VARIZIG Dilution Problems Reported

An issue came to our attention recently regarding varicella zoster immune globulin (VARIZIG), indicated for post-exposure prophylaxis against chickenpox in high-risk individuals, such as children and adults who are immunocompromised. The product is available as a kit (Figure 1) that contains a single vial of diluent along with a vial of 125 units of lyophilized powder (labeled as international units or IU, which ISMP deems an unsafe and unnecessary expression that is sometimes misread as IV).

The diluent is packaged as a single-dose vial containing 8.5 mL. VARIZIG is approved in the US for IM use only but approved in Canada for IM or IV use. According to the US label, only 1.25 mL of diluent is necessary for reconstitution of the 125 unit vial for IM use, resulting in a solution of 100 units per mL. In Canada where IV use is approved, 2.5 mL of diluent must be added to the vial.

Recently, in a US hospital emergency department (ED), a 5-year-old pediatric patient was to receive 125 units IM. However, a nurse misunderstood the instructions and used the entire volume of diluent (8.5 mL) to reconstitute the product. Rather than waste the dose, the nurse decided to divide the dose into two 3 mL injections and one 2.5 mL injection—for a total of 3 IM injections, which is bound to be traumatizing, particularly for a 5-year-old child. It is unclear why the instructions were misunderstood, but since only a fraction of the diluent (1.25 of the 8.5 mL) is necessary, it is likely that the packaging contributed to the error. We could also foresee a situation where the entire diluent is used to reconstitute the powder, and the practitioner assumes this provides the labeled 100 units per mL concentration, which would lead to a subtherapeutic dose.

The product is distributed in the US by Emergent Biosolutions and manufactured by its subsidiary, Cangene Biopharma, in Canada. According to Emergent Biosolutions, the diluent vial presently contains 8.5 mL because higher doses were originally used in Canada, and stability studies were conducted with larger diluent volumes. The company told us that Cangene has a new liquid form of the product under development that will not require reconstitution. The dosing for the new formulation is also weight-based and may require more than one vial according to a dosing chart in the package insert. For now, if you stock the lyophilized product, consider adding an auxiliary label that reminds practitioners to reconstitute with the volume listed in the labeling (1.25 mL per 125 unit vial, which provides 100 units per mL), and then to discard the remaining diluent. 

We also had a pharmacist express concern regarding the amount of sodium phosphate administered based on the diluent vial label. The label states that it contains “10 mM” of sodium phosphate, which seems to be a high dose of sodium phosphate for treating hypophosphatemia. But don’t confuse mM with mmol (as we did along with the reporter). Ten mM actually means 10 mmol per liter. Thus, the entire volume of diluent (8.5 mL) would provide 0.085 mmol of sodium phosphate, which is well below the maximum recommended dose of 0.36 mmol/kg (according to Lexicomp) whether given IV or IM.