FDA issued an emergency use authorization (EUA) for Actemra (tocilizumab) for the treatment of hospitalized adults and pediatric patients 2 years of age and older with COVID-19 who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Actemra is not authorized for use in outpatients with COVID-19.
In clinical trials of hospitalized patients with COVID-19, tocilizumab in addition to routine care, which included corticosteroids, was shown to reduce the risk of death through 28 days of follow-up and decrease the amount of time patients remained hospitalized. The risk of patients being placed on ventilators through 28 days of follow-up was also decreased.
Health care provider fact sheet: https://www.fda.gov/media/150321/download
Patient fact sheet: https://www.fda.gov/media/150320/download
Frequently Asked Questions for tocilizumab: https://www.fda.gov/media/150345/download
Further information may be found at:
ClinicalTrials.gov: https://clinicaltrials.gov/ct2/results?cond=Covid19&term=tocilizumab&cntry=&state=&city=&dist=&Search=Search
IDSA: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
Patients treated with tocilizumab are at an increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.
If a serious infection develops, interrupt tocilizumab until the infection is controlled.
Reported infections include:
Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before tocilizumab use and during therapy. Treatment for latent infection should be initiated prior to tocilizumab use.
Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated rather than localized disease.
Bacterial, viral, and other infections caused by opportunistic pathogens.
The risks and benefits of treatment with tocilizumab should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tocilizumab, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.
Note: In general, patients with severe or life-threatening cytokine release syndrome frequently have cytopenias or elevated liver transaminases due to the underlying disease state and/or its treatment; evaluate risk versus benefit of tocilizumab treatment in patients with severe or life-threatening cytokine release syndrome.
COVID-19, hospitalized patients (off-label use): Note: Under the emergency use authorization (EUA), use should be limited to patients with COVID-19 who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) (FDA 2021). US guideline recommendations on the role of tocilizumab vary but generally recommend for hospitalized patients with increasing oxygen requirements with or without elevated markers of systemic inflammation (IDSA [Bhimraj 2021]; NIH 2021).
IV: 8 mg/kg (patients ≥30 kg) or 12 mg/kg (patients <30 kg) as a single dose (maximum: 800 mg/dose) (FDA 2021), in combination with glucocorticoids (FDA 2021; Gordon 2021; IDSA [Bhimraj 2021]; NIH 2021; Rosas 2021). If clinical improvement does not occur, a second dose may be given ≥8 hours after the first dose (FDA 2021). Note: Avoid use in combination with baricitinib, except in a clinical trial (NIH 2021).
Cytokine release syndrome, severe or life-threatening:
Cytokine release syndrome, severe or life-threatening; due to bi-specific T-cell engaging therapy (off-label use): IV: 4 mg/kg once; may repeat the dose if clinical improvement does not occur within 24 to 48 hours (Lee 2014).
Cytokine release syndrome , severe or life-threatening; due to chimeric antigen receptor-T cell therapy:
Note: If clinical improvement does not occur after the first dose, up to 3 additional doses may be administered (with at least an 8-hour interval between consecutive doses). Tocilizumab may be administered as monotherapy or in combination with corticosteroids.
IV: Maximum dose: 800 mg per dose.
<30 kg: 12 mg/kg.
≥30 kg: 8 mg/kg.
Giant cell arteritis: Note: Do not initiate if ANC is <2,000/mm3, platelets are <100,000/mm3, or if ALT or AST are >1.5 times ULN. Interrupt therapy if a patient develops a serious infection until the infection is controlled.
SUBQ: 162 mg once every week (in combination with a tapering course of glucocorticoids); based on clinical considerations, may consider 162 mg once every other week (with a tapering course of glucocorticoids). Tocilizumab may be administered as monotherapy following discontinuation of glucocorticoids.
Rheumatoid arthritis: Note: Do not initiate if ANC is <2,000/mm3, platelets are <100,000/mm3, or if ALT or AST are >1.5 times ULN. Methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs) may be continued for the treatment of rheumatoid arthritis. Tocilizumab should not be used in combination with biologic DMARDs. Interrupt therapy if a patient develops a serious infection until the infection is controlled.
IV: Initial: 4 mg/kg once every 4 weeks; may be increased to 8 mg/kg once every 4 weeks based on clinical response (maximum dose: 800 mg).
SUBQ:
<100 kg: 162 mg once every other week; increase to 162 mg once every week based on clinical response.
≥100 kg: 162 mg once every week.
Transitioning from IV therapy to SUBQ therapy: Administer the first SUBQ dose instead of the next scheduled IV dose.
Systemic sclerosis-associated interstitial lung disease : Note: Do not initiate if ANC is <2,000/mm3, platelets are <100,000/mm3, or if ALT or AST are >1.5 times ULN. Interrupt therapy if a patient develops a serious infection until the infection is controlled.
SUBQ: 162 mg once every week.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, based on tocilizumab's molecular weight (148 kDa), it is unlikely to be significantly renally eliminated (expert opinion).
Hepatic impairment prior to treatment initiation: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Initiation of therapy in patients with active hepatic disease or hepatic impairment or in rheumatoid arthritis (RA) and giant cell arteritis (GCA) patients with baseline ALT or AST >1.5 × ULN is not recommended.
