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Table 5e. Characteristics of Immunomodulators

Last Updated: February 29, 2024

Table 5e. Characteristics of Immunomodulators
Drug NameDosing 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 Adults With 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)
  • 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.
  • For these drugs, the total daily dose equivalencies to DEX 6 mg (IV or PO) are: 
  • Prednisone 40 mg
  • Methylprednisolone 32 mg
  • Hydrocortisone 160 mg
Janus Kinase Inhibitors
Recommended by the Panel for the treatment of COVID-19 in certain hospitalized patients.
Baricitinib

FDA-Approved Doses for COVID-19 in Adults Aged ≥18 Years, per eGFR2

≥60 mL/min/1.73 m2
  • BAR 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first
30 to <60 mL/min/1.73 m2
  • BAR 2 mg PO once daily for 14 days or until hospital discharge, whichever comes first
15 to <30 mL/min/1.73 m2
  • BAR 1 mg PO once daily for 14 days or until hospital discharge, whichever comes first
<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 Years, per eGFR3
≥60 mL/min/1.73 m2
  • BAR 2 mg PO once daily for 14 days or until hospital discharge, whichever comes first
30 to <60 mL/min/1.73 m2
  • BAR 1 mg PO once daily for 14 days or until hospital discharge, whichever comes first
<30 mL/min/1.73 m2
  • Not recommended
    • Lymphoma and other malignancies
    • Thrombotic events (e.g., PE, DVT, arterial 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
    • Signs and symptoms of new infections
    • Dose modification 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 BAR treatment until the diagnosis of DILI is excluded.
    • BAR tablets can be taken PO or crushed, dispersed in water, and given via gastrostomy tube.2
    Availability
    • BAR is approved by the FDA for the treatment of COVID-19 in adults aged ≥18 years.2
    • BAR is available through an FDA EUA for children aged 2–17 years who require supplemental oxygen, NIV, MV, or ECMO.3
    Tofacitinib

    Dose for COVID-19 in Clinical Trials

    • Tofacitinib 10 mg PO twice daily for up to 14 days or until hospital discharge, whichever comes first4
    • Thrombotic events (e.g., PE, DVT, arterial thrombosis)
    • Anemia
    • Secondary infections
    • 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
    • Signs and symptoms of 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.
    Sarilumab

    Dose for COVID-19 in Clinical Trials

    • 1 dose of sarilumab 400 mg by IV infusion over 1 hour5,6
    • Neutropenia
    • Thrombocytopenia 
    • GI perforation
    • HSRs
    • Increased liver enzymes 
    • HBV reactivation
    • Infusion-related reactions
    • HSRs
    • Infusion-related reactions
    • CBC with differential
    • Liver enzymes
    • Elevated IL-6 may downregulate CYP enzymes; thus, use of sarilumab may lead to increased metabolism of coadministered 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/µL, or PLT <150,000 cells/µL.7
    Availability
    • 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.6,8
    • IV infusion of sarilumab should occur within 4 hours of its preparation; it can be stored at room temperature until administered. 
    Tocilizumab

    FDA-Approved Dose for COVID-19 in Hospitalized Adults 

    • 1 dose of tocilizumab 8 mg/kg actual body weight (up to 800 mg) by IV infusion over 1 hour 
    FDA EUA Doses 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.
    • HSRs
    • Infusion-related reactions
    • 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. 
    • HSRs
    • Infusion-related reactions
    • CBC with differential
    • 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/µL, or PLT <50,000 cells/µL.9
    • 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.9

     

    Cytotoxic T-Lymphocyte-Associated Antigen 4 Agonist
    Recommended by the Panel for the treatment of COVID-19 in certain hospitalized patients.
    Abatacept

    Dose for COVID-19 in Clinical Trials
    • 1 dose of abatacept 10 mg/kg actual body weight (up to 1,000 mg) by IV infusion over 30 minutes11
    • HSRs, including anaphylaxis
    • HBV reactivation
    • Secondary infections
    • Patients with COPD may develop more frequent respiratory AEs.
    • Headache
    • Upper respiratory infection, nasopharyngitis
    • Nausea
    • Anemia
    • HTN
    • Decrease in CD4 count 
    • Hypermagnesemia
    • Acute kidney injury12
    • HSRs
    • Infusion-related reactions
    • CBC with differential
    • Electrolytes
    • Renal function
    • Drug-drug interactions are unlikely between abatacept and medications that are CYP substrates, inhibitors, or inducers.
    • IV formulation of abatacept includes maltose, which may give falsely elevated blood glucose readings with certain blood glucose monitors (e.g., GDH-PQQ-based monitoring systems) on the day of infusion.
    • In ACTIV-1, 1 case of anaphylaxis and 2 infusion-related reactions were reported among abatacept recipients.11 
    Availability
    • The IV formulation of abatacept is commercially available.

     

    Tumor Necrosis Factor–Alpha Inhibitor
    Recommended by the Panel for the treatment of COVID-19 in certain hospitalized patients.
    Infliximab

    Dose for COVID-19 in Clinical Trials
    • 1 dose of infliximab 5 mg/kg actual body weight by IV infusion over 2 hours11
    • HSRs, including anaphylaxis
    • Infusion-related reactions
    • The following AEs are associated with chronic use of infliximab:
      • Hepatotoxicity
      • Cytopenia (e.g., leukopenia, neutropenia, thrombocytopenia, pancytopenia)
      • HBV reactivation
      • Secondary infections (e.g., invasive fungal infections, reactivation of latent TB)
      • Heart failure
      • CVA, MI, hypotension, hypertension, arrhythmias
      • Transient vision loss
      • Demyelinating disease
      • Lupus-like syndrome
      • Headache
      • Abdominal pain13
    • HSRs
    • Infusion-related reactions
    • CBC with differential
    • PLT 
    • Liver enzymes 
    • If infliximab is administered to patients with heart failure, they should be closely monitored.
    • Inhibition of cytokine activity may lead to increased metabolism of coadministered drugs that are CYP450 substrates.

