Table 5f. Characteristics of Immunomodulators

Last Updated: January 26, 2023

The information in this table is derived from data on the use of these drugs for FDA-approved indications or from clinical trials on their use in patients with COVID-19.
For dose modifications in patients with organ failure or those who require extracorporeal devices, please refer to product labels or EUAs, when available.
There are currently not enough data to determine whether certain medications can be safely coadministered with therapies for the treatment of COVID-19. When using concomitant medications with similar toxicity profiles, consider performing additional safety monitoring.
The potential additive, antagonistic, or synergistic effects and the safety of using certain combination therapies for the treatment of COVID-19 are unknown. Clinicians are encouraged to report AEs to the FDA Medwatch program.
For drug interaction information, please refer to product labels and visit the Liverpool COVID-19 Drug Interactions website.
For the Panel’s recommendations on using the drugs listed in this table, please refer to the drug-specific sections of the Guidelines, Therapeutic Management of Nonhospitalized Adults With COVID-19, and Therapeutic Management of Hospitalized Adults With COVID-19.

Table 5f. Characteristics of Immunomodulators
Drug Name	Dosing Regimens	Adverse Events	Monitoring Parameters	Drug-Drug Interaction Potential	Comments
Corticosteroid (Systemic) Recommended by the Panel for the treatment of COVID-19 in certain hospitalized patients.
Dexamethasone	Dose for COVID-19 DEX 6 mg IV or PO once daily for up to 10 days or until hospital discharge, whichever comes first¹	Hyperglycemia Secondary infections Reactivation of latent infections (e.g., HBV, HSV, strongyloidiasis, TB) Cases of disseminated strongyloidiasis have been reported in patients with COVID-19 during treatment with corticosteroids and tocilizumab. Psychiatric disturbances Avascular necrosis Adrenal insufficiency Increased BP Peripheral edema Myopathy (particularly if used with NMBAs)	Blood glucose BP Signs and symptoms of new infection	Moderate CYP3A4 inducer CYP3A4 substrate	If DEX is not available, an alternative corticosteroid (e.g., prednisone, methylprednisolone, hydrocortisone) can be used. The approximate total daily dose equivalencies for these glucocorticoids to DEX 6 mg (PO or IV) are: Prednisone 40 mg Methylprednisolone 32 mg Hydrocortisone 160 mg
Janus Kinase Inhibitors Baricitinib and tofacitinib: Recommended by the Panel for the treatment of COVID-19 in certain hospitalized patients. Ruxolitinib: Not recommended by the Panel for the treatment of COVID-19. Currently under investigation in clinical trials.
Baricitinib²	FDA-Approved Doses for COVID-19 in Adults Aged ≥18 Years² eGFR ≥60 mL/min/1.73 m² Baricitinib 4 mg PO once daily eGFR 30 to <60 mL/min/1.73 m² Baricitinib 2 mg PO once daily eGFR 15 to <30 mL/min/1.73 m² Baricitinib 1 mg PO once daily eGFR <15 mL/min/1.73 m² Not recommended FDA EUA Dose for Children Aged 9–17 Years³ Same as adults FDA EUA Doses for Children Aged 2 to <9 Years³ eGFR ≥60 mL/min/1.73m² Baricitinib 2 mg PO once daily eGFR 30 to <60 mL/min/1.73m² Baricitinib 1 mg PO once daily eGFR <30 mL/min/1.73m² Not recommended Duration of Therapy Up to 14 days or until hospital discharge	Lymphoma and other malignancies Thrombosis GI perforation Treatment-related changes in lymphocytes, neutrophils, Hgb, liver enzymes HSV reactivation Herpes zoster Secondary infections Serious cardiac-related events (e.g., MI, stroke)	CBC with differential Renal function Liver enzymes New infections	Dose modification is recommended when administering concurrently with a strong OAT3 inhibitor.	See the FDA label² and EUA³ for dosing guidance for patients with: ALC <200 cells/µL ANC <500 cells/µL If increases in ALT or AST are observed and DILI is suspected, interrupt baricitinib treatment until the diagnosis of DILI is excluded. Baricitinib tablets can be taken orally or crushed, dispersed in water, and given via gastrostomy tube.² Availability Baricitinib is approved by the FDA for the treatment of COVID-19 in adults aged ≥18 years.² Baricitinib is available through an FDA EUA for children aged 2–17 years who require supplemental oxygen, NIV, MV, or ECMO.³
