Tocilizumab
by Douglas Black, Pharm.D.
last updated
2022-11-26 14:46:31.233859-05:00
© Antimicrobial Therapy, Inc.
IL-6 Inhibitor, Tocilizumab
Usage and Dosing
- Tocilizumab is a recombinant humanized anti-interleukin 6 (IL-6) monoclonal antibody.
- Tocilizumab binds to both soluble and membrane-bound IL-6 receptors, and has been shown to inhibit IL-6-mediated signaling through those receptors.
- The most recent IDSA guidelines make a conditional recommendation, low certainty of evidence, for use of Tocilizumab in addition to standard of care, including corticosteroids, for progressive severe or critical disease in patients with COVID-19 pneumonia. (Link to most recently published IDSA review of IL-6 inhibitor studies here.) Revised NIH guidelines make similar recommendations.
- Tocilizumab should be given only in combination with dexamethasone (or another corticosteroid at an equivalent dose). Use of Tocilizumab should be avoided in patients with any of the following: (1) significant immunosuppression, particularly in those with a history of recent use of other biologic immunomodulating drugs; (2) alanine transaminase >5 times the upper limit of normal; (3) high risk for gastrointestinal perforation; (4) an uncontrolled, serious bacterial, fungal, or non-SARS-CoV-2 viral infection; (5) absolute neutrophil count <500 cells/µL; or (6) platelet count <50,000 cells/µL.
- Clinical trial results:
- Roche announced in a press release of that its phase III tocilizumab failed to meet its primary endpoint (7- category ordinal scale based on need for supplemental oxygen requirements, and intensive care and/or ventilator use) in hospitalized adult patients with severe COVID-19 associated pneumonia.
- Phase III double-blind randomized trial (N Engl J Med. 2020; 383:2333) of tocilizumab compared to placebo for hospitalized, moderately ill patients with confirmed COVID-19 found no difference in intubation or death, worsening of disease; or time to discontinuation of supplemental oxygen.
- Randomized controlled trial (N Engl J Med. 2021; 384:20) of tocilizumab versus placebo for hospitalized patients with COVID-19 pneumonia found that tocilizulmab reduced likelihood of progression to the composite outcome of mechanical ventilation or death, but did not improve survival.
- Randomized ongoing international, multifactorial, adaptive platform trial (NEJM 2021, Feb 25; NEJMoa2100433. doi: 10.1056/NEJMoa2100433) of ICU patients receiving high-flow nasal cannula oxygen support, non-invasive or mechanical ventilation, or pressor support reported improved outcomes, including mortality with Tocilizumab (353 patients).
- RECOVERY open-label trial (pre-print in medRxIV, not peer reviewed) of 2022 patients randomized to tocilizumab compared with 2094 patients randomized to usual care (82% of patients overall were taking a systemic corticosteroids) reported a mortality benefit at 28 days with tocilizumab , 596 deaths (29%) vs. 694 deaths (33%) (p=0·007). Tocilizumab also increased the probability of discharge alive within 28 days from 47% to 54% (p<0·0001). Trends toward benefit, not reaching statistical significance in most cases, were seen in several patient subgroups , including those requiring only supplemental oxygen and non-invasive ventilation, but not mechanical ventilation. Tocilizumab in combination with corticosteroids reduced mortality compared to those receiving corticosteroids and usual care 457/1664 (27%) vs. 565/1721 (33%), RR= 0.80 (95% CI 0.70−0.90)], but not in those not receiving corticosteroids).
- On June 24 2021, the US FDA issued an EUA for 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 ECMO. FDA news release here. Healthcare provider fact sheet here.
- Tocilizumab is not authorized for use in outpatients with COVID-19.
- Black box warning (from FDA-approved prescribing information): Serious infections due to bacterial, mycobacterial, fungal, viral, or other opportunistic pathogens.
Adult Dose
- COVID-19, hospitalized adults and pediatric patients (≥2 years of age):
- Weight <30 kg: 12 mg/kg as a single IV infusion over 60 minutes.
- Weight ≥30 kg: 8 mg/kg as a single IV infusion over 60 minutes.
- Maximum dosage: 800 mg per infusion.
