Table 4b. Characteristics of Immunomodulators Under Evaluation for the Treatment of COVID-19

Last Updated: February 11, 2021

Table 4b. Characteristics of Immunomodulators Under Evaluation for the Treatment of COVID-19
Drug Name	Dosing Regimen There are no approved doses for the treatment of COVID-19. The doses listed here are for approved indications or from reported experiences or clinical trials.	Adverse Effects	Monitoring Parameters	Drug-Drug Interaction Potential	Panel Recommendations, Comments, and Links to Clinical Trials
Corticosteroids
Dexamethasone	Dose for COVID-19: Dexamethasone 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) Psychiatric disturbances Avascular necrosis Adrenal insufficiency Increased blood pressure Peripheral edema Myopathy (particularly if used with neuromuscular blocking agents) When used during outbreaks of other novel coronavirus infections (i.e., MERS and SARS), corticosteroid therapy was associated with delayed virus clearance.^2,3	Blood glucose Blood pressure Signs and symptoms of new infection When initiating dexamethasone, consider appropriate screening and treatment to reduce the risk of Strongyloides hyperinfection in patients at high-risk of strongyloidiasis (e.g., patients from tropical, subtropical, or warm temperate regions or who engage in agricultural activities) or fulminant reactivations of HBV.^4-6	Moderate CYP3A4 inducer CYP3A4 substrate Although coadministration of RDV and dexamethasone has not been formally studied, a clinically significant PK interaction is not predicted (Gilead, written communication, August 2020).	For the Panel’s recommendations on the use of corticosteroids, please see Therapeutic Management of Patients With COVID-19. If dexamethasone is not available, an alternative corticosteroid such as prednisone, methylprednisolone, or hydrocortisone can be used. The approximate total daily dose equivalencies for these glucocorticoids to dexamethasone 6 mg (PO or IV) are: prednisone 40 mg, methylprednisolone 32 mg, and hydrocortisone 160 mg. A list of clinical trials is available: Dexamethasone
Interferons
Interferon Alfa	PegIFN Alfa-2a Dose for MERS: PegIFN alfa-2a 180 mcg SQ once weekly for 2 weeks^7,8 IFN Alfa-2b Dose for COVID-19 in Clinical Trials: Nebulized IFN alfa-2b 5 million international units twice daily (no duration listed in the study methods)⁹	Flu-like symptoms (e.g., fever, fatigue, myalgia)¹⁰ Injection site reactions Liver function abnormalities Decreased blood counts Worsening depression Insomnia Irritability Nausea Vomiting Hypertension Induction of autoimmunity	CBC with differential Liver enzymes; avoid if Child-Pugh Score >6 Depression, psychiatric symptoms Reduce dose in patients with CrCl <30 mL/min.	Low potential for drug interactions Inhibition of CYP1A2	The Panel recommends against the use of IFNs for the treatment of patients with severe and critical COVID-19, except in a clinical trial (AIII). For COVID-19, IFN alfa has primarily been used as nebulization and usually as part of a combination regimen. Neither nebulized IFN alfa-2b nor IFN alfa-1b are FDA-approved for use in the United States. Use with caution with other hepatotoxic agents. Reduce dose if ALT >5 times ULN; discontinue if bilirubin level also increases. Reduce dose or discontinue if neutropenia or thrombocytopenia occur. A list of clinical trials is available: Interferon
Interferon Beta	IFN Beta-1a Dose for MERS: IFN beta-1a 44 mcg SQ 3 times weekly⁸ Dose for COVID-19: Dose and duration un-known IFN Beta-1b Dose for COVID-19: IFN beta-1b 8 million international units SQ every other day, up to 7 days total¹¹	Flu-like symptoms (e.g., fever, fatigue, myalgia)¹² Leukopenia, neutropenia, thrombocytopenia, lymphopenia Liver function abnormalities (ALT > AST) Injection site reactions Headache Hypertonia Pain Rash Worsening depression Induction of autoimmunity	Liver enzymes CBC with differential Worsening CHF Depression, suicidal ideation	Low potential for drug interactions	The Panel recommends against the use of IFNs for the treatment of patients with severe or critical COVID-19, except in a clinical trial (AIII). There are insufficient data to recommend either for or against the use of IFN beta for the treatment of early (i.e., <7 days from symptom onset) mild to moderate COVID-19. Use with caution with other hepatotoxic agents. Reduce dose if ALT >5 times ULN. A list of clinical trials is available: Interferon Availability: Several products are available in the United States; product doses differ. IFN Beta-1a Products: Avonex, Rebif IFN Beta-1b Products: Betaseron, Extavia
Interleukin-1 Inhibitor
