Remdesivir
Corey Diamond, PharmD
As a beneficial treatment for COVID-19, remdesivir (Veklury–Gilead Sciences) was rapidly introduced to market through FDA’s emergency use authorization in May 2020 with little known about its adverse effects. However, one adverse drug event that has been reported in the drug labeling but has eluded specific description is remdesivir I.V. infiltration—leakage of the I.V. solution out of the vein and into the surrounding interstitial space.
In an attempt to describe its clinical manifestations more accurately, a team of researchers based at Amsterdam University Medical Center recently published a case series in the American Journal of Health-System Pharmacy of 3 hospitalized patients who presented with remdesivir infiltration. The authors hypothesize that the adverse effects recorded may be related to the I.V. remdesivir solution’s pH.
An abridged case overview
In the research paper, van Merendonk and colleagues first present the case of a 91-year-old female who exhibited signs of extravasation on day 4 of remdesivir therapy. It presented as a swollen area about 3 by 3 centimeters around at the peripheral I.V. site on her left wrist. In addition, the area showed redness and felt cooler to the touch compared to the tissue immediately adjacent. After a failed attempt to aspirate the solution using an empty syringe, the medical team employed the “disperse-and-dilute” treatment method to try and diffuse the drug throughout the affected area in addition to the standard general care. This method incorporated warm compresses and a 255-unit injection of a hyaluronidase solution into the I.V. site.
After 18 hours post-infiltration, the site remained swollen and cool with the new addition of a hematoma. By week 4, the site no longer presented with a hematoma and exhibited decreased swelling. The swelling persisted by week 6 with no further reduction in size. Fortunately, at no point during this course did the patient report pain or discomfort.
The second case in the research paper is perhaps more encouraging in terms of outcome. On day 2 of therapy, a 72-year-old male complained of swelling and pain around the I.V. administration site on the right hand. While the medical team did not employ general care techniques after discontinuation of the remdesivir infusion due to unfamiliarity with the procedure (see sidebar), they did administer local hyaluronidase.
Swelling around the site and a small hematoma were visible after a couple of hours post-infiltration, but by day 7, the symptoms had subsided substantially. At 4 weeks follow-up, the patient reported no symptoms and presented with no visible signs of infiltration.
Lastly, the authors present the case of a 67-year-old female with a course very similar to the 91-year-old female patient. On day 2 of therapy, the patient complained of tenderness at the I.V. site on the right wrist. Upon inspection, the medical team observed tenderness, redness, and swelling 3 centimeters in diameter. They used general care techniques, including an attempt to aspirate the site, however in this case, hyaluronidase was not administered. A week post-infiltration, a rust-colored redness covered the area, with no signs of edema or symptoms of pain. By the fourth-week mark, all signs and symptoms had essentially resolved.
Possible mechanism of toxicity
The principal theory behind remdesivir’s possible infiltration toxicity that van Merendonk and colleagues posit stems mainly from the infusion’s pH. The authors’ claim, which was sourced from an uncited personal communication with Gilead Sciences, is that the pH of a diluted infusion of remdesivir is approximately 4.
According to a review of extravasation injuries of noncytotoxic medication published by Reynolds and colleagues in Pharmacotherapy in 2014, solutions below a pH of 5 have a propensity to cause cellular desiccation, eschars, and—in particular—coagulative necrosis. Patients often present with edema, vasoconstriction, sloughing, and ulceration at the infiltration site. Additionally, the authors highlight a particular diluent within remdesivir’s formulation, sulfobutylether-β-cyclodextrin (SBE-β-CD), a cyclodextrin excipient.
Considering that there is only one other case report of remdesivir extravasation, published in the Indian Journal of Critical Care Medicine in February 2021, this case series at least provides some measure of guidance to other clinicians who may encounter a similar problem.
General initial support for extravasation
- Stop infusion. Leave needle in place.
- Aspirate as much extravasated solution as possible.
- Avoid manual pressure over area.
- Remove canula and mark area with pen or take a picture.
- Note the hour.
- Notify physician and administer antidote if available.
- Elevate limb (for 48 hours) and immobilize it.
- Administer analgesic if necessary.
Source: Ann Pharmacother 2020 Aug;54(8):804–814.