Hepatotoxicity during treatment: RA, GCA, and systemic sclerosis-associated interstitial lung disease (SSc-ILD):
>1 to 3 × ULN: Adjust concomitant disease-modifying antirheumatic drugs (for RA and SSc-ILD) or immunomodulatory agents (for GCA) as appropriate. For patients receiving IV therapy with persistent increases >1 to 3 × ULN, reduce dose to 4 mg/kg or interrupt until ALT/AST have normalized. For patients receiving SUBQ therapy with persistent increases >1 to 3 × ULN, reduce injection frequency to every other week or interrupt therapy until ALT/AST have normalized; resume therapy at every other week, then increase frequency to every week as clinically appropriate.
>3 to 5 × ULN (confirmed with repeat testing): Interrupt until ALT/AST <3 × ULN and follow dosage adjustments recommended for liver enzyme abnormalities >1 to 3 × ULN. For persistent increases >3 × ULN, discontinue.
>5 × ULN: Discontinue.
(For additional information see "Tocilizumab: Pediatric drug information")
COVID-19 (hospitalized patients who are receiving systemic corticosteroids), treatment: Very limited data available: Children ≥2 years and Adolescents:
Note: Emergency authorization in pediatric patients for COVID-19 is supported by efficacy data from adult patients; safety and dosing for COVID-19 are extrapolated from use for other indications (FDA 2021). The National Institutes of Health guidelines state that there are insufficient data to recommend for or against tocilizumab in hospitalized children with COVID-19; if tocilizumab is used, it should be in combination with dexamethasone (NIH 2021). Not recommended for use in patients with ANC <1,000/mm3, platelets <50,000/mm3, or in patients with active hepatic disease or hepatic impairment (FDA 2021).
<30 kg: IV: 12 mg/kg/dose once; if clinical signs or symptoms worsen or do not improve after initial dose, may repeat dose once ≥8 hours after initial dose (FDA 2021).
≥30 kg: IV: 8 mg/kg/dose once; maximum dose: 800 mg/dose; if clinical signs or symptoms worsen or do not improve after initial dose, may repeat dose once ≥8 hours after initial dose (FDA 2021).
Cytokine release syndrome (CRS) due to chimeric antigen receptor T-cell therapy; severe or life-threatening: Children ≥2 years and Adolescents: May be used alone or in combination with corticosteroids.
<30 kg: IV: 12 mg/kg/dose once; if no clinical improvement after initial dose, may repeat dose every 8 hours for up to 3 additional doses.
≥30 kg: IV: 8 mg/kg/dose once; if no clinical improvement after initial dose, may repeat dose every 8 hours for up to 3 additional doses; maximum single dose: 800 mg/dose.
Cytokine release syndrome (CRS) due to bi-specific T-cell engaging therapy, severe or life-threatening: Very limited data available (Barrett 2014; Maude 2014a); optimal dose not established: Children ≥2 years and Adolescents: IV: 8 mg/kg/dose once; some experts suggest may repeat the dose if clinical improvement does not occur within 24 to 48 hours (Lee 2014; Teachey 2013); dosing based on expert recommendations and a case report of a 7-year old who received blinatumomab as part of a Phase I clinical trial and developed CRS; a single 8 mg/kg dose of tocilizumab was used (patient weight was not provided) and within 12 hours a significant clinical response observed (Teachey 2013); other reports of experience in pediatric patients are lacking.
Polyarticular juvenile idiopathic arthritis (PJIA): Children ≥2 years and Adolescents: Note: Do not initiate if ANC is <2,000/mm3, platelets are <100,000/mm3, or if ALT or AST are >1.5 times ULN. Dose adjustment should not be made based solely on a single-visit body weight measurement due to fluctuations in body weight. May be used as monotherapy or in combination with methotrexate. Variable routes of administration (IV, SubQ) and dosing; use precaution to ensure appropriate dose/route.
IV:
<30 kg: 10 mg/kg/dose every 4 weeks.
≥30 kg: 8 mg/kg/dose every 4 weeks; maximum dose: 800 mg/dose.
SUBQ:
<30 kg: 162 mg/dose once every 3 weeks.
≥30 kg: 162 mg/dose once every 2 weeks.
Conversion from IV to SUBQ dosing: Administer the first SUBQ dose instead of the next scheduled IV dose.
Systemic juvenile idiopathic arthritis (SJIA): Children ≥2 years and Adolescents: Note: Do not initiate if ANC is <2,000/mm3, platelets are <100,000/mm3 or if ALT or AST are >1.5 times ULN. Dose adjustment should not be made based solely on a single-visit body weight measurement due to fluctuations in body weight. May be used as monotherapy or in combination with methotrexate.
IV:
<30 kg: 12 mg/kg/dose every 2 weeks.
≥30 kg: 8 mg/kg/dose every 2 weeks; maximum dose: 800 mg/dose.
SUBQ:
<30 kg: 162 mg/dose once every 2 weeks.
≥30 kg: 162 mg/dose once every week.