Anakinra	Dose for Rheumatoid Arthritis: Anakinra 100 mg SQ once daily Dose for COVID-19: Dose and duration vary by study Has also been used as IV infusion	Neutropenia (particularly with concomitant use of other agents that can cause neutropenia) Anaphylaxis Headache Nausea Diarrhea Sinusitis Arthralgia Flu-like symptoms Abdominal pain Injection site reactions Liver enzyme elevations	CBC with differential Renal function (reduce dose in patients with CrCl <30 mL/min) Liver enzymes	Use with TNF-blocking agents is not recommended due to increased risk of infection.	There are insufficient data for the Panel to recommend either for or against the use of IL-1 inhibitors (e.g., anakinra) for the treatment of COVID-19. A list of clinical trials is available: Anakinra
Interleukin-6 Inhibitors
Anti-Interleukin-6 Receptor Monoclonal Antibodies
Sarilumab¹³	*Dose for COVID-19 in Clinical Trial (See ClinicalTrials.gov* Identifier NCT04315298):** Sarilumab 400 mg IV (single dose)¹⁴ REMAP-CAP evaluated sarilumab for IV administration, which is not the approved formulation in the United States.	Neutropenia, thrombocytopenia Gastrointestinal perforation HSR Increased liver enzymes HBV reactivation Infusion reaction possible	Monitor for HSR Monitor for infusion reactions Neutrophils Platelets Liver enzymes	Elevated IL-6 may downregulate CYP enzymes; use of sarilumab may lead to increased metabolism of drugs that are CYP450 substrates. Effects on CYP450 may persist for weeks after therapy.	For patients who are within 24 hours of admission to the ICU and who require invasive or noninvasive mechanical ventilation or high-flow oxygen (>0.4 FiO₂/30 L/min of oxygen flow), there are insufficient data to recommend either for or against the use of sarilumab for the treatment of COVID-19. For patients who do not require ICU-level care or who are admitted to the ICU but do not meet the above criteria, the Panel recommends against the use of sarilumab for the treatment of COVID-19, except in a clinical trial (BIIa). Treatment with sarilumab may mask signs of acute inflammation or infection (i.e., by suppressing fever and CRP levels). A list of clinical trials is available: Sarilumab
Tocilizumab¹⁵	Dose for COVID-19 in Clinical Trial: Tocilizumab 8 mg/kg IV once Dose should not exceed tocilizumab 800 mg. If tocilizumab is used, administer with a course of dexamethasone therapy.	Infusion-related reactions HSR Gastrointestinal perforation Hepatotoxicity Treatment-related changes in neutrophils, platelets, lipids, and liver enzymes HBV reactivation	Monitor for HSR Monitor for infusion reactions Neutrophils Platelets Liver enzymes	Elevated IL-6 may downregulate CYP enzymes; use of tocilizumab may lead to in-creased metabo-lism of drugs that are CYP450 substrates. Effects on CYP450 may persist for weeks after therapy.	For patients who are within 24 hours of admission to the ICU and who require invasive or noninvasive mechanical ventilation or high-flow oxygen (>0.4 FiO₂/30 L/min of oxygen flow), there are insufficient data to recommend either for or against the use of tocilizumab for the treatment of COVID-19. Some Panel members would administer a single dose of tocilizumab (8 mg/kg actual body weight up to 800 mg) in addition to dexamethasone to patients who meet the above criteria and who are also exhibiting rapid progression of respiratory failure. For patients who do not require ICU-level care or who are admitted to the ICU but do not meet the above criteria, the Panel recommends against the use of tocilizumab for the treatment of COVID-19, except in a clinical trial (BIIa). May mask signs of acute inflammation or infection (i.e., by suppressing fever and CRP levels). The SQ formulation of tocilizumab is not intended for IV administration. A list of clinical trials is available: Tocilizumab
Anti-Interleukin-6 Monoclonal Antibody
Siltuximab	Dose for Multicentric Castleman Disease: Siltuximab 11 mg/kg administered over 1 hour by IV infusion every 3 weeks¹⁶ Dose for COVID-19: Dose and duration unknown	Infusion-related reaction HSR Gastrointestinal perforation Neutropenia Hypertension Dizziness Rash Pruritus Hyperuricemia	Monitor for HSR Monitor for infusion reactions Neutrophils	Elevated IL-6 may downregulate CYP enzymes; use of siltuximab may lead to increased metabolism of drugs that are CYP450 substrates. Effects on CYP450 may persist for weeks after therapy.	The Panel recommends against the use of siltuximab for the treatment of COVID-19, except in a clinical trial (AIIa). May mask signs of acute inflammation or infection (i.e., by suppressing fever and CRP levels). A list of clinical trials is available: Siltuximab
Kinase Inhibitors
Bruton’s Tyrosine Kinase Inhibitors
