Conservation of Drugs: The Impact of Acute Immunomodulator Prescribing for COVID-19 on Rheumatology Patients

In its COVID-19 treatment guidelines, the National Institutes of Health (NIH) lists several drugs commonly prescribed for patients with rheumatic conditions as potential therapies in those who are hospitalized for COVID-19 and require high-flow oxygen, noninvasive ventilation, intermittent ventilation (IMV) or extracorporeal membrane oxygenation (ECMO), as of Aug. 25, 2021, and current as this is written. The four immunomodulators mentioned in the guidelines are: baricitinib (Olumiant), tocilizumab (Actemra), tofacitinib (Xeljanz) and sarilumab (Kevzara).^1,8 Baricitinib or tocilizumab is preferred over tofacitinib and sarilumab; however, with national and worldwide shortages, and barriers to access, tofacitinib and sarilumab are listed as alternatives.

Tocilizumab and sarilumab are interleukin-6 (IL-6) antagonists. Endogenous IL-6 is induced by inflammatory stimuli and mediates a variety of immunological responses. Inhibition of IL-6 receptors by tocilizumab or sarilumab leads to a reduction in cytokine and acute phase reactant production. Preventing the release of these immune-activating and/or inflammatory molecules could help reduce inflammation and the cytokine storm associated with increased morbidity and mortality from COVID-19.

In both the REMAP-CAP and RECOVERY trials, tocilizumab was shown to have a benefit on mortality in patients with rapid respiratory decompensation. Baricitinib and tofacitinib are Janus kinase (JAK) inhibitors.^2,3 JAK inhibitors have anti-cytokine effects, reducing the release of cytokines. Baricitinib, specifically, has potential antiviral effects, interfering with a virus’ ability to enter and infect susceptible cells. In the COV-BARRIER trial, baricitinib also showed a reduction in mortality among patients with COVID-19 treated with the drug.⁴ This may explain why baricitinib is the preferred JAK inhibitor in the treatment of COVID-19 patients.

The use of these agents to combat COVID-19 in hospitalized patients created the potential for worldwide shortages of these agents and the possibility of interrupted treatment regimens for patients with rheumatic disease. On Sept. 3, 2021, Genentech released the following statement: “During this time, availability of Actemra will vary. We expect additional intermittent periods of stockouts in the months ahead, especially if the pandemic continues at the current pace.”⁵

The website, Genentech, has provided updates on the evolving situation (initially in August 2021) stating that subcutaneous formulations of tocilizumab continue to be available, although it admits to a limited supply.⁶ Then, most recently in March 2022, Genentech released a statement on the media portion of their website, stating availability of both the intravenous and subcutaneous formulations varies over time and is challenging to predict. ⁵ An attempt was made to reach Genentech by phone for comment on the status of the tocilizumab shortage. A senior manager for corporate relations, referred us back to the March media statement.

Specialty pharmacies are having interruptions in the availability of tocilizumab and are held to allocations—meaning they can order only what they had previously ordered on average for the past several months. In mid-October of 2021, patients across the country were notified the Genentech Access Solutions program may not have tocilizumab to consistently ship to patients who receive medications through the patient financial assistance program and could be added to a waiting list to receive their drug when the product becomes available.

It is difficult to predict how many patients worldwide this issue affects. However, at one academic medical center, the University of Kentucky, 18% of patients on Actemra were relying on the manufacturer patient assistance program for their medication, and 50% of those patients had to be switched to an alternate therapy. Upon changing a patient to a different therapy, the prescribing and financial assistance process is started over, which can result in a delay in therapy. This process includes prescribing, prior authorization, appeal and application to a new patient assistance program, which can result in months without therapy and worsening of disease status.

What You Can Do

In August 2021, the ACR issued a statement supporting the substitution of the IV formulation with the SQ formulation, and if the SQ formulation was unavailable, switching the medication to one with a similar mechanism of action.⁷ This is consistent with what pharmacists are reporting in clinical practice according to pharmacy network chats on the Vizient Community website. 

With the current issues surrounding acquisition of Actemra, and other biologic agents that are being used for COVID-19 indications, our personal recommendation would be to reserve prescribing of these agents to those who are already stable on therapy and for those whose disease has no alternative approved treatments.

For patients on these medications who are having issues when trying to refill their medication, providers will need to make a patient-centered decision based on the patient’s disease status, stability on the medication, improvement from baseline and previously tried therapies. Options include:

• Finding a pharmacy with a consistent inventory of affected medications;
• Reducing the frequency of doses; or
• Switching to a different medication within the same class.

Keep in mind that these options may be less effective for the patient and lead to increased disease activity and deteriorating health.

Communication with prescribers and patients, pharmacies and manufacturers is important. For example, the University of Kentucky specialty pharmacy and rheumatology clinic collaborated to generate an active list of patients on the affected medications. Then, each patient was assessed on where they were filling their medication and if their pharmacy was able to obtain the medication consistently at that time, and staff troubleshooted accordingly. Open communication with patients and the interdisciplinary team is imperative to ensure patients are not without medication. 

Ultimately, it is up to rheumatologists to maintain open communication and have plans in place to ensure patients are able to obtain their medications.

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Sara Jo Santangelo is a pharmacy intern for the University of Kentucky (UK) Specialty Pharmacy and is pursuing a Doctor of Pharmacy at the UK College of Pharmacy. 

 

Wendy Ramey, BSPharm, RPh, CSP, is a clinic-based specialty pharmacist with the University of Kentucky Specialty Pharmacy’s rheumatology program. She received her Specialty Pharmacist Certification in October 2016.

 

References

1. COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health. 2022 March 16.
2. REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med. 2021 Apr 22;384(16):1491–1502.
3. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): A randomized, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637–1645.
4. Marconi VC, Ramanan AV, de Bono S, et al. Efficacy and safety of baricitinib for the treatment of hospitalized adults with COVID-19 (COV-BARRIER): A randomized, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021;9(12):1407–1418.
5. Update on Actemra (tocilizumab) supply in the U.S. [media statement]. Genentech. 2021 Sep 3; current as of 2022 March.
6. Purchasing Actemra (tocilizumab) [media statement]. Genentech. 2021 Aug 30; current as of 2022 March.
7. From the College. ACR guidance on tocilizumab allocation during shortage. The Rheumatologist. 2021 Sep 1.
8. Reuters staff. EU evaluates tocilizumab as COVID-19 treatment. The Rheumatologist. 2021 Aug 18.