Conversion from IV to SUBQ dosing: Administer the first SUBQ dose instead of the next scheduled IV dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity:
Polyarticular and systemic juvenile idiopathic arthritis (SJIA): Children ≥2 years and Adolescents:
Non-hematologic toxicity: Dose reductions have not been studied; however, dose interruptions are recommended for liver enzyme abnormalities (see Hepatic Impairment). In addition, consider interrupting or discontinuing concomitant methotrexate and/or other medications and hold tocilizumab dosing until the clinical situation has been assessed. For hypersensitivity reactions, stop the infusion immediately and discontinue permanently. For infection (serious, opportunistic, or sepsis), interrupt treatment until infection resolved.
Hematologic toxicity: Dose reductions have not been studied; however, dose interruptions are recommended for low neutrophil counts and low platelets similar to recommendations provided for adult rheumatoid arthritis patients (see the following):
Adults:
Neutropenia:
ANC >1,000/mm3: Maintain dose.
ANC 500 to 1,000/mm3: Interrupt therapy; when ANC >1,000/mm3, resume IV tocilizumab at 4 mg/kg (may increase to 8 mg/kg as clinically appropriate) or resume SubQ tocilizumab at every other week dosing (increase frequency to every week as clinically appropriate).
ANC <500/mm3: Discontinue.
Thrombocytopenia:
Platelets 50,000 to 100,000/mm3: Interrupt therapy; when platelet count is >100,000/mm3, resume IV tocilizumab at 4 mg/kg (may increase to 8 mg/kg as clinically appropriate) or resume SUBQ tocilizumab at every other week dosing (increase frequency to every week as clinically appropriate).
Platelets <50,000/mm3: Discontinue.
Children ≥2 years and Adolescents:
Mild to moderate renal impairment: No dosage adjustment required.
Severe renal impairment: There are no dosage adjustments provided in the manufacturer's labeling (not studied).
COVID-19: Children ≥2 years and Adolescents: There are no dosage adjustments provided in the fact sheet for health care providers; not recommended for use in patients with active hepatic disease or hepatic impairment (ie, ALT/AST >10 × ULN). Decision for use should balance potential risks and benefits (FDA 2021).
Polyarticular and systemic juvenile idiopathic arthritis (SJIA): Children ≥2 years and Adolescents:
Baseline: There are no dosage adjustments provided in the manufacturer's labeling (not studied); not recommended for use in patients with active hepatic disease or hepatic impairment.
Hepatotoxicity during therapy: Dose reductions have not been studied in pediatric patients; however, dose interruptions and reductions are recommended for liver enzyme abnormalities similar to those for adult rheumatoid arthritis patients.
ALT/AST >1 to 3 x ULN (persistent): Consider dose reduction or interrupt until ALT/AST have normalized.
ALT/AST >3 to 5 x ULN (confirmed with repeat testing): Interrupt until ALT/AST <3 x ULN and then reinitiate at a reduced dose. For persistent increase in ALT/AST >3 x ULN, discontinue.
ALT/AST >5 x ULN: Discontinue.
Hypersensitivity (anaphylaxis or other clinically significant hypersensitivity reaction): Stop immediately and discontinue permanently.
Infection (serious infection, opportunistic infection, or sepsis): Interrupt treatment until the infection is controlled.
Rheumatoid arthritis, giant cell arteritis, and systemic sclerosis-associated interstitial lung disease:
Neutropenia:
ANC >1,000/mm3: Maintain dose.
ANC 500 to 1,000/mm3: Interrupt therapy; when ANC >1,000/mm3, resume IV tocilizumab at 4 mg/kg, then may increase to 8 mg/kg as clinically appropriate or resume SUBQ tocilizumab at every other week dosing, then increase frequency to every week as clinically appropriate.
ANC <500/mm3: Discontinue.
Thrombocytopenia:
Platelets 50,000 to 100,000/mm3: Interrupt therapy; when platelet count is >100,000/mm3, resume IV tocilizumab at 4 mg/kg, then may increase to 8 mg/kg as clinically appropriate or resume SUBQ tocilizumab at every other week dosing, then increase frequency to every week as clinically appropriate.
Platelets <50,000/mm3: Discontinue.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Actemra: 80 mg/4 mL (4 mL); 200 mg/10 mL (10 mL); 400 mg/20 mL (20 mL) [contains polysorbate 80]
Solution Auto-injector, Subcutaneous [preservative free]:
Actemra ACTPen: 162 mg/0.9 mL (0.9 mL) [contains polysorbate 80]
Solution Prefilled Syringe, Subcutaneous [preservative free]:
Actemra: 162 mg/0.9 mL (0.9 mL) [contains polysorbate 80]
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Actemra: 80 mg/4 mL (4 mL); 200 mg/10 mL (10 mL); 400 mg/20 mL (20 mL) [contains polysorbate 80]
Solution Auto-injector, Subcutaneous:
Actemra: 162 mg/0.9 mL (0.9 mL) [contains polysorbate 80]
Solution Prefilled Syringe, Subcutaneous:
Actemra: 162 mg/0.9 mL (0.9 mL) [contains polysorbate 80]
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125472s044lbl.pdf#page=49, must be dispensed with this medication.