Ruxolitinib	Dose for FDA-Approved Indications Ruxolitinib 5–20 mg PO twice daily Dose for COVID-19 in Clinical Trials Ruxolitinib 5 mg PO twice daily for 14 days⁴	Thrombocytopenia Anemia Neutropenia Liver enzyme elevations Risk of infection Dizziness Headache Diarrhea CPK elevation Herpes zoster	CBC with differential Liver enzymes New infections	Requires dose modification when administered with strong CYP3A4 inhibitor Avoid use with fluconazole doses >200 mg.	May require dose modification in patients with hepatic impairment, moderate or severe renal impairment, or thrombocytopenia
Tofacitinib	Dose for COVID-19 in Clinical Trials Tofacitinib 10 mg PO twice daily for up to 14 days or until hospital discharge⁵	Thrombotic events (e.g., PE, DVT, arterial thrombosis) Anemia Risk of infection GI perforation Diarrhea Headache Herpes zoster Lipid elevations Liver enzyme elevations Lymphoma and other malignancies Serious cardiac-related events (e.g., MI, stroke)	CBC with differential Liver enzymes New infections	Requires dose modification when administered with strong CYP3A4 inhibitors or when used with a moderate CYP3A4 inhibitor that is coadministered with a strong CYP2C19 inhibitor Coadministration with strong CYP3A4 inducers is not recommended.	Avoid use in patients with ALC <500 cells/mm³, ANC <1,000 cells/mm³, or Hgb <9 grams/dL. May require dose modification in patients with moderate or severe renal impairment or moderate hepatic impairment
Interleukin-6 Inhibitors
Anti-Interleukin-6 Receptor Monoclonal Antibodies Recommended by the Panel for the treatment of COVID-19 in certain hospitalized patients.
Sarilumab⁶	Dose for COVID-19 in Clinical Trials Single dose of sarilumab 400 mg IV^7,8	Neutropenia Thrombocytopenia GI perforation HSR Increased liver enzymes HBV reactivation Infusion-related reaction	HSR Infusion reactions Neutrophils PLT Liver enzymes	Elevated IL-6 may downregulate CYP enzymes; thus, use of sarilumab may lead to increased metabolism of drugs that are CYP substrates. The effects of sarilumab on CYP enzymes may persist for weeks after the drug is stopped.	Sarilumab is not recommended in patients with ALT or AST >1.5 times the upper limit of the reference range, ANC <2,000 cells/mm³, or PLT <150,000 cells/mm³.⁶ Treatment with sarilumab may mask signs of acute inflammation or infection by suppressing fever and CRP levels. Availability An IV formulation of sarilumab is not approved by the FDA, but in clinical trials, a single SUBQ dose (using the prefilled syringes, not the prefilled pen) of sarilumab 400 mg was reconstituted in 100 cc 0.9% NaCl and given as an IV infusion over 1 hour.^8,9 IV infusion of sarilumab should occur within 4 hours of its preparation; it can be stored at room temperature until administered.
Tocilizumab¹⁰	FDA-Approved Doses for COVID-19 in Hospitalized Adults Tocilizumab 8 mg/kg (maximum 800 mg) by IV infusion over 1 hour FDA EUA Dose for COVID-19 in Hospitalized Children Body Weight ≥30 kg Tocilizumab 8 mg/kg by IV infusion over 1 hour Body Weight <30 kg Tocilizumab 12 mg/kg by IV infusion over 1 hour For All Doses If clinical signs or symptoms worsen or do not improve following the first infusion, 1 additional dose may be administered at least 8 hours after the first dose.	Infusion-related reaction HSR GI perforation Hepatotoxicity Treatment-related changes on laboratory tests for neutrophils, PLT, lipids, and liver enzymes HBV reactivation Secondary infections Cases of disseminated strongyloidiasis have been reported in patients with COVID-19 during treatment with tocilizumab and corticosteroids.	HSR Infusion reactions Neutrophils PLT Liver enzymes	Inhibition of IL-6 may lead to increased metabolism of coadministered drugs that are CYP450 substrates. The effects of tocilizumab on CYP enzymes may persist for weeks after the drug is stopped.	Tocilizumab is not recommended in patients with ALT or AST >10 times the upper limit of the reference range, ANC <1,000 cells/mm³, or PLT <50,000 cells/mm³.¹¹ The SUBQ formulation of tocilizumab is not intended for IV administration. Availability IV tocilizumab is approved by the FDA for the treatment of COVID-19 in hospitalized adults aged ≥18 years.¹⁰ Tocilizumab is available through an FDA EUA for the treatment of COVID-19 in certain hospitalized children aged 2–17 years.¹¹
Anti-Interleukin-6 Monoclonal Antibody Not recommended by the Panel for the treatment of COVID-19. Currently under investigation in clinical trials.
