Doses Behind Some Methotrexate Overdoses?
A middle-aged patient with rheumatoid arthritis was admitted to the hospital with a sore throat, mouth ulcers, rash, fever, and chills after mistakenly taking methotrexate three tablets twice a day for 4 days in a row instead of the prescribed three tablets in the morning and three tablets in the evening once a week. The pharmacy label stated: "Take 6 tablets by mouth weekly. Take 3 tablets in AM and 3 tablets in PM."
Although the daily administration of methotrexate is a well-recognized error that we have repeatedly published, it continues to happen. In the approved labeling for this drug, single oral doses of 7.5 mg once weekly are recommended for initial treatment of rheumatoid arthritis. However, divided oral dosages of 2.5 mg at 12-hour intervals for three doses, given as a course once weekly, are also recommended. It appears that the use of "divided doses" is adding to the confusion. To reduce the risk of errors, the U.S. FDA should change the only approved dosing regimen in the product labeling to "once weekly as a single dose" for the treatment of rheumatoid arthritis and other nononcologic indications, as appropriate. This would reinforce the need to program computers to default to a weekly dose, and avoid the confusing instructions on a patient's prescription label that results when the divided dosage regimens are used. It would also be helpful for FDA to distribute a warning to healthcare professionals to bring more attention to this ongoing problem.
As we have said many times, safety would also be enhanced if patient packs were required for methotrexate for nononcologic use. For example, a 4-week dose pack that provides six, 2.5 mg tablets per week (15 mg) would likely have prevented the above overdose. Other weekly dosages should also be available in patient packs. When oral dosage forms are not suitable, two companies also provide methotrexate for injection in autoinjector devices. RASUVO and OTREXUP are available in multiple strengths for weekly self-injection.