- If clinical signs or symptoms worsen or do not improve after the initial dose, consider administering an additional dose at least 8 hours after the initial dose.
- Preparation:
- Weight <30 kg: use 50 mL bag of 0.9% or 0.45% sodium chloride for injection.
- Weight ≥30 kg: use 100 mL bag of 0.9% or 0.45% sodium chloride for injection.
- Drug is supplied in 20 mg/mL vials (multiple sizes) for further dilution.
- Withdraw a volume from the bag equal to the volume of tocilizumab required for the patient's dose (0.4 mL/kg for an 8 mg/kg dose, 0.6 mL/kg for a 12 mg/kg dose), then slowly add the tocilizumab. Mix by inverting the bag to avoid foaming.
- Stability of diluted infusion solution:
- Using 0.9% sodium chloride: 24 hours at room temperature or 2-8°C. Protect from light.
- Using 0.45% sodium chloride: 4 hours at room temperature, or 24 hours at 2-8°C. Protect from light.
Pediatric Dose
- Age ≥2 years: see Adult Dose.
Renal Adjustment
- No dosage adjustment in patients with mild or moderate renal impairment.
- No data in patients with severe impairment.
Hepatic Adjustment
- Not recommended in patients with active hepatic disease or hepatic impairment.
Adverse Effects
- Serious infections due to bacterial, mycobacterial, fungal, viral, or other opportunistic pathogens
- Gastrointestinal perforations
- Hepatotoxicity
- Neutropenia, thrombocytopenia
- Lipid abnormalities
- Hypersensitivity reactions, including anaphylaxis
- Demyelinating disorders
- Malignancy
Pharmacology
| Class | IgG monoclonal antibody |
| PK/PD Index | No data |
| Pharmaceutical Preparation |
Injectable |
| Pregnancy Risk Summary | Animal data suggested potential risk to fetus. Human data insufficient. |
|---|---|
| Food Effect1 | - |
| Oral Absorption2 (%) |
- |
| Peak Serum Level3 (μg/mL) |
151 (8 mg/kg IV, SD)
|
| Protein Binding (%) |
No data |
| Average Serum Half-life4 |
≈21.5 days (terminal) |
| Elimination | Catabolized (similar to IgG) |
| Biliary Penetration5 (%) | No data |
| CSF/Blood Penetration6 (%) |
No data |
| Therapeutic Levels in CSF7 | No data |
| Volume of Distribution8 (Vd) |
8.75 L |
| AUC9 (μg*hr/mL) |
No data |
| CYP450, Transporter Interactions |
See Major Drug Interactions |
- Notes:
- 1 Adult preparations unless otherwise noted.
- 2 Absorption under optimal conditions.
- 3 Total drug; adjust for protein binding to determine free drug concentration.
- SD = after single dose
- SS = steady state after multiple doses
- 4 Assumes CrCl > 80 mL/min
- 5 Peak concentration in bile/peak concentration in serum x 100
- 6 CSF levels with inflammation
- 7 Judgment based on drug dose & organism susceptibility. CSF concentration ideally ≥10x above MIC.
- 8 Volume of Distribution (Vd):
- V/F = Vd/oral bioavailability
- Vss = Vd at steady state
- Vss/F = Vd at steady state/oral bioavailability
- 9 Area under the plasma concentration versus time curve
Major Drug Interactions
- Hepatic CYP450 enzymes are down-regulated by infection and inflammatory stimuli, including cytokines such as IL-6. Therefore, treatment with tocilizumab may restore CYP450 activity, leading to increased metabolism (and decreased activity) of CYP450 substrates. For example, a 28% and 57% decrease in omeprazole and simvastatin exposure, respectively, has been observed one week after a single dose of tocilizumab.
- Exercise caution when using tocilizumab in patients receiving CYP450 substrates with a narrow therapeutic index.
- The effect of tocilizumab on CYP450 activity may persist for several weeks after stopping therapy.
Comments
- Supplied as 80 mg/4 mL, 200 mg/10 mL, and 400 mg/20 mL single-dose vials for further dilution before IV administration.
- Storage: 2-8ºC.