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Table 4f. Characteristics of Immunomodulators

Last Updated: December 16, 2021

  • The information in this table is derived from data on the use of these drugs for FDA-approved indications or in investigational trials, and it is supplemented with data on their use in patients with COVID-19, when available.
  • For dose modifications for patients with organ failure or those who require extracorporeal devices, please refer to product labels, 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 4f. Characteristics of Immunomodulators
Drug NameDosing Regimen
The doses listed are for approved indications or from clinical trials or clinical experience in patients with COVID-19.
Adverse Events Monitoring Parameters Drug-Drug Interaction Potential Comments and Links to Clinical Trials
Colchicine
Not approved by the FDA and not recommended by the Panel for the treatment of COVID-19. Currently under investigation in clinical trials.
ColchicineDose for COVID-19 in COLCORONA Trial:
  • Colchicine 0.5 mg twice daily for 3 days and then once daily for 27 days1
  • Diarrhea
  • Nausea
  • Vomiting
  • Cramping
  • Abdominal pain
  • Bloating
  • Loss of appetite
  • Neuromyotoxicity (rare)2
  • Blood dyscrasias (rare)
  • CBC
  • Renal function
  • Hepatic function
  • P-gp and CYP3A4 substrate
  • The risk of myopathy may be increased with the concomitant use of certain HMG-CoA reductase inhibitors (e.g., atorvastatin, lovastatin, simvastatin) due to potential competitive interactions mediated by P-gp and CYP3A4 pathways.
  • Fatal colchicine toxicity has been reported in individuals with renal or hepatic impairment who used colchicine in conjunction with P-gp inhibitors or strong CYP3A4 inhibitors.
  • Use of colchicine should be avoided in patients with severe renal insufficiency, and those with moderate renal insufficiency who receive the drug should be monitored for AEs.
  • A list of clinical trials is available: Colchicine
Availability:
  • In the COLCORONA trial, 0.5 mg colchicine tablets were used for dosing; in the United States, colchicine is available as 0.6 mg tablets.
Corticosteroids (Inhaled)
Not approved by the FDA and 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 for up to 14 days3,4
  • 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.
Ciclesonide (Inhaled)Dose for COVID-19 in Clinical Trials:
  • Ciclesonide 160 mcg: 2 MDI inhalations twice daily for 30 days5
  • 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
  • Effect of strong CYP3A4 inhibitors on ciclesonide exposure is not expected to be as significant as that on budesonide.
Corticosteroids (Systemic)
Recommended by the Panel for the treatment of COVID-19 in certain nonhospitalized and hospitalized patients.
Dexamethasone (Systemic)Dose for COVID-19:
  • DEX 6 mg IV or PO once daily for up to 10 days or until hospital discharge, whichever comes first6
  • 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 neuromuscular blocking agents)
  • Blood glucose
  • BP
  • Signs and symptoms of new infection
  • Cases of disseminated strongyloidiasis have been reported in patients with COVID-19 during treatment with corticosteroids and tocilizumab. Prophylactic treatment for strongyloidiasis (e.g., with IVM) should be considered for persons from areas where Strongyloides is endemic.7
  • Moderate CYP3A4 inducer
  • CYP3A4 substrate
  • Although coadministration of RDV and DEX has not been formally studied, a clinically significant PK interaction is not predicted (Gilead, written communication, August 2020).
  • 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
  • A list of clinical trials is available: Dexamethasone
Fluvoxamine
Not approved by the FDA and not recommended by the Panel for the treatment of COVID-19. Currently under investigation in clinical trials.
Fluvoxamine

Dose for COVID-19 in Clinical Trials:

  • Various dosing regimens used, including:
    • Fluvoxamine 50 mg twice daily
    • Fluvoxamine 100 mg twice daily
    • Fluvoxamine 100 mg 3 times daily
  • Nausea
  • Diarrhea
  • Dyspepsia
  • Asthenia
  • Insomnia
  • Somnolence
  • Sweating
  • Suicidal ideation (rare)
  • Hepatic function
  • Drug interactions
  • Monitor for withdrawal symptoms when tapering dose
  • CYP2D6 substrate
  • Fluvoxamine inhibits several CYP isoenzymes (CYP1A2, CYP2C9, CYP3A4, CYP2C19, CYP2D6)
  • Coadministration of tizanidine, thioridazine, alosetron, or pimozide with fluvoxamine is contraindicated.
  • Fluvoxamine may enhance anticoagulant effects of antiplatelets and anticoagulants; consider additional monitoring when these drugs are used concomitantly with fluvoxamine.
  • The use of MAOIs concomitantly with fluvoxamine or within 14 days of treatment with fluvoxamine is contraindicated.
  • A list of clinical trials is available: Fluvoxamine
Interleukin-1 Inhibitors
Not approved by the FDA and not recommended by the Panel for the treatment of COVID-19. Currently under investigation in clinical trials.
Anakinra

