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 weeks7,8

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:

  • 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