IV : Allow diluted solution for infusion to reach room temperature prior to administration; infuse over 60 minutes using a dedicated IV line. Do not infuse other agents through same IV line. Do not administer IV push or IV bolus. If additional doses are necessary for the management of cytokine-release syndrome, the interval between doses should be at least 8 hours. Do not use if opaque particles or discoloration is visible.
Note: In response to tocilizumab use for COVID-19, the possibility that supplies of the IV formulation may become limited or unavailable prompted the manufacturer, Genentech, to evaluate use of the SUBQ formulation for IV administration. Though Genentech does not recommend the use of the SUBQ formulation diluted in IV bags for infusion, they have provided the following stability information; no information is available on safety and efficacy of the SUBQ formulation administered as an IV infusion (Genentech data on file):
No physicochemical incompatibilities were observed with the following investigational study conditions using tocilizumab prefilled syringes (PFS):
• Tocilizumab PFS diluted in a 100 mL NS IV bag made of materials such as PVC, polyolefin, polyethylene (PE), and polypropylene (PP). No NS was removed prior to injecting tocilizumab PFS.
• Two doses were tested: Low dose (1 PFS injected into a 100 mL NS bag, leading to a protein concentration of 1.6 mg/mL [total dose: 162 mg]) and high dose (6 PFS injected into a 100 mL NS bag leading to a concentration of 9.2 mg/mL [total dose: 972 mg]). Note: Tocilizumab doses exceeding 800 mg/infusion are not recommended in patients with rheumatoid arthritis or cytokine-release syndrome.
• IV solutions were stored for 24 hours at room temperature.
• Simulated infusions were conducted over 2 hours using an infusion rate of 19.6 mL/hour (infusion volume of 40 mL) with infusion administration sets made of PVC, PE, polybutadiene, or polyurethane equipped with a 0.2 or 0.22 micrometer polyethersulfone or polysulfone inline filter.
• Compatibility with other drugs and indwelling catheters, such as peripherally inserted central catheters and central venous access devices, were not tested.
SUBQ: Allow to reach room temperature (30 minutes for prefilled syringe; 45 minutes for autoinjector) prior to use. Do not use if particulate matter or discoloration is visible; solution should be clear and colorless to pale yellow. Administer the full amount in the prefilled syringe or autoinjector. Rotate injection sites; avoid injecting into moles, scars, or tender, bruised, red, or hard skin. After proper training, patients may self-inject, or the patient's caregiver may administer tocilizumab.
Rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis: When transitioning from IV administration to SUBQ administration, give the first SUBQ dose instead of the next scheduled IV dose.
Giant cell arteritis: Should only be administered SUBQ (IV administration is not approved for giant cell arteritis).
Systemic sclerosis-associated interstitial lung disease: Should only be administered SUBQ using prefilled syringe (IV administration is not approved for systemic sclerosis-associated interstitial lung disease); use with the ACTPen autoinjector has not been studied.
IV: Allow diluted solution to reach room temperature prior to administration; infuse over 60 minutes using a dedicated IV line. Do not administer IV push or IV bolus. Do not use if opaque particles or discoloration are visible.
SUBQ: Administer the full amount (162 mg/0.9 mL) in the prefilled syringe. Allow to reach room temperature prior to use. Do not use if particulate matter or discoloration is visible; solution should be clear and colorless to pale yellow. Rotate injection sites; avoid injecting into moles, scars, or tender, bruised, red, or hard skin. After proper training, patients may self-inject, or the patient's caregiver may administer tocilizumab using prefilled syringe. Use of the autoinjector in pediatric patients has not been studied.
Note: In response to tocilizumab use for COVID-19, the possibility that supplies of the IV formulation may become limited or unavailable prompted the manufacturer, Genentech, to evaluate use of the SUBQ formulation for IV administration. Though Genentech does not recommend the use of the SUBQ formulation diluted in IV bags for infusion, they have provided the following stability information; no information is available on safety and efficacy of the SUBQ formulation administered as an IV infusion (Genentech data on file):
No physicochemical incompatibilities were observed with the following investigational study conditions using tocilizumab prefilled syringes (PFS):
• Tocilizumab PFS diluted in a 100 mL NS IV bag made of materials such as PVC, polyolefin, polyethylene (PE), and polypropylene (PP). No NS was removed prior to injecting tocilizumab PFS.
• Two doses were tested: Low dose (1 PFS injected into a 100 mL NS bag, leading to a protein concentration of 1.6 mg/mL [total dose: 162 mg]) and high dose (6 PFS injected into a 100 mL NS bag leading to a concentration of 9.2 mg/mL [total dose: 972 mg]). Note: Tocilizumab doses exceeding 800 mg/infusion are not recommended in patients with rheumatoid arthritis or cytokine-release syndrome.
• IV solutions were stored for 24 hours at room temperature.
• Simulated infusions were conducted over 2 hours using an infusion rate of 19.6 mL/hour (infusion volume of 40 mL) with infusion administration sets made of PVC, PE, polybutadiene, or polyurethane equipped with a 0.2 or 0.22 micrometer polyethersulfone or polysulfone inline filter.
• Compatibility with other drugs and indwelling catheters, such as peripherally inserted central catheters and central venous access devices, were not tested.