FDA-Approved Dose for Rheumatoid Arthritis:

  • Anakinra 100 mg SQ once daily

Dose for COVID-19 in Clinical Trials:

  • Dose and duration vary by study.
  • Has also been used as IV infusion.
  • Neutropenia (particularly when used concomitantly with other agents that can cause neutropenia)
  • Anaphylaxis and angioedema
  • Headache
  • Nausea
  • Diarrhea
  • Sinusitis
  • Arthralgia
  • Flu-like symptoms
  • Abdominal pain
  • Injection site reactions
  • Liver enzyme elevations
  • CBC with differential
  • Liver enzymes
  • Renal function; reduce dose if CrCl <30 mL/min.
  • Use with TNF-blocking agents is not recommended due to increased risk of infection.
  • Avoid concomitant administration of live vaccines.
  • Anakinra for IV administration is not an approved formulation in the United States.8
  • A list of clinical trials is available: Anakinra
Canakinumab

FDA-Approved Dose for Systemic Juvenile Idiopathic Arthritis:

  • Canakinumab 4 mg/kg (maximum 300 mg) SQ every 4 weeks9

Dose for COVID-19 in Clinical Trials:

  • Dose and duration vary by study.
CAN-COVID Trial:
  • Single weight-based dose of canakinumab in 250 mL of 5% dextrose by IV infusion over 2 hours:10
    • 40 to <60 kg: 450 mg
    • 60–80 kg: 600 mg
    • >80 kg: 750 mg
  • 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.
  • Avoid concomitant administration of live vaccines.
  • Canakinumab for IV administration is not an approved formulation in the United States.9
  • A list of clinical trials is available: Canakinumab
Interleukin-6 Inhibitors
Anti-Interleukin-6 Receptor Monoclonal Antibodies
Recommended by the Panel for the treatment of COVID-19 in certain nonhospitalized and hospitalized patients.
Sarilumab11

Dose for COVID-19 in Clinical Trials:

  • Single dose of sarilumab 400 mg IV12
  • The IV formulation of sarilumab is not approved by the FDA, but in a clinical trial, a single SQ dose (using the prefilled syringe, not the prefilled pen) of sarilumab 400 mg was reconstituted in 100 cc 0.9% NaCl and given as an IV infusion over a 1-hour period.
  • Sarilumab infusion should be used within 4 hours of preparation; it can be stored at room temperature until administered.
  • Neutropenia, thrombocytopenia
  • GI perforation
  • HSR
  • Increased liver enzymes
  • HBV reactivation
  • Infusion-related reaction
  • HSR
  • Infusion reactions
  • Neutrophils
  • Platelets
  • 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.
  • Treatment with sarilumab may mask signs of acute inflammation or infection by suppressing fever and CRP levels.
  • A list of clinical trials is available: Sarilumab

Availability:

  • Sarilumab for IV administration is not an approved formulation in the United States.
Tocilizumab13

EUA Dose for COVID-19

For Hospitalized Patients Aged ≥2 Years Based on Body Weight:
  • <30 kg: Tocilizumab 12 mg/kg administered by IV infusion over 1 hour
  • ≥30 kg: Tocilizumab 8 mg/kg (maximum dose 800 mg) administered by IV infusion over 1 hour
  • Per the EUA, if clinical signs or symptoms worsen or do not improve following the first infusion, 1 additional dose of tocilizumab 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, platelets, lipids, and liver enzymes
  • HBV reactivation
  • Secondary infections
  • HSR
  • Infusion reactions
  • Neutrophils
  • Platelets
  • Liver enzymes
  • Cases of disseminated strongyloidiasis have been reported in patients with COVID-19 during treatment with tocilizumab and corticosteroids. Prophylactic treatment for strongyloidiasis (e.g., with IVM) should be considered for persons from areas where Strongyloides is endemic.7
  • Elevated IL-6 may downregulate CYP enzymes; use of tocilizumab may lead to increased metabolism of drugs that are CYP substrates.
  • The effects of tocilizumab on CYP enzymes may persist for weeks after the drug is stopped.
  • Tocilizumab use should be avoided in patients who are significantly immunocompromised. The safety of using tocilizumab plus a corticosteroid in immunocompromised patients is unknown.
  • The SQ formulation of tocilizumab is not intended for IV administration.
  • A list of clinical trials is available: Tocilizumab
Availability:
  • IV tocilizumab, which has been approved for non-COVID-19 indications, is available commercially and through an FDA EUA for the treatment of COVID-19 in hospitalized adults and pediatric patients aged ≥2 years who are receiving systemic corticosteroids and require supplemental oxygen, NIV, MV, or ECMO. The EUA does not authorize the use of tocilizumab for SQ administration for the treatment of COVID-19.14
Anti-Interleukin-6 Monoclonal Antibody
Not approved by the FDA and 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 administered over 1 hour by IV infusion every 3 weeks15

