FDA Authorizes Tocilizumab Monoclonal Antibody for Treatment of COVID-19

On June 24, 2021, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for the drug ACTEMRA (tocilizumab) for the treatment of hospitalized adults and pediatric patients (2 years of age and older) 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. The recommended dosage for emergency use of ACTEMRA authorized under this EUA is 12 mg/kg for patients less than 30 kg weight and 8 mg/kg for patients at or above 30 kg weight. ACTEMRA should be administered as a single 60‑minute intravenous (IV) infusion. If clinical signs or symptoms worsen or do not improve after the first dose, one additional infusion of ACTEMRA may be administered at least 8 hours after the initial infusion. The maximum dosage in COVID-19 patients is 800 mg per infusion.

In COVID-19 patients, ACTEMRA should not be administered if patients have any other concurrent active infection, including localized infection. Use ACTEMRA with caution in patients who may be at increased risk for gastrointestinal perforation. ACTEMRA is not recommended in COVID-19 patients with an absolute neutrophil count (ANC) less than 1000 per mm³, platelet count below 50,000 per mm³, or ALT or AST above 10 times the upper limit of the reference range. Monitor ALT, AST, neutrophils and platelet counts according to current standard clinical practice. Monitor patients for signs and symptoms potentially indicative of demyelinating disorders and exercise caution in considering the use of ACTEMRA in patients with preexisting or recent onset demyelinating disorders. ACTEMRA is not recommended in patients with active hepatic disease or hepatic impairment. Avoid use of live vaccines concurrently with ACTEMRA. Additional information regarding these Warnings and Precautions can be found in the Fact Sheet for Health Care Providers and in the detailed Full Prescribing Information for ACTEMRA linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

MOA: Tocilizumab is a monoclonal antibody that reduces inflammation by blocking the interleukin-6 (IL-6) receptor.

General PK: The PK of tocilizumab in COVID-19 adult patients was estimated by a population PK analysis of a dataset composed of 380 adult patients treated with 8 mg/kg IV. Following a single 8 mg/kg IV dose of tocilizumab, the estimated median (range) Cmax and concentration on Day 28 of tocilizumab were 151 (77.5-319) mcg/mL and 0.229 (0.00119-19.4) mcg/mL, respectively. For two doses of 8 mg/kg intravenous tocilizumab separated by 8 hours, the estimated median (range) Cmax of tocilizumab was 290 (152-604) mcg/mL.

Distribution:

In COVID-19 adult patients treated with one or two infusions of 8 mg/kg IV separated by 8 hr, the estimated central volume of distribution of tocilizumab was 4.52 L, and the estimated peripheral volume of distribution was 4.23 L, resulting in a volume of distribution of 8.75 L.

Elimination:

In COVID-19 adult patients, tocilizumab serum concentrations were below the limit of quantification after 35 days on average following one infusion of 8 mg/kg IV. The estimated average linear clearance was 17.6 mL/hr in patients with baseline ordinal scale category 3 (OS 3, patients requiring supplemental oxygen), 22.5 mL/hr in patients with baseline OS 4 (patients requiring high-flow oxygen or non-invasive ventilation), 29 mL/hr in patients with baseline OS 5 (patients requiring mechanical ventilation), and 35.4 mL/hr in patients with baseline OS 6 (patients requiring ECMO or mechanical ventilation and additional organ support).

Drug Interactions

Inhibition of IL-6 may lead to increased metabolism of drugs that are CYP450 substrates. Caution should be exercised when co-administering ACTEMRA with CYP3A4 substrate drugs where decrease in effectiveness is undesirable. The effect of ACTEMRA on CYP450 enzyme activity may persist for several weeks after stopping therapy.

Use in Specific Populations

In COVID-19 adult patients, tocilizumab exposure following body-weight-based IV dosing was dependent on body weight and disease severity. Within a specified OS category, compared to patients with a mean body weight of 80 kg, exposure was 20% lower in patients weighing less than 60 kg. Exposure in patients weighing more than 100 kg was in the same range as exposure in patients with a mean body weight of 80 kg. For an 80 kg patient, exposure decreases as disease severity increases; for each category increase on the OS, exposure decreases consistently by 13%.

Additional details on the effect of different covariates (e.g., age, gender, race, body weight, hepatic impairment, renal impairment) on the PK of tocilizumab can be found in the detailed Full Prescribing Information for ACTEMRA linked below.

Pediatric Population

Pediatric use under this EUA is supported by evidence justifying emergency use of ACTEMRA for the treatment of COVID-19 in hospitalized adults who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO, as well as safety and dosing information of ACTEMRA in pediatric patients for other uses. ACTEMRA is not authorized or approved for the emergency use for patients younger than 2 years of age.

Efficacy and Safety

The issuance of an EUA is different than FDA approval. In determining whether to issue an EUA, the FDA evaluates the totality of available evidence and carefully balances any known or potential risks with any known or potential benefits of the product for use during an emergency. Based on the FDA’s review of the totality of the scientific evidence available, the agency has determined that it is reasonable to believe that ACTEMRA may be effective in treating COVID-19 for the authorized population. And, when used to treat COVID-19 for the authorized population, the known and potential benefits of ACTEMRA outweigh the known and potential risks for the drug. There are no adequate, approved and available alternative treatments to ACTEMRA for the treatment of COVID-19 in hospitalized adults and pediatric patients (2 years of age or older) who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO.

Efficacy

The data supporting the ACTEMRA EUA are based on four clinical trials and included one randomized, controlled, open-label, platform trial [Randomised Evaluation of COVID-19 Therapy (RECOVERY)] and three randomized, double-blind, placebo-controlled trials (EMPACTA, COVACTA and REMDACTA) in hospitalized patients with severe COVID-19 pneumonia. Detailed information on these clinical trials can be found in the Fact Sheet for Health Care Providers linked below.

Safety

Common side effects of ACTEMRA observed in the COVID-19 trials include constipation, anxiety, diarrhea, insomnia, hypertension and nausea. Detailed information on the safety of ACTEMRA can be found in the Fact Sheet for Health Care Providers linked below.

Additional Information

The Fact Sheet for Health Care Providers provides essential information about using ACTEMRA in treating COVID-19 as authorized and is available at https://go.usa.gov/x6egU. A fact sheet for patients, parents, and caregivers is available at https://go.usa.gov/x6eg7 and contains information for understanding the potential risks and potential benefits of taking ACTEMRA, including side effects. Full Prescribing Information for ACTEMRA in available on Drugs@FDA and can be accessed at https://go.usa.gov/x6eg8.

The EUA authority allows FDA to help strengthen the nation’s public health protections against chemical, biological, radiological, and nuclear threats by facilitating the availability and use of medical countermeasures needed during public health emergencies. For additional information on the EUA authority and EUAs for COVID-19, please visit https://go.usa.gov/xs8x4.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.