Skip To Main Content

Adverse reactions from clinical studies 1

The adverse reaction rates observed in the clinical studies of ACTEMRA used to suppport this Emergency Use Authorization cannot be directly compared to rates in the clinical studies of ACTEMRA for FDA-approved indications and may not reflect the rates observed in clinical practice.

The safety evaluation of ACTEMRA in COVID-19 was based on 4 clinical trials. These included one randomized, controlled, open-label, platform trial [Randomised Evaluation of COVID-19 Therapy (RECOVERY)] and 3 randomized, double-blind, placebo controlled trials (EMPACTA, COVACTA, and REMDACTA). Safety data from RECOVERY is not provided here as collection of adverse event data was limited. In EMPACTA, COVACTA, and REMDACTA, a total of 974 patients were exposed to ACTEMRA. Patients in EMPACTA, COVACTA, and REMDACTA received a single, 60-minute infusion of intravenous ACTEMRA 8 mg/kg (maximum dose of 800 mg). If clinical signs or symptoms worsened or did not improve, one additional dose of ACTEMRA 8 mg/kg could be administered between 8–24 hours after the initial dose.

EMPACTA (NCT04372186) was a global, Phase 3, randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of intravenous ACTEMRA in combination with standard of care (SoC) in hospitalized adult patients with COVID-19 pneumonia. The safety analysis was based on 250 patients in the ACTEMRA arm and 127 patients in the placebo arm.

During the study, there were 29 (12%) deaths in the ACTEMRA arm and 15 (12%) in the placebo arm. Serious adverse events occurred in 38 (15%) patients in the ACTEMRA arm and 25 (20%) in the placebo arm. Serious infections occurred in 13 (5%) patients in the ACTEMRA arm and 9 (7%) in the placebo arm. Adverse reactions occurring in at least 3% of patients in the ACTEMRA arm and more commonly than observed in the placebo arm are summarized in Table 1.

Table 1. Adverse reactions occurring in at least 3% of patients in the ACTEMRA arm and more commonly than observed in the placebo arm through Day 60a

a Patients are counted once for each category regardless of the number of reactions

COVACTA (NCT04320615) was a global, Phase 3, randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of intravenous ACTEMRA in combination with standard of care (SoC) in adult patients hospitalized with COVID-19 pneumonia. The safety analysis was based on 295 patients in the ACTEMRA arm and 143 patients in the placebo arm.

During the study, there were 72 (24%) deaths in the ACTEMRA arm and 36 (25%) in the placebo arm. Serious adverse events occurred in 116 (39%) patients in the ACTEMRA arm and 64 (45%) in the placebo arm. Serious infections occurred in 71 (24%) patients in the ACTEMRA arm and 42 (29%) in the placebo arm. Adverse reactions occurring in at least 3% of patients in the ACTEMRA arm and more commonly than observed in the placebo arm are summarized in Table 2.

Table 2. Adverse reactions occurring in at least 3% of patients in the ACTEMRA arm and more commonly than observed in the placebo arm through Day 60a

REMDACTA (NCT04409262) was a global, Phase 3, randomized, double-blind, placebo-controlled, multicenter study conducted to assess the efficacy and safety of intravenous ACTEMRA in combination with remdesivir (RDV) compared with matching placebo in combination with RDV in hospitalized patients with COVID-19 pneumonia; only adult patients enrolled. The safety analysis was based on 429 patients in the ACTEMRA + RDV arm and 213 patients in the placebo + RDV arm.

During the study, there were 98 (23%) deaths in the ACTEMRA + RDV arm and 55 (26%) deaths in the placebo +RDV arm. Serious adverse events occurred in 141 (33%) patients in the ACTEMRA + RDV arm and 76 (36%) in the placebo + RDV arm. Serious infections occurred in 97 (23%) patients in the ACTEMRA + RDV arm and 59 (28%) in the placebo + RDV arm. Adverse reactions occurring in at least 3% of patients in the ACTEMRA + RDV arm and more commonly than observed in the placebo + RDV arm are summarized in Table 3.

Table 3. Adverse reactions occurring in at least 3% of patients in the ACTEMRA + RDV arm and more commonly than observed in the placebo + RDV Arm through Day 60a

a Patients are counted once for each category regardless of the number of reactions
RDV=remdesivir

The most common adverse reactions (≥3%) reported in ACTEMRA-treated patients and at least 1% more commonly than in the placebo arm from the pooled safety-evaluable population from the Phase 3, randomized, double-blind, studies EMPACTA, COVACTA, and REMDACTA were constipation, anxiety, diarrhea, insomnia, hypertension, and nausea.

