Tocilizumab recipients are at increased risk for developing serious infections that may lead to hospitalization or death. Severe 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 tocilizumab. During and after treatment with tocilizumab, closely monitor all patients for the development of signs and symptoms of infection including the possible development of tuberculosis (TB) in patients who tested negative for latent TB infection before tocilizumab use. If a serious infection develops, interrupt tocilizumab until the infection is controlled. Carefully consider the risks and benefits of continued tocilizumab therapy in patients with chronic or recurrent infection. Infections of various types were reported during clinical trials with tocilizumab. In adults hospitalized with COVID-19, rates of infection and serious infection among those who received 8 mg/kg tocilizumab (n = 974) was 30% and 19%, respectively, as compared to 32% and 23%, respectively, in patients who received placebo (n = 483). Urinary tract infections were reported in 5% of tocilizumab treated patients and 4% of placebo patients. In rheumatoid arthritis patients, upper respiratory tract infection occurred in 7% of patients receiving tocilizumab 8 mg/kg, in 6% of those receiving tocilizumab 4 mg/kg plus DMARDs, and in 8% of patients who received tocilizumab 8 mg/kg plus DMARDs. Naso-pharyngitis was reported in 4% to 7% of patients, and bronchitis was reported in 3% to 4% of patients. The rate of serious infections in the adult tocilizumab 4 mg/kg plus DMARD group was 4.4 events per 100 patient-years, and in the 8 mg/kg plus DMARD group, the rate was 5.3 events per 100 patient-years. Among pediatric patients who received tocilizumab, the rate of serious infections was 11.5 per 100 patient-years for those with systemic juvenile idiopathic arthritis (JIA), 12.2 per 100 patient-years for those with polyarticular JIA and weight less than 30 kg, and 4 per 100 patient-years for those with polyarticular JIA and a weight of 30 kg or more. There is an overall higher incidence of infections in patients with giant cell arteritis (GCA) compared to those with rheumatoid arthritis. The rate of infection or serious infection was 200.2/9.7 events per 100 patient-years in the weekly tocilizumab group and 160.2/4.4 events per 100 patient-years in the tocilizumab every other week group compared to 156/4.2 events per 100 patient-years in the placebo group receiving a 26-week prednisone taper and 210.2/12.5 events per 100 patient-years in the placebo group receiving a 52-week prednisone taper. The rate of serious infections in a cardiovascular outcomes study was 4.5 per 100 patient-years with tocilizumab 8 mg/kg IV, with or without DMARDs, every 4 weeks compared to 3.2 per 100 patient-years with etanercept 50 mg subcutaneously, with or without DMARDs. During clinical trials for any indication, the most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, otitis media, and bacterial arthritis. Among opportunistic infections, tuberculosis (pulmonary or extrapulmonary disease), cryptococcus infection, aspergillosis, candidiasis, and pneumocystosis were reported with tocilizumab. Patients who presented with disseminated rather than localized disease and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in tocilizumab clinical studies. No cases of hepatitis B reactivation were observed in the trials; however, patients who screened positive for hepatitis were excluded.[38283]

Gastrointestinal perforation primarily as a complication of diverticulitis was reported in clinical trials. The overall rate of GI perforation with IV tocilizumab was 0.26 events per 100 patient years. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory drugs, corticosteroids, or methotrexate. The relative contribution of tocilizumab to the development of gastrointestinal perforations is unknown. Upper abdominal pain occurred in 2% of 288 patients who got tocilizumab 8 mg/kg, in 3% of 774 patients who got tocilizumab 4 mg/kg plus DMARDS, and in 3% of 1582 patients who got tocilizumab 8 mg/kg plus DMARDS. Gastritis occurred in 1% of 288 patients who got tocilizumab 8 mg/kg, in 1% of 774 patients who got tocilizumab 4 mg/kg plus DMARDS, and in 2% of 1582 patients who got tocilizumab 8 mg/kg plus DMARDS. Oral ulceration occurred in 2% of 288 patients who got tocilizumab 8 mg/kg, in 1% of 774 patients who got tocilizumab 4 mg/kg plus DMARDS, and in 2% of 1582 patients who got tocilizumab 8 mg/kg plus DMARDS. Use tocilizumab cautiously in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with fever, new onset abdominal symptoms, and changes in bowel habits for early identification of gastrointestinal perforation.[38283]