Acalabrutinib	Dose for FDA-Approved Indications: Acalabrutinib 100 mg PO every 12 hours Dose for COVID-19: Dose and duration unknown	Hemorrhage Cytopenias (neutropenia, anemia, thrombocytopenia, lymphopenia) Atrial fibrillation and flutter Infection Headache Diarrhea Fatigue Myalgia	CBC with differential Signs and symptoms of bleeding (particularly when coadministered with anticoagulant or antiplatelet therapy) Monitor for cardiac arrhythmias Monitor for new infections	Avoid concomitant use with strong CYP3A inhibitors or inducers. Dose reduction may be necessary with moderate CYP3A4 inhibitors. Avoid concomitant PPI use. H2-receptor antagonist should be administered 2 hours after acalabrutinib.	The Panel recommends against the use of BTK inhibitors for the treatment of COVID-19, except in a clinical trial (AIII). Avoid use in patients with severe hepatic impairment. Patients with underlying cardiac risk factors, hypertension, or acute infections may be predisposed to atrial fibrillation. A list of clinical trials is available: Acalabrutinib
Ibrutinib	Dose for FDA-Approved Indications: Ibrutinib 420 mg or 560 mg PO once daily Dose for COVID-19: Dose and duration unknown	Hemorrhage Cardiac arrhythmias Serious infections Cytopenias (thrombocytopenia, neutropenia, anemia) Hypertension Diarrhea Musculoskeletal pain Rash	CBC with differential Blood pressure Signs and symptoms of bleeding (particularly when coadministered with anticoagulant or antiplatelet therapy) Monitor for cardiac arrhythmias Monitor for new infections	Avoid concomitant use with strong CYP3A inhibitors or inducers. Dose reduction may be necessary with moderate CYP3A4 inhibitors.	The Panel recommends against the use of BTK inhibitors for the treatment of COVID-19, except in a clinical trial (AIII). Avoid use in patients with severe baseline hepatic impairment. Dose modifications required in patients with mild or moderate hepatic impairment. Patients with underlying cardiac risk factors, hypertension, or acute infections may be predisposed to cardiac arrhythmias. A list of clinical trials is available: Ibrutinib
Zanubrutinib	Dose for FDA-Approved Indications: Zanubrutinib 160 mg PO twice daily or 320 mg PO once daily Dose for COVID-19: Dose and duration unknown	Hemorrhage Cytopenias (neutropenia, thrombocytopenia, anemia, leukopenia) Atrial fibrillation and flutter Infection Rash Bruising Diarrhea Cough Musculoskeletal pain	CBC with differential Signs and symptoms of bleeding Monitor for cardiac arrhythmias Monitor for new infections	Avoid concomitant use with moderate or strong CYP3A inducers. Dose reduction required with moderate and strong CYP3A4 inhibitors.	The Panel recommends against the use of BTK inhibitors for the treatment of COVID-19, except in a clinical trial (AIII). Dose reduction required in patients with severe hepatic impairment. A list of clinical trials is available: Zanubrutinib
Janus Kinase Inhibitors
Baricitinib¹⁷	Dose for Rheumatoid Arthritis: Adults: Baricitinib 2 mg PO once daily Dose for COVID-19:¹⁸ Adults: Baricitinib 4 mg PO once daily for 14 days or until hospital discharge Children: Limited data are available. Dose per the FDA EUA: Aged ≥9 years: Baricitinib 4 mg PO once daily for 14 days or until hospital discharge Aged ≥2 years to <9 years: Baricitinib 2 mg PO once daily for 14 days or until hospital discharge See full prescribing information for dosage recommendations in patients with renal impairment or hepatic impairment.¹⁷	Lymphoma and other malignancies Thrombosis Gastrointestinal perforation Treatment-related changes in lymphocytes, neutrophils, Hgb, liver enzymes HSV Herpes zoster	CBC with differential Renal function Liver enzymes Monitor for new infections	Dose modification is recommended when concurrently administering with a strong OAT3 inhibitor. Avoid administration of live vaccines.	There are insufficient data for the Panel to recommend either for or against the use of baricitinib in combination with RDV for the treatment of COVID-19 in hospitalized patients, when corticosteroids can be used. In the rare circumstance when corticosteroids cannot be used, the Panel recommends baricitinib in combination with RDV for the treatment of COVID-19 in hospitalized nonintubated patients who require oxygen supplementation (BIIa). The Panel recommends against the use of baricitinib without RDV, except in a clinical trial (AIII). There are insufficient data for the Panel to recommend either for or against the use of baricitinib in combination with corticosteroids for the treatment of COVID-19. Because both agents are potent immunosuppressants, there is a potential for an additive risk of infection. Baricitinib is not recommended for patients with severe hepatic or renal impairment. Baricitinib is available through the FDA EUA for the treatment of COVID-19 in combination with RDV for hospitalized adults and pediatric patients aged ≥2 years who require supple-mental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation.¹⁸ A list of clinical trials is available: Baricitinib