Cytokine release syndrome, severe or life-threatening: Treatment of chimeric antigen receptor (CAR) T-cell induced severe or life-threatening cytokine release syndrome in patients ≥2 years of age.
Giant cell arteritis: Treatment of giant cell arteritis (GCA) in adult patients.
Polyarticular juvenile idiopathic arthritis: Treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients ≥2 years of age.
Rheumatoid arthritis: Treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).
Systemic juvenile idiopathic arthritis: Treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients ≥2 years of age.
Systemic sclerosis-associated interstitial lung disease: Indicated to slow the rate of decline in pulmonary function in adult patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).
COVID-19, hospitalized patients; Cytokine release syndrome, severe or life-threatening; due to BiTE therapy
Tocilizumab may be confused with sarilumab.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Incidence as reported for adults unless otherwise noted. Incidence as reported for monotherapy and combination therapy.
>10%:
Endocrine & metabolic: Increased serum cholesterol (19% to 20%; children and adolescents: ≤2%)
Gastrointestinal: Constipation (6% to 13%)
Hematologic & oncologic: Neutropenia (children and adolescents <30 kg: 26%; children and adolescents ≥30 kg: 4%; adults: 3% to 4%)
Hepatic: Increased serum alanine aminotransferase (≤36%), increased serum aspartate aminotransferase (≤22%)
Local: Injection site reaction (SubQ: children and adolescents: 15% to 44% [higher incidence occurred in weight ≥30 kg]; adults: 7% to 10%)
Miscellaneous: Infusion-related reaction (4% to 20%)
1% to 10%:
Cardiovascular: Deep vein thrombosis (3%), hypertension (6% to 7%), peripheral edema (<2%), septic shock (6%)
Dermatologic: Skin rash (2%)
Endocrine & metabolic: Hyperglycemia (5%), hypoglycemia (3%), hypokalemia (5%), hypothyroidism (<2%), increased LDL cholesterol (9% to 10%; children and adolescents: ≤2%), weight gain (<2%)
Gastrointestinal: Diarrhea (children, adolescents, and adults: ≥5%), gastric ulcer (<2%), gastritis (1%), nausea (4%), oral mucosa ulcer (2%), stomatitis (<2%), upper abdominal pain (2%)
Genitourinary: Urinary tract infection (8%)
Hematologic & oncologic: Leukopenia (<2%), thrombocytopenia (children, adolescents, and adults: 1% to 4%)
Hepatic: Increased serum bilirubin (<2%)
Immunologic: Antibody development (children and adolescents: ≤6%; adults: ≤2%, including neutralizing)
Infection: Herpes simplex infection (<2%)
Nervous system: Anxiety (3% to 6%), delirium (5%), dizziness (3%), headache (3% to 7%), insomnia (4% to 5%), pain (3%)
Ophthalmic: Conjunctivitis (<2%)
Renal: Acute kidney injury (7%), nephrolithiasis (<2%)
Respiratory: Bronchitis (3%), cough (<2%), dyspnea (<2%), nasopharyngitis (7%), pneumonia (8%), upper respiratory tract infection (7%)
<1%: Hypersensitivity: Anaphylaxis, hypersensitivity reaction
Frequency not defined:
Cardiovascular: Hypotension
Dermatologic: Pruritus, urticaria
Endocrine & metabolic: Increased HDL cholesterol
Hematologic & oncologic: Malignant neoplasm
Hypersensitivity: Angioedema
Infection: Infection (including severe infection)
Nervous system: Chronic inflammatory demyelinating polyneuropathy
Neuromuscular & skeletal: Multiple sclerosis
Otic: Otitis media
Postmarketing:
Dermatologic: Cellulitis, Stevens-Johnson syndrome
Gastrointestinal: Diverticulitis of the gastrointestinal tract, gastroenteritis, gastrointestinal perforation, pancreatitis
Hepatic: Hepatic failure, hepatic injury (Genovese 2017), hepatitis, hepatotoxicity, jaundice
Infection: Aspergillosis, atypical mycobacterial infection, bacterial infection, candidiasis, cryptococcosis, fungal infection, herpes zoster infection (including exacerbation), opportunistic infection, protozoal infection, sepsis, viral infection
Neuromuscular & skeletal: Septic arthritis
Respiratory: Active tuberculosis, infection due to an organism in genus Pneumocystis, tuberculosis
Known hypersensitivity to tocilizumab or any component of the formulation
Canadian labeling: Additional contraindications (not in the US labeling): Active infections
Concerns related to adverse effects:
• GI perforation: Use with caution in patients at increased risk for GI perforation; perforation has been reported, typically secondary to diverticulitis. Promptly evaluate if new symptoms of GI perforation occur.
• Hematologic effects: Neutropenia and thrombocytopenia may occur; may require treatment interruption, dose or interval modification, or discontinuation. Monitor neutrophils and platelets.
• Hepatic effects: Hepatic injury, resulting in liver transplant or death, has been reported. May occur months to years after treatment initiation and may present with marked elevations of hepatic transaminases (>5 × ULN) or signs or symptoms of hepatic dysfunction with mildly elevated transaminases. May require treatment interruption, dose or interval modification, or discontinuation. Monitor LFTs; patients receiving concomitant hepatotoxic drugs (eg, methotrexate) are at an increased risk of developing elevated transaminases.