Tocilizumab may cause neutropenia, and patient's neutrophil counts need to be assessed before and during drug receipt. Pooled safety data from adults hospitalized with COVID-19, found 3.4% of patients who received 8 mg/kg tocilizumab (n = 974) had neutrophil counts below 1,000/mm³ as compared to 0.5% of patients who received placebo (n = 483). In the 6-month, controlled clinical studies for rheumatoid arthritis, decreases in neutrophil counts below 1,000/mm³ occurred in 1.8% of patients who received tocilizumab 4 mg/kg/dose and in 3.4% of patients who received tocilizumab 8 mg/kg/dose as compared with 0.1% of patients who received placebo. Decreases in neutrophil counts below 500/mm³ occurred in 0.4% of patients who received tocilizumab 4 mg/kg/dose and in 0.3% of patients who received tocilizumab 8 mg/kg/dose as compared with 0.1% of patients who received placebo. Approximately half of the instances of absolute neutrophil count (ANC) below 1,000/mm³ occurred within 8 weeks of starting tocilizumab. After subcutaneous tocilizumab receipt, 2.9% to 3.7% of tocilizumab recipients had a neutrophil count below 1,000/mm³. Among pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA), 3.7% receiving IV treatment and 15.4% receiving subcutaneous treatment had a neutrophil count below 1,000/mm³ whereas 7% of patients with systemic juvenile idiopathic arthritis (SJIA) did (vs. none in the placebo group). Of note, neutropenia was more frequently observed in patients weighing less than 30 kg (25.9%) than those weighing 30 kg or more (4%) in the subcutaneous administration group. Over an average duration of 73 weeks, a decreased neutrophil count occurred in 17% of tocilizumab recipients. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience, and no clear relationship between decreases in neutrophils below 1,000/mm³ and the occurrence of serious infections was noted. Among healthy patients who received tocilizumab 2 to 28 mg/kg/dose, the ANC nadir occurred 3 to 5 days after tocilizumab receipt. Neutrophils then recovered towards baseline in a dose dependent manner. A similar pattern of ANC after tocilizumab receipt was noted in patients with rheumatoid arthritis.[38283]

Tocilizumab may cause thrombocytopenia, and patient's platelet counts need to be assessed before and during drug receipt. Pooled safety data from adults hospitalized with COVID-19, found 3.2% of patients who received 8 mg/kg tocilizumab (n = 974) had platelet counts below 50,000/mm³ as compared to 1.5% of patients who received placebo (n = 483). In the 6-month, controlled clinical studies for rheumatoid arthritis, decreases in platelet counts below 100,000/mm³ occurred in 1.3% of patients who received tocilizumab 4 mg/kg and in 1.7% of patients who received tocilizumab 8 mg/kg as compared with 0.5% of patients who received placebo. Among patients with polyarticular juvenile idiopathic arthritis (PJIA), 1% had decreases in platelet count of 50,000/mm³ or less. Of patients with systemic juvenile idiopathic arthritis (SJIA), decreases in platelet count of no more than 100,000/mm³ were noted in 1% of tocilizumab recipients and in 3% of placebo recipients at the end of the 12-week control phase. Over an average duration of 73 weeks, 4% of tocilizumab recipients had a decreased platelet count. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials.[38283]

