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While the FDA's June of tocilizumab (Actemra) for severe COVID-19 was a welcome development during a deadly pandemic, patients who rely on the medication for other conditions are now facing shortages.

Among the non-COVID patients that physicians remain concerned about are those being treated for rheumatoid arthritis (RA), and those with cytokine release syndrome associated with cancer therapy.

"We have seen a shortage in the IV form," Elizabeth Volkmann, MD, a rheumatologist at the University of California Los Angeles (UCLA), told 乌鸦传媒.

Genentech, who manufactures the drug, hasn't been able to keep up with the demand, she noted.

At UCLA, Volkmann said that she has been working with pharmacy members to prioritize patients who must get the IV form of the drug, including patients with RA who have tried other biologics and treatments that failed.

"For many of these patients, tocilizumab wasn't the first medication that they tried for their RA," Volkmann noted. "It was the third, fourth, or fifth medication that they tried."

These patients may be fearful to move to something else that won't work, she added. The pandemic has already been stressful enough for the immunocompromised. Add the burden of not being able to get their medication, and "it's a tremendous amount of psychosocial stress."

Volkmann said that she first received notifications from Genentech and the UCLA pharmacy about the shortage in mid-August, which was about the same time that COVID-19 cases caused by the Delta variant were peaking.

She explained that it was important for her to reach out to her 20 patients on IV tocilizumab to communicate the shortage before they learned of it elsewhere, and to come up with a contingency plan with each of them. So far, all of these patients have been able to continue to receive tocilizumab, she noted, but the situation has been challenging for both providers and patients.

"It is unusual," Volkmann said of the shortage, especially in the U.S. However, during the pandemic, there have also been shortages of other medications, including hydroxychloroquine, which is used to treat lupus.

As the numbers of COVID-19 cases continue to decline, the situation may improve, Volkmann pointed out. Manufacturers generate product based on trends, and they don't want to produce more than they need.

"I think the manufacturer is likely adjusting its modeling to determine how much they need to produce," she continued.

John Davis III, MD, a rheumatologist at the Mayo Clinic in Rochester, Minnesota, told 乌鸦传媒 in an email that his institution is also experiencing a shortage of tocilizumab.

"Initially, this was mainly the IV formulation, but patients and physicians are reporting difficulty accessing the subcutaneous product," Davis said. "This is affecting hundreds of patients in our practice."

The issue is "most acute and problematic" for patients with giant cell arteritis, he added. "These patients have no FDA-approved alternative except high-dose prednisone. That is not a good option considering the increased risk of infectious complications, including more severe COVID-19 disease and related complications."

"A major issue is that for government payers, the coverage from a patient standpoint is best for the IV formulation administered in an infusion therapy center," Davis noted. "This means converting to the subcutaneous formulation may not be covered or may have higher out-of-pocket expenses for the patient."

"Commercial plans may not cover alternative options to tocilizumab on their formulary plans, so this can be a barrier to converting to other options for these patients," he added.

Tocilizumab is also used to treat cancer patients with cytokine release syndrome, which can occur after CAR T-cell therapy. In some cases, the condition can be life-threatening.

Ryan Bookout, PharmD, pharmacy supervisor at Moffitt Cancer Center in Tampa, Florida, told 乌鸦传媒 in an email that his team identified acquisition issues with the drug from its wholesaler at the end of July.

"We began to proactively audit our tocilizumab stock, use in COVID-19 patients and CAR-T patients," Bookout said. "We also began a prospective look at our upcoming admissions to the CAR-T service line, looking at a future state admission modeling of 4 weeks and then changing this to 6-week modeling."

"In preparation for a possible true absence of tocilizumab within the market, we reached out to all of our CAR-T manufacturers to determine the best acceptable processes to keep taking care of patients and bringing them to therapy with CAR-T," he continued.

That has included determining pharmaceutical options that the team can rely on to effectively treat cytokine release syndrome and/or neurotoxicity, he said. At this point, "we have only had to generate these thought processes," he added.

Given the nationwide shortages of tocilizumab, the Cleveland Clinic's blood and marrow transplant and cell therapy program and its pharmacy teams have worked closely with manufacturers to identify supply issues.

"We have ensured that we have an adequate supply of tocilizumab on site for our transplant and CAR T-cell standard-of-care therapies, as well as clinical research, so as not to impact patient care," a spokesperson from Cleveland Clinic told 乌鸦传媒 in an email. "The program has also developed cytokine release syndrome treatment guidelines that involve the use of similar agents to mitigate and treat this side effect of CAR T-cell therapy in case of further limitations in supply."

As for the manufacturer, a spokeswoman for Genentech pointed 乌鸦传媒 to its most recent from September 3, which noted that it had begun receiving scheduled replenishments of the drug in the U.S., and was anticipating additional replenishments of IV and subcutaneous formulations in the coming weeks and months.

"We expect additional intermittent periods of stockouts in the months ahead, especially if the pandemic continues at the current pace," the statement continued. "We recognize the urgency around the situation and understand the frustration that patients, their families and healthcare providers are experiencing due to these supply constraints."

Genentech and Roche are "working as quickly as possible to expedite replenishments and increase manufacturing capacity and supply, including through active collaboration with external partners. Genentech has implemented new distribution strategies for hospital and clinic customers to enable access for the greatest number of patients, as supply permits," the statement concluded.

The statement also instructed hospitals and practices to contact their authorized distributors for the most up-to-date information on product availability.

"These are really difficult times ... in this country, typically we haven't had to face these challenges," Volkmann said. "The pandemic is challenging us in this way."

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