• Herpes zoster reactivation: Herpes zoster reactivation has been reported.
• Hyperlipidemia: Therapy is associated with increases in total cholesterol, triglycerides, low-density lipoprotein, and/or high-density lipoprotein.
• Hypersensitivity: May cause hypersensitivity or anaphylaxis; anaphylactic events including fatalities have been reported with IV administration; hypersensitivity reactions have occurred in patients who were premedicated, in patients with and without a prior history of hypersensitivity, and as early as the first infusion. Medications for the treatment of hypersensitivity reactions should be available for immediate use. Patients should seek medical attention if symptoms of hypersensitivity reaction occur with SUBQ use. Stop immediately and permanently discontinue treatment in patients who develop a hypersensitivity reaction to tocilizumab. In clinical studies, reactions requiring treatment discontinuation included generalized erythema, rash, and urticaria.
• Infections: [US Boxed Warning]: Serious and potentially fatal infections (including active tuberculosis, invasive fungal, bacterial, viral, protozoal, and other opportunistic infections) have been reported in patients receiving tocilizumab; infection may lead to hospitalization or death. Most of the serious infections have occurred in patients on concomitant immunosuppressive therapy. Patients should be closely monitored for signs and symptoms of infection during and after treatment. If serious infection occurs during treatment, withhold tocilizumab until infection is controlled. Prior to treatment initiation, carefully consider risk versus benefit in patients with chronic or recurrent infections, tuberculosis exposure, history of or current opportunistic infection, underlying conditions predisposing to infection, or patients residing in or with travel to areas of endemic tuberculosis or endemic mycosis. The most common serious infections occurring have included pneumonia, UTI, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, and bacterial arthritis. Do not administer tocilizumab to a patient with an active infection, including localized infection. Interrupt treatment for serious infection, opportunistic infection, or sepsis.
• Malignancy: Use of tocilizumab may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined; however, malignancies were observed in clinical trials.
• Tuberculosis: [US Boxed Warning]: Tuberculosis (pulmonary or extrapulmonary) has been reported in patients receiving tocilizumab; both reactivation of latent infection and new infections have been reported. Patients should be tested for latent tuberculosis infection before and during therapy; consider treatment of latent tuberculosis used prior to tocilizumab treatment. Some patients who test negative prior to therapy may develop active infection; monitor for signs and symptoms of tuberculosis during and after treatment in all patients. Patients should be evaluated for tuberculosis risk factors with a tuberculin skin test prior to starting therapy. Consider antituberculosis treatment in patients with a history of latent or active tuberculosis if adequate treatment course cannot be confirmed, and for patients with risk factors for tuberculosis despite a negative test.
Disease-related concerns:
• Demyelinating CNS disease: Use with caution in patients with preexisting or recent onset CNS demyelinating disorders; rare cases of CNS demyelinating disorders (multiple sclerosis and chronic inflammatory demyelinating polyneuropathy) have occurred.
• Hepatic impairment: Use is not recommended in patients with active hepatic disease or hepatic impairment. Initiation of therapy in rheumatoid arthritis (RA) and giant cell arteritis (GCA) patients with baseline ALT or AST >1.5 × ULN is not recommended.
Concurrent drug therapy issues:
• Biological disease-modifying antirheumatic drugs: Concomitant use with other biological disease-modifying antirheumatic drugs (DMARDs) (eg, tumor necrosis factor blockers, IL-1 receptor blockers, anti-CD20 monoclonal antibodies, selective costimulation modulators) has not been studied and should be avoided due to the increased risk of infection.
Special populations:
• Elderly: Infection has been reported at a higher incidence in elderly patients compared with younger adults; use with caution in elderly patients.
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Other warnings/precautions:
• Appropriate use: SUBQ administration is only indicated for adult patients with rheumatoid arthritis, giant cell arteritis (GCA), and systemic sclerosis-associated interstitial lung disease (SSc-ILD), and pediatric patients with polyarticular juvenile idiopathic arthritis. Do not use SUBQ injection for IV infusion. Do not administer IV for the treatment of GCA and SSc-ILD. SUBQ administration with the prefilled ACTPen autoinjector has not been studied in SSc-ILD.
• Immunizations: Patients should be brought up to date with all immunizations before initiating therapy. Live vaccines should not be given concurrently; there are no data available concerning secondary transmission of infection from live vaccines in patients receiving therapy.
Reactivation of TB has been reported in pediatric patients receiving biologic response modifiers (infliximab and etanercept); prior to therapy, patients with no TB risk factors should be screened for latent TB infection (LTBI) with an age appropriate test (ie, <5 years of age: Tuberculin skin test, and ≥5 years of age: IGRA [interferon gamma release assay]); if any TB risk factors are present or symptoms, both LTBI screening tests should be performed (AAP [Davies 2016])
None known.