Serious cases of hepatotoxicity have been reported with intravenous and subcutaneous tocilizumab therapy; some of these cases resulted in hepatic failure, liver transplant, or death. A majority of the cases presented with elevated hepatic enzymes more than 5-times the upper limit of normal (ULN); however, other cases presented with mild elevations along with signs and symptoms of liver impairment. The time to onset ranged from weeks to years following initiation of tocilizumab therapy, with a median latency of 98 days. Hepatitis, drug-induced liver injury, and jaundice have been reported with postmarketing use of tocilizumab. Patients should have liver function tests (LFTs) monitored during tocilizumab treatment. Check LFTs before tocilizumab receipt, 4 to 8 weeks after the start of therapy for the first 6 months, and then every 3 months thereafter in adult patients. For pediatric patients with either polyarticular or systemic juvenile idiopathic arthritis (PJIA or SJIA), monitor LFTs at the time of the second infusion and then every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA.[38283] [65165] In the 6-month, controlled clinical studies for rheumatoid arthritis, 36% of patients who received tocilizumab 8 mg/kg monotherapy developed an ALT up to 3-times the ULN and 22% experienced AST levels up to 3-times the ULN. Increases in ALT greater than 3- to-5 times ULN occurred in 1%, and increases in ALT of more than 5-times ULN occurred in 0.7%. In a study of 1,538 patients with moderate to severe rheumatoid arthritis, 5.3% and 2.2% of patients developed ALT or AST elevations more than 3-times the ULN, respectively. In addition, one patient developed serious drug-induced hepatitis with hyperbilirubinemia. Increased frequency and magnitude of transaminase elevations were observed when potentially hepatotoxic drugs were used in combination with tocilizumab. For example, among 1,582 patients who received 8 mg/kg tocilizumab plus DMARDs, increases in ALT up to 3-times ULN, greater than 3- to 5-times the ULN, and greater than 5-times the ULN occurred in 48%, 5%, and 1.5% of patients, respectively. Modification of the treatment regimen, such as a reduction in the concomitant DMARD dose, tocilizumab interruption, or tocilizumab dose reduction resulted in a decrease or normalization of liver enzymes. Among pediatric patients with PJIA, 4% had ALT levels 3-times ULN or greater, and less than 1% had AST levels 3-times ULN or greater. Among patients with SJIA, 5% had ALT levels 3-times ULN or greater, and 3% had AST levels greater than 3-times ULN. Over an average duration of 73 weeks in the SJIA extension study, ALT levels 3-times ULN or higher were noted in 13%, and AST levels 3-times ULN or greater were noted in 5%. Among adult patients with rheumatoid arthritis, increases in ALT levels 3-times ULN or greater were noted in 6.5% of weekly subcutaneous tocilizumab recipients and in 3.4% of every other week recipients. In adults hospitalized with COVID-19, 11.7% of patients who received 8 mg/kg of tocilizumab (n = 974) and 9.9% of patients who received placebo (n = 483) had ALT or AST levels at or above 5-times the ULN. Of note, elevated ALT or AST levels may occur in patients hospitalized with COVID-19, and multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19.[38283]

Tocilizumab may cause hyperlipidemia and hypertriglyceridemia, and patient's lipid parameters need to be assessed during drug receipt. In clinical trials, lipid parameters were first assessed 6 weeks after tocilizumab initiation. Increases in total cholesterol, LDL, HDL, and triglycerides were noted at this time point, but the concentrations remained stable with continued tocilizumab receipt. Triglyceride concentrations greater than 500 mg/dL were rarely observed. In regard to hypercholesterolemia, the mean LDL increase from baseline to week 24 was 25 mg/dL among recipients of tocilizumab 8 mg/kg IV as monotherapy. The mean HDL increase was 4 mg/dL, and the mean LDL/HDL ratio increased by 0.26. ApoB/ApoA1 ratios were essentially unchanged, and elevated lipids responded to lipid-lowering agents. After SC tocilizumab for rheumatoid arthritis, sustained elevations in total cholesterol more than 240 mg/dL were noted in 19% of weekly tocilizumab recipients, in 19.6% of every other week tocilizumab recipients, and in 10.2% of placebo recipients. Among patients with systemic juvenile idiopathic arthritis, 1.5% of tocilizumab recipients had a total cholesterol concentration more than 1.5 to 2 times the upper limit of normal (ULN) as compared with none of the placebo recipients.  Assess lipid parameters approximately 4 to 8 weeks after tocilizumab initiation. Subsequently, it is recommended to manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.[38283]

Tocilizumab may increase the risk of a new primary malignancy. Tocilizumab is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of cancer. Malignancies were observed in clinical studies for rheumatoid arthritis, but the impact of tocilizumab receipt on the development of malignancies is not known. Over 6 months, 15 malignancies were diagnosed in tocilizumab IV recipients as compared with 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the tocilizumab groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years). In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24-week, controlled period.[38283]

Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), and hypersensitivity reactions have been reported during postmarketing use of tocilizumab. Postmarketing reports of anaphylaxis, anaphylactic shock, anaphylactoid reactions (such as angioedema), and death have occurred in patients receiving a range of intravenous (IV) tocilizumab doses, with or without concomitant arthritis therapies. These events have occurred in people with and without previous hypersensitivity reactions, in those who received premedication to tocilizumab, and have occurred as early as the first IV infusion. In clinical trials, anaphylaxis or hypersensitivity reactions requiring therapy discontinuation were generally observed during the second to fourth tocilizumab IV infusion , with an incidence of 0.1% to 0.2%. As a comparison, hypersensitivity reactions requiring treatment discontinuation were reported in 0.7% of patients in the subcutaneous tocilizumab clinical trials. For pediatric IV tocilizumab recipients, none of the 188 patients with polyarticular juvenile idiopathic arthritis and 0.9% of 112 patients with systemic juvenile idiopathic arthritis experienced hypersensitivity reactions that required treatment discontinuation. Six of 54 pediatric patients with systemic juvenile idiopathic arthritis (SJIA) developed a hypersensitivity reaction during or within 24 hours of tocilizumab IV; 3 of the reactions were considered serious and required treatment discontinuation. Examples of reactions that required treatment discontinuation include generalized erythema, rash, and urticaria. Infusion-related reactions, defined as events that occurred during or within 24 hours of tocilizumab IV infusion receipt, were noted in 4% to 20.2% of recipients and consisted of hypertension, headache, nausea, hypotension, dizziness, rash, pruritus, urticaria, diarrhea, epigastric discomfort, and arthralgia. In clinical trials of IV tocilizumab for rheumatoid arthritis, rash occurred in 2% to 4% of patients, dyspnea or cough in less than 2%, hypertension in 4% to 6%, headache in 5% to 7%, and dizziness in 2% to 3%. Consider the diagnosis of hypersensitivity or anaphylaxis in any patient who has an IV infusion reaction. Despite prompt medical intervention, one woman died within 24 hours of an anaphylactic event. She experienced lightheadedness and hypotension during her fourth tocilizumab infusion, which was stopped after her symptoms developed. During her fifth infusion 2 weeks later, she experienced dizziness and hypotension moments after the start of the infusion despite premedication with steroids and antihistamines. She became apneic and unresponsive before dying.[38283] [43101] [69541] [70425]

A mild to moderate injection site reaction (7.1% to 10%) including erythema, pruritus, pain, and hematoma has been noted with subcutaneous tocilizumab administration in adult patients. As a comparison, 2.4% to 4.1% of subcutaneous placebo recipients had a local reaction. A higher frequency of injection site reaction (28.8% to 41.2%) was observed in pediatric patients receiving subcutaneous tocilizumab. All reactions were mild in severity, but, in the polyarticular arthritis group, occurred more commonly in patients weighing 30 kg or more (44%) compared to those weighing less than 30 kg (14.8%). The majority of injection site reactions resolved without any treatment, and none necessitated drug discontinuation.[38283]

Tocilizumab may increase the risk of macrophage activation syndrome (hemophagocytic lymphohistiocytosis or MAS), which is a life-threatening disorder that may develop in patients with rheumatic conditions, especially systemic juvenile idiopathic arthritis (SJIA). Limited data from clinical development experience do not suggest that tocilizumab increases the incidence of MAS; during clinical trials for SJIA, 3 cases were observed in 112 patients who received tocilizumab. Two patients had tocilizumab receipt interrupted, and one patient had tocilizumab discontinued for MAS. All three received treatment, and the MAS resolved without sequelae. Of note, infection is a trigger for MAS, and tocilizumab is associated with an increased risk of serious infections. Be attentive to symptoms of infection or worsening arthritis symptoms; SJIA worsening is also a trigger for macrophage activation syndrome.[38283] [54707]

Antibody formation against tocilizumab occurred in 46 of 2,876 adult patients with rheumatoid arthritis (1.6%) who received IV tocilizumab; 5 of the 46 had an associated, medically significant hypersensitivity reaction that led to tocilizumab withdrawal. Thirty adult patients developed neutralizing antibodies to tocilizumab. In polyarticular juvenile idiopathic arthritis trials, 1 patient receiving IV tocilizumab and 3 patients receiving subcutaneous tocilizumab developed positive antibodies without developing a clinically significant hypersensitivity reaction. Of the 2 patients in the systemic juvenile idiopathic arthritis (SJIA) trials that developed positive antibodies, one patient experienced symptoms associated with an anaphylactic reaction (urticaria and angioedema) and the other developed macrophage activation syndrome; both patients discontinued therapy. After subcutaneous drug receipt, 0.9% of 1,454 adult patients with rheumatoid arthritis developed anti-tocilizumab antibodies, and all but 1 patient also developed neutralizing antibodies. The rate is consistent with previous IV experience, and no correlation of antibody development to adverse events or loss of clinical response was observed. In the systemic sclerosis-associated interstitial lung disease studies, 3 of the 169 patients (1.8%) developed antibodies of neutralizing potential; none of the patients experienced hypersensitivity reactions.[38283]