Siltuximab	FDA-Approved Dose for Multicentric Castleman Disease Siltuximab 11 mg/kg by IV infusion over 1 hour every 3 weeks¹² Dose for COVID-19 Dose and duration unknown	Infusion-related reaction HSR GI perforation Neutropenia HTN Dizziness Rash Pruritus Hyperuricemia	Neutrophils HSR Infusion reactions	Elevated IL-6 may downregulate CYP enzymes; use of siltuximab may lead to increased metabolism of drugs that are CYP substrates. The effects of siltuximab on CYP enzymes may persist for weeks after therapy is stopped.	Siltuximab is not recommended in patients with ANC <1,000 cells/mm³, Hgb >17 g/dL, or PLT <75,000 cells/mm³.¹² Treatment with siltuximab may mask signs of acute inflammation or infection by suppressing fever and CRP levels.
Interleukin-1 Inhibitors Anakinra: Received an FDA EUA for the treatment of COVID-19 in certain hospitalized adults. There is insufficient evidence for the Panel to recommend either for or against its use. Canakinumab: Not recommended by the Panel for the treatment of COVID-19.
Anakinra	FDA EUA Dose for COVID-19 in Hospitalized Patients Aged ≥18 Years Anakinra 100 mg SUBQ once daily for 10 days Dose for CrCl <30 mL/min Anakinra 100 mg SUBQ every other day for 5 total doses over 10 days.¹³	Neutropenia (particularly when used concomitantly with other agents that can cause neutropenia) HSR, including anaphylaxis and angioedema Secondary infections Injection site reactions Liver enzyme elevations Hyperkalemia Hypernatremia Rash	CBC with differential; assess neutrophils before starting treatment and during therapy. BMP Liver enzymes Renal function	Use with TNF-blocking agents is not recommended due to increased risk of infection.	Contraindicated in patients with known hypersensitivity to proteins derived from Escherichia coli, anakinra, or any component of the product¹³ Patients with <1,500 neutrophils/mm³ were excluded from participation in the SAVE-MORE study.¹⁴ Availability SUBQ anakinra is available through an FDA EUA.¹³
Canakinumab	FDA-Approved Dose for Systemic JIA Canakinumab 4 mg/kg (maximum 300 mg) SUBQ every 4 weeks¹⁵	HSR Neutropenia Nasopharyngitis Diarrhea Respiratory tract infections Bronchitis Gastroenteritis Pharyngitis Musculoskeletal pain Vertigo Abdominal pain Injection site reactions Liver enzyme elevations	HSR CBC with differential Liver enzymes	Binding of canakinumab to IL-1 may increase formation of CYP enzymes and alter metabolism of drugs that are CYP substrates. Use with TNF-blocking agents is not recommended due to potential increased risk of infection.	Canakinumab for IV administration is not an approved formulation in the United States.¹⁵
Corticosteroids (Inhaled) Not recommended by the Panel for the treatment of COVID-19. Currently under investigation in clinical trials.