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Anifrolumab: Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) may enhance the immunosuppressive effect of Anifrolumab. Risk X: Avoid combination
Anti-TNF Agents: Tocilizumab may enhance the immunosuppressive effect of Anti-TNF Agents. Risk X: Avoid combination
Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Belimumab: May enhance the immunosuppressive effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combination
Biologic Disease-Modifying Antirheumatic Drugs (DMARDs): May enhance the immunosuppressive effect of other Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: In the US, after receipt of the single dose COVID-19 adenovirus vector vaccine (Janssen), administer an additional 2nd dose using an mRNA COVID-19 vaccine, at least 28 days after the primary vaccine dose, in patients taking immunosuppressive therapies. Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Consider administration of a 3rd dose of COVID-19 vaccine, at least 28 days after completion of the primary 2-dose series, in patients 5 years of age and older taking immunosuppressive therapies. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers): Interleukin-6 (IL-6) Inhibiting Therapies may decrease the serum concentration of CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers): Interleukin-6 (IL-6) Inhibiting Therapies may decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification
Echinacea: May diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Management: Consider avoiding echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. Risk D: Consider therapy modification
Inebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate 2 to 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If post-exposure rabies vaccination is required during immunosuppressant therapy, administer a 5th dose of vaccine and check for rabies antibodies. Risk D: Consider therapy modification
Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Inactivated). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Based on limited data, tocilizumab may be considered for use in patients with rheumatic and musculoskeletal diseases who are planning to become pregnant; however, treatment should be discontinued once pregnancy is confirmed. Conception should be planned during a period of quiescent/low disease activity (ACR [Sammaritano 2020]).
Information related to paternal use of tocilizumab is limited (Hoeltzenbein 2016). Therefore, recommendations are not available for use in patients with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020]).
Tocilizumab crosses the placenta (Moriyama 2020; Saito 2018; Saito 2019a; Tada 2019). Tocilizumab is a humanized monoclonal antibody (IgG1). Potential placental transfer of human IgG is dependent upon the IgG subclass, maternal serum concentrations, newborn birth weight, and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).
Postmarketing data reviewed through 2014 have not shown an increased rate of congenital malformations or a pattern of specific malformations following in utero exposure to tocilizumab. The review included pregnancy outcome data from 399 women who received tocilizumab for rheumatic disorders; the majority received a dose during the first trimester or within 6 weeks of conception. Using this data, the incidence of preterm birth and spontaneous abortion may be increased when compared to the background rate, but these outcomes may also be influenced by maternal disease and concomitant medications (Hoeltzenbein 2016). Outcome data are limited when maternal use continues throughout pregnancy (Dalkilic 2019; Hoeltzenbein 2016; Kaneko 2016; Nakajima 2016; Saito 2018; Saito 2019a; Tada 2019).
Until additional information is available, tocilizumab is not currently recommended for the treatment of rheumatic and musculoskeletal diseases during pregnancy. Tocilizumab should be discontinued once pregnancy is confirmed (ACR [Sammaritano 2020]).
Data collection to monitor pregnancy and infant outcomes following exposure to tocilizumab is ongoing. Health care providers or pregnant patients are encouraged to enroll exposed pregnancies in the Genentech Actemra registry (877-311-8972).
Tocilizumab is currently available under FDA emergency use authorization (EUA) for the treatment of COVID-19 (FDA 2021). Outcome information specific to use in pregnancy for COVID-19 is limited (Abdullah 2021; Jiménez-Lozano 2021; Naqvi 2020; San-Juan 2020). Use for the treatment of COVID-19 in pregnancy is not currently recommended (NIH 2021).
The risk of severe illness from COVID-19 infection is increased in pregnant patients, and pregnancy is one of the high-risk medical conditions defined by the CDC. An increased risk of adverse pregnancy outcomes may also occur in COVID-19–positive patients with symptomatic infection. These include preterm birth, preeclampsia, coagulopathy, and stillbirth. Pregnant patients with symptomatic COVID-19 infection are more likely to require ICU admission, mechanical ventilation, and ventilatory support (ECMO) compared to nonpregnant symptomatic patients. Maternal age and comorbidities may also increase the risk of severe illness in pregnant and recently pregnant patients (ACOG 2021; NIH 2021). Information related to the treatment of COVID-19 during pregnancy continues to emerge; refer to current guidelines for the treatment of pregnant patients.
The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have developed an algorithm to aid practitioners in assessing and managing pregnant patients with suspected or confirmed COVID-19 (https://www.acog.org/covid-19; https://www.smfm.org/covid19). Interim guidance is also available from the CDC for pregnant patients who are diagnosed with COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov/hcp/inpatient-obstetric-healthcare-guidance.html).
Data collection to monitor maternal and infant outcomes following exposure to COVID-19 during pregnancy is ongoing. Health care providers are encouraged to enroll patients exposed to COVID-19 during pregnancy in the Organization of Teratology Information Specialists pregnancy registry (877-311-8972; https://mothertobaby.org/join-study/).
Tocilizumab is present in breast milk (Moriyama 2020; Saito 2018; Saito 2019a; Saito 2019b; Tada 2019).
