Table 4f. Characteristics of Immunomodulators

Last Updated: December 16, 2021

Table 4f. Characteristics of Immunomodulators
Drug Name	Dosing 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.
Colchicine	Dose 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 days^3,4	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.	A list of clinical trials is available: Inhaled Budesonide
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.	A list of clinical trials is available: Ciclesonide
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.	A list of clinical trials is available: Intravenous Immunoglobulin
Key: AE = adverse event; ALC = absolute lymphocyte count; ALT = alanine transaminase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 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; Hgb = hemoglobin; HSR = hypersensitivity reaction; HSV = herpes simplex virus; HTN = hypertension; IL = interleukin; IV = intravenous; IVIG = intravenous immunoglobulin; IVM = ivermectin; MAOI = monoamine oxidase inhibitor; MDI = metered dose inhaler; MI= myocardial infarction; MV = mechanical ventilation; NaCl = sodium chloride; NIV = noninvasive ventilation; OAT = organic anion transporter; the Panel = the COVID-19 Treatment Guidelines Panel; PE = pulmonary embolism; P-gp= P-glycoprotein; PK = pharmacokinetic; PO = orally; RDV = remdesivir; SQ = subcutaneous; TB = tuberculosis; TNF = tumor necrosis factor; TRALI = transfusion-related acute lung injury

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