Budesonide (Inhaled)	Dose for COVID-19 in Clinical Trials Budesonide 800 mcg oral inhalation twice daily until symptom resolution or up to 14 days^16,17	Secondary infections Oral thrush Systemic AEs (less common)	Signs of AEs involving the oral mucosa or throat, including thrush Signs of systemic corticosteroid effects (e.g., adrenal suppression)	CYP3A4 substrate Do not use with strong CYP3A4 inhibitors.	No comments
Ciclesonide (Inhaled)	Dose for COVID-19 in Clinical Trials Ciclesonide 160 mcg as 2 MDI inhalations twice daily for 30 days¹⁸	Secondary infections Oral thrush Systemic AEs (less common)	Signs of AEs involving the oral mucosa or throat, including thrush Signs of systemic corticosteroid effects (e.g., adrenal suppression)	CYP3A4 substrate Strong CYP3A4 inhibitors are expected to have less effect on ciclesonide exposure than on budesonide exposure.	No comments
Key: AE = adverse event; ALC = absolute lymphocyte count; ALT = alanine transaminase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BMP = basic metabolic panel; BP = blood pressure; CBC = complete blood count; CPK = creatine phosphokinase; CrCl = creatinine clearance; CRP = C-reactive protein; CYP = cytochrome P450; DEX = dexamethasone; DILI = drug-induced liver injury; DVT = deep vein thrombosis; ECMO = extracorporeal membrane oxygenation; eGFR = estimated glomerular filtration rate; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; GI = gastrointestinal; HBV = hepatitis B virus; Hgb = hemoglobin; HSR = hypersensitivity reaction; HSV = herpes simplex virus; HTN = hypertension; IL = interleukin; IV = intravenous; JIA = juvenile idiopathic arthritis; MDI = metered dose inhaler; MI = myocardial infarction; MV = mechanical ventilation; NaCl = sodium chloride; NIV = noninvasive ventilation; NMBA = neuromuscular blocking agent; OAT = organic anion transporter; the Panel = the COVID-19 Treatment Guidelines Panel; PE = pulmonary embolism; PLT = platelet count; PO = oral; SUBQ = subcutaneous; TB = tuberculosis; TNF = tumor necrosis factor

References

Randomised Evaluation of COVID-19 Therapy (RECOVERY). Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19. 2020. Available at: https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19. Accessed January 20, 2023.
Baricitinib (Olumiant) [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/207924s006lbl.pdf.
Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization (EUA) of baricitinib. 2022. Available at: https://www.fda.gov/media/143823/download.
Cao Y, Wei J, Zou L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol. 2020;146(1):137-146.e3. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32470486.
Guimarães PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with COVID-19 pneumonia. N Engl J Med. 2021;385(5):406-415. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34133856.
Sarilumab (Kevzara) [package insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761037s001lbl.pdf.
REMAP-CAP Investigators. Effectiveness of tocilizumab, sarilumab, and anakinra for critically ill patients with COVID-19: the REMAP-CAP COVID-19 immune modulation therapy domain randomized clinical trial. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.06.18.21259133v2.
Sivapalasingam S, Lederer DJ, Bhore R, et al. Efficacy and safety of sarilumab in hospitalized patients with COVID-19: a randomized clinical trial. Clin Infect Dis. 2022;75(1):e380-e388. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35219277.
REMAP-CAP Investigators. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med. 2021;384(16):1491-1502. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33631065.
Tocilizumab (Actemra) [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125276s138lbl.pdf.
Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization for Actemra (tocilizumab). 2021. Available at: https://www.fda.gov/media/150321/download.
Siltuximab (Sylvant) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125496s018lbl.pdf.
Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization for Kineret. 2022. Available at: https://www.fda.gov/media/163075/download.
Kyriazopoulou E, Poulakou G, Milionis H, et al. Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled Phase 3 trial. Nat Med. 2021;27(10):1752-1760. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34480127.
Canakinumab (Ilaris) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125319s100lbl.pdf.
Ramakrishnan S, Nicolau DV Jr, Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a Phase 2, open-label, randomised controlled trial. Lancet Respir Med. 2021;9(7):763-772. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33844996.
Yu LM, Bafadhel M, Dorward J, et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. 2021;398(10303):843-855. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34388395.
Clemency BM, Varughese R, Gonzalez-Rojas Y, et al. Efficacy of inhaled ciclesonide for outpatient treatment of adolescents and adults with symptomatic COVID-19: a randomized clinical trial. JAMA Intern Med. 2022;182(1):42-49. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34807241.