In a report of 2 cases, breast milk concentrations peaked ~3 days after an IV maternal dose, then gradually decreased (Saito 2018). Although tocilizumab was detected in the serum of 1 infant at birth following in utero exposure, concentrations rapidly decreased and were not detectable by 4 weeks of age, even though the infant was exclusively breastfed (Saito 2019a).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Although data related to use in lactating patients are limited, adverse events have not been reported in breastfed infants (Nakajima 2016; Saito 2018; Saito 2019a). Concentrations of tocilizumab are expected to be limited in breast milk due to large molecular weight. Also, because tocilizumab is unlikely to be absorbed via the infant GI tract, use of tocilizumab may be considered in patients who are breastfeeding (ACR [Sammaritano 2020]).
Interim guidance is available from the Centers for Disease Control and Prevention for the care of lactating patients who are diagnosed with COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov/hcp/care-for-breastfeeding-women.html). Information related to COVID-19 and breastfeeding is also available from the World Health Organization (https://www.who.int/news/item/28-04-2020-new-faqs-address-healthcare-workers-questions-on-breastfeeding-and-covid-19).
COVID-19: ALT/AST, neutrophils, platelets (per current standard clinical practice); signs and symptoms of demyelinating disorders (FDA 2021).
Chronic therapy: Latent TB screening prior to therapy initiation (all patients); neutrophils, platelets (prior to therapy, 4 to 8 weeks after start of therapy, and every 3 months thereafter [rheumatoid arthritis {RA}, giant cell arteritis {GCA}, systemic sclerosis-associated interstitial lung disease {SSC-ILD}]); ALT/AST, alkaline phosphatase, and total bilirubin (prior to therapy, every 4 to 8 weeks after start of therapy for the first 6 months, and every 3 months thereafter [RA, GCA, SSc-ILD]); neutrophils, platelets, ALT/AST (prior to therapy, at second administration, and every 2 to 4 weeks [systemic juvenile idiopathic arthritis] or 4 to 8 weeks [polyarticular juvenile idiopathic arthritis] thereafter); additional liver function tests (eg, bilirubin) as clinically indicated; lipid panel (prior to and 4 to 8 weeks following initiation of therapy, then subsequently according to current guidelines); monitor all patients for signs and symptoms of infection (prior to, during, and after therapy); signs and symptoms of CNS demyelinating disorders; new onset abdominal symptoms.
Tocilizumab is an antagonist of the interleukin-6 (IL-6) receptor. Endogenous IL-6 is induced by inflammatory stimuli and mediates a variety of immunological responses. Inhibition of IL-6 receptors by tocilizumab leads to a reduction in cytokine and acute phase reactant production.
Onset (cytokine release syndrome [CRS]): Median time to defervescence: 4 hours (Fitzgerald 2017); Fever and hypotension often resolve within a few hours (Lee 2014); Blood pressure stabilization: 1 to 3 days (Abboud 2016; Maude 2014b). A median of 1 dose (range: 1 to 4) was required for management of CRS due to chimeric antigen receptor T-cell therapy.
Distribution: Vdss: Children and Adolescents: Systemic juvenile idiopathic arthritis (SJIA): 4.01 L; Polyarticular juvenile idiopathic arthritis (PJIA): 4.08 L; Adults: Rheumatoid arthritis (RA): 6.4 L; Giant cell arteritis (GCA): 7.46 L; Systemic sclerosis-associated interstitial lung disease (SSc-ILD): 6.74 L.
Bioavailability: SUBQ: 80% (GCA, RA, SSc-ILD); 95% (SJIA); 96% (PJIA).
Half-life elimination:
IV: Concentration dependent: Steady state: Children and Adolescents: SJIA: Up to 16 days; PJIA: Up to 17 days; Adults: RA: Up to 11 to 13 days.
SUBQ: Concentration dependent: Children and Adolescents: SJIA: Up to 14 days; PJIA: Up to 10 days; Adults: RA: Up to 5 days (every-other-week dosing) or up to 13 days (every-week dosing); GCA: 4.2 to 7.9 days (every other week dosing) or 18.3 to 18.9 days (every-week dosing); SSc-ILD: 12.1 to 13 days (every-week dosing).
Time to peak: SUBQ: ~3 days (for every-week dosing); ~4.5 days (for every-2-week dosing).
Body weight:
RA: For IV administration, the body weight-based dose (8 mg/kg) resulted in ~86% higher exposure in patients who weighed >100 kg in comparison with patients who weighed <60 kg.
GCA: Higher exposure was observed in patients with lower body weight. For the 162 mg every week dosing regimen, the steady-state Cavg was 51% higher in patients with body weight <60 kg compared with patients weighing between 60 to 100 kg. For the 162 mg every-other-week regimen, the steady-state Cavg was 129% higher in patients with body weight <60 kg compared with patients weighing between 60 to 100 kg.
Solution (Actemra Intravenous)
80 mg/4 mL (per mL): $138.35
200 mg/10 mL (per mL): $138.35
400 mg/20 mL (per mL): $138.35
Solution Auto-injector (Actemra ACTPen Subcutaneous)
162 mg/0.9 mL (per 0.9 mL): $1,291.24
Solution Prefilled Syringe (Actemra Subcutaneous)
162 mg/0.9 mL (per 0.9 mL): $1,291.24
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