    Availability

    • Infliximab is available as an originator biologic or a biosimilar.

     

    Anti-C5a Monoclonal Antibody
    Received an FDA EUA for the treatment of COVID-19 when it is administered within 48 hours of MV or ECMO. There is insufficient evidence for the Panel to recommend either for or against its use.
    Vilobelimab

    FDA EUA Dose for COVID-19 in Hospitalized Adults Receiving MV or ECMO

    • Vilobelimab 800 mg by IV infusion after dilution, for a maximum of 6 doses; start treatment within 48 hours of intubation (Day 1) followed by administration on Days 2, 4, 8, 15, and 22 if patient is still hospitalized (even if discharged from ICU)
    • Secondary infections
    • Infusion-related reactions
    • Delirium
    • PE
    • HTN
    • Pneumothorax
    • DVT
    • Liver enzyme elevations 
    • Hypoxemia
    • Thrombocytopenia
    • Pneumomediastinum
    • Supraventricular tachycardia
    • Constipation
    • Rash
    • Signs and symptoms of new infections
    • Infusion-related reactions
    • CBC with differential
    • Liver enzymes
    • None expected

    Availability

    • Vilobelimab is not approved by the FDA, but it is commercially available for use in hospitalized adults with COVID-19, as authorized by the EUA.14
     
    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:
    The Panel recommends against the use of canakinumab for the treatment of COVID-19, except in a clinical trial.
    Anakinra

    FDA EUA Dose for COVID-19 in Hospitalized Patients Aged ≥18 Years

    • Anakinra 100 mg SUBQ once daily for 10 days
    Dose for Patients With CrCl <30 mL/min
    • Anakinra 100 mg SUBQ every other day for 5 total doses over 10 days15
    • Neutropenia (particularly when used concomitantly with other agents that can cause neutropenia)
    • HSRs, 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 potential increased risk of infection.
    • Contraindicated in patients with known hypersensitivity to proteins derived from Escherichia coli, anakinra, or any component of the product15 
    Canakinumab
    Dose for COVID-19 in Clinical Trials
    • Canakinumab 450–750 mg (based on body weight) by IV infusion over 2 hours16,17

    FDA-Approved Dose for Systemic JIA

    • Canakinumab 4 mg/kg (maximum 300 mg) SUBQ every 4 weeks18
    • HSRs
    • Neutropenia
    • Nasopharyngitis
    • Diarrhea
    • Respiratory tract infections
    • Bronchitis 
    • Gastroenteritis
    • Pharyngitis
    • Musculoskeletal pain
    • Vertigo
    • Abdominal pain
    • Injection site reactions
    • Liver enzyme elevations
    • HSRs
    • 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.
    Availability
    • The IV formulation of canakinumab is not approved by the FDA for use in the United States.18 
    Corticosteroids (Inhaled)
    There is insufficient evidence for the Panel to recommend either for or against the use of inhaled corticosteroids for the treatment of COVID-19.
    Budesonide (Inhaled)Dose for COVID-19 in Clinical Trials
    • Budesonide 800 µg oral inhalation twice daily until symptom resolution or for up to 14 days19,20
    • Secondary infections
    • Oral thrush
    • Systemic AEs are not common, but they may occur when budesonide is coadministered with a strong CYP3A4 inhibitor.
    • 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 µg as 2 MDI inhalations twice daily for 30 days21
    • 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 or fluticasone exposure.
    • No comments
    Fluticasone (Inhaled)
    Dose for COVID-19 in Clinical Trials
    • Fluticasone 200 µg as 1 MDI inhalation once daily for 14 days22
    • Secondary infections
    • Oral thrush
    • Systemic AEs are not common, but they may occur when fluticasone is coadministered with a strong CYP3A4 inhibitor.
    • 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

    References

    1. 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 23, 2024.
    2. Baricitinib (Olumiant) [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/207924s006lbl.pdf.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. Sarilumab (Kevzara) [package insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761037s001lbl.pdf.
    8. 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.
    9. 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.
    10. Tocilizumab (Actemra) [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125276s138lbl.pdf.
    11. O’Halloran JA, Ko ER, Anstrom KJ, et al. Abatacept, cenicriviroc, or infliximab for treatment of adults hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA. 2023;330(4):328-339. Available at: https://pubmed.ncbi.nlm.nih.gov/37428480.
    12. Abatacept (Orencia) [package insert]. Food and Drug Administration. 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125118s240lbl.pdf.
    13. Infliximab (Remicade) [package insert]. Food and Drug Administration. 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/103772s5401lbl.pdf.
    14. Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization for Gohibic. 2023. Available at: https://www.fda.gov/media/166824/download.
    15. Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization for Kineret. 2022. Available at: https://www.fda.gov/media/163075/download.
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    17. Hepprich M, Mudry JM, Gregoriano C, et al. Canakinumab in patients with COVID-19 and type 2 diabetes - a multicentre, randomised, double-blind, placebo-controlled trial. EClinicalMedicine. 2022;53:101649. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36128334.
    18. Canakinumab (Ilaris) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125319s100lbl.pdf.
    19. 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.
    20. 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.
    21. 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.
    22. Boulware DR, Lindsell CJ, Stewart TG, et al. Inhaled fluticasone furoate for outpatient treatment of COVID-19. N Engl J Med. 2023;389(12):1085-1095. Available at: https://www.ncbi.nlm.nih.gov/pubmed/37733308.