Refer to Section 6 Adverse Reactions of the FDA-approved Prescribing Information for additional information on adverse reactions associated with chronic use of ACTEMRA.

AUTHORIZED USE

ACTEMRA is authorized for use under an Emergency Use Authorization (EUA) for the treatment of coronavirus disease 2019 (COVID-19) in 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 FDA-approved for this use.

ACTEMRA is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of ACTEMRA under section 564(b)(1) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

ACTEMRA is contraindicated in patients with known hypersensitivity to ACTEMRA.

WARNINGS AND PRECAUTIONS

Serious Infections

In COVID-19 patients, ACTEMRA should not be administered if patients have any other concurrent active infection, including localized infection.

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including ACTEMRA. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, and bacterial arthritis. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with ACTEMRA. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis).

The risks and benefits of treatment should be considered prior to initiating ACTEMRA in patients with chronic or recurrent infection, or who have a history of a serious or an opportunistic infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with ACTEMRA, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants.

A patient who develops a new infection during treatment with ACTEMRA should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient; initiate appropriate antimicrobial therapy, and closely monitor the patient.

Gastrointestinal Perforations

Events of gastrointestinal perforation have been reported in clinical trials for chronic indications, primarily as complications of diverticulitis, in patients treated with ACTEMRA. Use ACTEMRA with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation.

Hepatotoxicity

Patients hospitalized with COVID-19 may have elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels. Multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19.

During randomized, controlled studies, treatment with ACTEMRA was associated with a higher incidence of transaminase elevations. Serious cases of hepatic injury have been observed in patients taking intravenous or subcutaneous ACTEMRA chronically. In this setting, the time to onset for cases ranged from months to years after treatment initiation with ACTEMRA.

The decision to administer ACTEMRA should balance the potential benefit against the risks of acute treatment with ACTEMRA. ACTEMRA is not recommended in COVID-19 patients with elevated ALT or AST above 10 times the upper limit of the reference range. When ACTEMRA is used for treatment of COVID-19, ALT and AST should be monitored according to current standard clinical practice.

Laboratory Parameters

In randomized, controlled trials, patients receiving ACTEMRA had higher rates of neutropenia, thrombocytopenia, and elevations of ALT or AST.

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.

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have been reported in association with ACTEMRA and anaphylactic events with a fatal outcome have been reported with intravenous infusion of ACTEMRA. These events have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of ACTEMRA. ACTEMRA for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of ACTEMRA immediately and discontinue ACTEMRA permanently. Do not administer ACTEMRA to patients with known hypersensitivity to ACTEMRA.

Demyelinating Disorders

The impact of treatment with ACTEMRA on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in rheumatoid arthritis clinical studies. Monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of ACTEMRA in patients with preexisting or recent onset demyelinating disorders.

Active Hepatic Disease and Hepatic Impairment

ACTEMRA is not recommended in patients with active hepatic disease or hepatic impairment.

Vaccinations

Avoid use of live vaccines concurrently with ACTEMRA as clinical safety has not been established. The interval between live vaccinations and initiation of ACTEMRA therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ACTEMRA.

No data are available on the effectiveness of vaccination in patients receiving ACTEMRA.

MOST COMMON ADVERSE REACTIONS

Most common adverse reactions (incidence ≥3%) are constipation, anxiety, diarrhea, insomnia, hypertension, and nausea.

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

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ACTEMRA during pregnancy. Healthcare providers are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.

The limited available data with ACTEMRA in pregnant women are not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage. ACTEMRA should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.

Lactation

No information is available on the presence of tocilizumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.

You or your designee must report all SERIOUS ADVERSE EVENTS or MEDICATION ERRORS potentially related to ACTEMRA (1) by submitting FDA Form 3500 online, (2) by downloading this form and then submitting by mail or fax, or (3) contacting the FDA at 1-800-FDA-1088 to request this form. Please also provide a copy of this form to Genentech at [email protected] or call 1-888-835-2555.

Please see additional information in Fact Sheet for Healthcare Providers Fact Sheet for Patients and Parents/Caregivers , and FDA Letter of Authorization .

Please see additional Important Safety Information in full Prescribing Information , including BOXED WARNING and other risks associated with chronic use of ACTEMRA.

As a healthcare practitioner, you must communicate to the patient and/or caregiver information consistent with the Fact Sheet for Patients and Parents/Caregivers  and provide them with a copy of this Fact Sheet prior to administration of ACTEMRA. However, if providing this information will delay the administration of ACTEMRA to a degree that would endanger the life of a patient, the information must be provided to the parent and/or caregiver as soon as feasible after ACTEMRA administration.