PEDIATRIC PEGFILGRASTIM
Improved safety needed
The Institute for Safe Medication Practices (ISMP) has received error reports involving pediatric patients who are receiving injectable medications as outpatients that require the removal of "partial doses" from a prefilled syringe. For example, Amgen's NEULASTA (pegfilgrastim), which is used primarily for the prevention of chemotherapy-induced neutropenia, is only available in a 6 mg prefilled syringe, the intended dose for adults. Since Amgen is the product's sponsor, the same is true for biosimilar versions, such as ZIEXTENZO (pegfilgrastim-bmez) (see photo above). However, the package insert includes a table for dosing pediatric patients under 45 kg that includes volumes less than 0.6 mL (6 mg).
Despite the weight-based pediatric dosing, the product labeling also states, "Note: The Neulasta prefilled syringe is not designed to allow for direct administration of doses less than 0.6 mL (6 mg). The syringe does not have graduation marks, which are necessary to accurately measure doses of Neulasta less than 0.6 mL (6 mg). Thus, the direct administration to patients requiring dosing of less than 0.6 mL (6 mg) is not recommended due to the potential for dosing errors."
The error reports reviewed by ISMP indicate that parents are sometimes instructed to withdraw a partial dose from the prefilled syringe using an empty sterile syringe and needle. While this is certainly not a risk-free option, parents of children who need this drug may have no other choice since pegfilgrastim injection is not available in a vial.
If used in a hospital, pharmacists would be unlikely to dispense the prefilled syringe for administration when only a partial dose is prescribed. Instead, the exact dose would be prepared under a laminar flow hood.
ISMP has contacted the US FDA about this concern. Amgen and biosimilar manufacturers need to provide a vial presentation and/or add graduation marks to prefilled syringes so smaller doses can be measured. Also, in conjunction with making a vial available, syringe manufacturers will need to make pediatric syringes available to deliver smaller doses.
ISMP has recently learned that in October 2019, the FDA issued an "Order Letter" to the sponsor of Neulasta for a postmarketing requirement or commitment that includes the development of an appropriate formulation that can be used to administer Neulasta directly and accurately to pediatric patients who require doses less than 6 mg. The FDA also sent similar letters to the pegfilgrastim biosimilar manufacturers. In the letter, the FDA stated that a pediatric presentation, such as a vial or a pediatric-sized, prefilled syringe (with a suitable concentration) would be an "appropriate formulation" alternative.
VESICANT INJURY
Inadvertent intra-arterial injection
A patient admitted to the ED with acute pancreatitis received promethazine 25 mg that was intended for IV administration but was inadvertently administered intra-arterially. The patient immediately experienced excruciating pain and erythema from his fingertips to his shoulder, followed by duskiness of his fingers and arm. After 48 hours, the patient was still experiencing severe pain. The patient told ISMP that he is now facing possible amputation of the affected digits. Promethazine is a phenothiazine derivative that possesses antihistaminic, sedative, anti-motion-sickness, antiemetic, and anticholinergic effects. Because promethazine injection is a vesicant, parenteral administration can result in severe tissue damage regardless of the route of administration. The labeling states that, due to the proximity of arteries and veins in the areas used for I.V. injection, extreme care should be exercised to avoid perivascular extravasation or accidental intra-arterial injection. However, as the present case indicates, it may not always be possible to prevent intra-arterial injection. No proven management of unintentional intra-arterial injection or perivascular extravasation exists. The ISMP 2020-2021 Targeted Medication Safety Best Practices for Hospitals recommend the removal of injectable promethazine from all areas of the organization, including the pharmacy, classifying it as a nonstocked, nonformulary medication. Furthermore, the Best Practices call for an automatic therapeutic substitution policy to convert all injectable promethazine orders to another antiemetic, and the removal of injectable promethazine from all drug order screens, order sets, and protocols. Although the product labeling notes the I.M. preferred route, the Best Practices recommend avoiding I.M. promethazine because it can also cause tissue damage or be accidentally injected intra-arterially.