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.
  • Treatment with siltuximab may mask signs of acute inflammation or infection by suppressing fever and CRP levels.
  • A list of clinical trials is available: Siltuximab
Kinase Inhibitors
Janus Kinase Inhibitors
Baricitinib and Tofacitinib: Recommended by the Panel for the treatment of COVID-19 in certain nonhospitalized and hospitalized patients.
Ruxolitinib: Not approved by the FDA and not recommended by the Panel for the treatment of COVID-19. Currently under investigation in clinical trials.
Baricitinib16

EUA Dose for COVID-1917
For Adults and Children Aged ≥9 Years Based on eGFR:

  • ≥60 mL/min/1.73 m2: Baricitinib 4 mg PO once daily
  • 30 to <60 mL/min/1.73 m2: Baricitinib 2 mg PO once daily
  • 15 to <30 mL/min/1.73 m2: Baricitinib 1 mg PO once daily
  • eGFR <15 mL/min/1.73 m2: Not recommended

For Children Aged 2 to <9 Years Based on eGFR:

  • ≥60 mL/min/1.73m2: Baricitinib 2 mg PO once daily
  • 30 to <60 mL/min/1.73m2: Baricitinib 1 mg PO once daily
  • <30 mL/min/1.73m2: Not recommended

Duration of Therapy:

  • For 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
  • 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.
  • Avoid concomitant administration of live vaccines.
  • Baricitinib for the treatment of COVID-19 is available through an FDA EUA. See the EUA 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.
  • A list of clinical trials is available: Baricitinib

Availability:

  • Baricitinib, which has been approved for non-COVID-19 indications, is available commercially and through an EUA for the treatment of hospitalized patients with COVID-19 aged ≥2 years.17
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 days18
  • Thrombocytopenia
  • Anemia
  • Neutropenia
  • Liver enzyme elevations
  • Risk of infection
  • Dizziness
  • Headache
  • Diarrhea
  • CPK elevation
  • Herpes zoster
  • CBC with differential
  • Liver enzymes
  • New infections
  • Dose modification required when administered with strong CYP3A4 inhibitor.
  • Avoid use with fluconazole doses >200 mg.
  • Dose modification may be required in patients with hepatic impairment, moderate or severe renal impairment, or thrombocytopenia.
  • A list of clinical trials is available: Ruxolitinib
Tofacitinib

Dose for COVID-19 in Clinical Trial:

  • Tofacitinib 10 mg PO twice daily for up to 14 days or until hospital discharge19
  • 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
  • Dose modifications required 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 concomitant administration of live vaccines.
  • 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
Primarily used for the treatment of multi-system inflammatory syndrome in children (MIS-C). Currently under investigation in clinical trials.
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.
  • Transfusion-related reactions
  • Vital signs at baseline and during and after infusion
  • Renal function; discontinue treatment if function deteriorates.
  • IVIG may interfere with immune response to certain vaccines.

References

  1. Tardif JC, Bouabdallaoui N, L'Allier PL, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a Phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med. 2021;9(8):924-932. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34051877.
  2. Colchicine (Colcrys) [package insert]. Food and Drug Administration. 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf.
  3. 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.
  4. 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 Sep 4;398(10303):843-855. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34388395.
  5. 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. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34807241.
  6. 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 February 9, 2021.
  7. Stauffer WM, Alpern JD, Walker PF. COVID-19 and dexamethasone: a potential strategy to avoid steroid-related strongyloides hyperinfection. JAMA. 2020;324(7):623-624. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32761166.
  8. Anakinra (Kineret) [package insert]. Food and Drug Administration. 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103950s5136lbl.pdf.
  9. Canakinumab (Ilaris) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125319s100lbl.pdf.
  10. Caricchio R, Abbate A, Gordeev I, et al. Effect of canakinumab vs placebo on survival without invasive mechanical ventilation in patients hospitalized with severe COVID-19: a randomized clinical trial. JAMA. 2021;326(3):230-239. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34283183.
  11. Sarilumab (Kevzara) [package insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761037s001lbl.pdf.
  12. Regeneron and Sanofi provide update on U.S. Phase 2/3 adaptive-designed trial of KEVZARA® (sarilumab) in hospitalized COVID-19 patients [press release]. 2020.
  13. Tocilizumab (Actemra) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125276s131lbl.pdf.
  14. 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.
  15. Siltuximab (Sylvant) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125496s018lbl.pdf.
  16. Baricitinib (Olumiant) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207924s001lbl.pdf.
  17. Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization (EUA) of baricitinib. 2021. Available at: https://www.fda.gov/media/143823/download.
  18. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32470486.
  19. Guimaraes 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.