Ruxolitinib	Dose for FDA-Approved Indications: Ruxolitinib 5 mg–20 mg PO twice daily Dose for COVID-19 in Clinical Trials: Ruxolitinib 5 mg–20 mg PO twice daily, for 14 days	Thrombocytopenia Anemia Neutropenia Liver enzyme elevations Risk of infection Dizziness Headache Diarrhea CPK elevation Herpes zoster	CBC with differential Liver enzymes Monitor for new infections	Dose modifications required when administered with strong CYP3A4 inhibitors. Avoid use with doses of fluconazole >200 mg.	The Panel recommends against the use of JAK inhibitors (other than baricitinib) for the treatment of COVID-19, except in a clinical trial (AIII). Dose modification may be required in patients with moderate or severe renal impairment, hepatic impairment, or thrombocytopenia. A list of clinical trials is available: Ruxolitinib
Tofacitinib	Dose for FDA-Approved Indications: Tofacitinib 5 mg PO twice daily for rheumatoid and psoriatic arthritis Tofacitinib 10 mg PO twice daily for ulcerative colitis Dose for COVID-19: Dose and duration unknown; a planned COVID-19 clinical trial will evaluate tofacitinib 10 mg twice daily for 14 days.	Thrombotic events (pulmonary embolism, DVT, arterial thrombosis) Anemia Risk of infection Gastrointestinal perforation Diarrhea Headache Herpes zoster Lipid elevations Liver enzyme elevations Lymphoma and other malignancies	CBC with differential Liver enzymes Monitor for new infections	Dose modifications required when administered with strong CYP3A4 inhibitors or when used with a moderate CYP3A4 inhibitor coadministered with a strong CYP2C19 inhibitor. Avoid administration of live vaccines.	The Panel recommends against the use of JAK inhibitors (other than baricitinib) for the treatment of COVID-19, except in a clinical trial (AIII). Avoid use in patients with ALC <500 cells/mm³, ANC <1,000 cells/mm³, or Hgb <9 grams/dL. Dose modification may be required in patients with moderate or severe renal impairment or moderate hepatic impairment. A list of clinical trials is available: Tofacitinib
Non-SARS-CoV-2 Specific Immunoglobulin
Non-SARS-CoV-2 Specific Immunoglobulin	Dose varies based on indication and formulation.	Allergic reactions including anaphylaxis Renal failure Thrombotic events Aseptic meningitis syndrome Hemolysis TRALI Transmission of infectious pathogens AEs may vary by formulation. AEs may be increased with high-dose, rapid infusion, or in patients with underlying conditions.	Monitor for transfusion-related reactions Monitor vital signs at baseline and during and after infusion Discontinue if renal function deteriorates during treatment.	IVIG may interfere with immune response to certain vaccines.	The Panel recommends against the use of non-SARS-CoV-2 specific IVIG for the treatment of COVID-19, except in a clinical trial (AIII). This recommendation should not preclude the use of IVIG when otherwise indicated for the treatment of complications that arise during the course of COVID-19. A list of clinical trials is available: Intravenous Immunoglobulin
Key: AE = adverse effect or adverse event; ALC = absolute lymphocyte count; ALT = alanine transaminase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BTK = Bruton’s tyrosine kinase; CBC = complete blood count; CHF = congestive heart failure; CrCl = creatinine clearance; CPK = creatine phosphokinase; CRP = C-reactive protein; CYP = cytochrome P; DVT = deep vein thrombosis; EIND = Emergency Investigational New Drug; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; FiO₂ = fraction of inspired oxygen; HBV = hepatitis B; Hgb = hemoglobin; HSR = hypersensitivity reaction; HSV = herpes simplex virus; IFN = interferon; IL-1 = interleukin-1; IL-6 = interleukin-6; IV = intravenous; IVIG = intravenous immunoglobulin; JAK = Janus kinase; MERS = Middle East respiratory syndrome; OAT = organic anion transporter; PEG-IFN = pegylated interferon; PK = pharmacokinetic; PO = orally; PPI = proton pump inhibitor; REMAP-CAP = A Randomised, Embedded, Multi-Factorial, Adaptive Platform Trial for Community-Acquired Pneumonia; RDV = remdesivir; SARS = severe acute respiratory syndrome; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SQ = subcutaneous; TACO = transfusion-associated circulatory overload; TB = tuberculosis; the Panel = the COVID-19 Treatment Guidelines Panel; TNF = tumor necrosis factor; TRALI = transfusion-related acute lung injury; ULN = upper limit of normal