Pancreatitis has been reported with the postmarketing use of tocilizumab.[38283]

Multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in clinical studies of tocilizumab. Closely monitor patients for signs and symptoms potentially indicative of demyelinating disorders, such as optic neuritis or other visual impairment, peripheral neuropathy (numbness or tingling), or unusual fatigue or weakness.[38283]

Safety data are available from 974 hospitalized adults who received intravenous tocilizumab doses of 8 mg/kg (maximum dose of 800 mg) to treat COVID-19. Adverse events occurring in at least 3% of drug recipients included anxiety (4%), constipation (9%), diarrhea (4%), hypertension (4%), hypokalemia (4%), insomnia (4%), and nausea (3%).[38283] [66757]

Patients who receive tocilizumab are at increased risk for developing serious infections that may lead to hospitalization or death. Infections include active tuberculosis and invasive fungal infections including candidiasis, aspergillosis, and pneumocystis. Bacterial, viral, and other infections due to opportunistic pathogens have been reported. Most patients who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids. Cases of severe and disseminated strongyloidiasis have been reported following use of tocilizumab in combination with corticosteroids to treat patients with coronavirus disease 2019 (COVID-19). The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend administering ivermectin as prophylactic treatment before giving tocilizumab with a corticosteroid to patients from strongyloidiasis endemic areas.[65314] Patients with an invasive fungal infection may present with disseminated disease, and tuberculosis may present as pulmonary or extrapulmonary disease. Evaluate patients for tuberculosis risk factors before starting tocilizumab. Also, test patients for latent tuberculosis before and during tocilizumab therapy. In patients with COVID-19, testing for latent infection is not necessary prior to initiation of treatment with tocilizumab. Initiate treatment for latent infection before tocilizumab use. Consider anti-tuberculosis therapy prior to tocilizumab initiation for 2 patient groups: patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed and patients with a negative test for latent tuberculosis but with risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Carefully consider the risks and benefits of tocilizumab before initiating therapy in patients with chronic or recurrent infection, who have been exposed to tuberculosis, with a history of a serious or opportunistic infection, with underlying conditions that may predispose them to infection (e.g., patients with advanced or uncontrolled diabetes mellitus, human immunodeficiency virus (HIV) infection, or immunosuppression), or who have resided or traveled in areas of endemic tuberculosis or endemic mycoses. Tocilizumab initiation is not recommended for patients with an absolute neutrophil count (ANC) less than 2,000 cells/mm³, tocilizumab discontinuation is advised for an ANC less than 500 cells/mm³, and tocilizumab interruption is advised for an ANC between 500 cells/mm³ and 1,000 cells/mm³. For treatment of COVID-19, tocilizumab treatment is not recommended in patients with an ANC less than 1,000 cells/mm³, however, the NIH COVID-19 guidelines recommend caution if the ANC is less than 500 cells/mm³.[65314] Closely monitor patients for the development of signs and symptoms of infection during and after tocilizumab treatment; signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants. Consider the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to taking tocilizumab. Do not administer tocilizumab to a patient with an active infection, including localized infections. If a serious infection such as sepsis or influenza or an opportunistic infection develops, interrupt tocilizumab receipt until the infection is controlled. If a new infection develops during tocilizumab receipt, complete a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient.[38283]

Intravenous (IV) tocilizumab must be given by a health care professional with appropriate medical support to manage anaphylaxis. Serious hypersensitivity reactions, including anaphylactic events with fatal outcomes, have developed in patients receiving IV doses of tocilizumab, with and without concomitant therapies. These events have occurred in patients with and without previous hypersensitivity reactions, in IV tocilizumab recipients who received premedication, and have occurred as early as the first infusion. Serious rash, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), has also been reported in tocilizumab recipients with autoinflammatory conditions. If a hypersensitivity reaction occurs, immediately discontinue tocilizumab, treat promptly, and monitor until signs and symptoms resolve. For subcutaneous tocilizumab, instruct patients to seek immediate medical attention if signs of a hypersensitivity reaction develop.[38283] [69541] [70425]

For most indications, initiation of tocilizumab is not recommended for thrombocytopenia defined as a platelet count below 100,000 cells/mm³ or for neutropenia defined as an absolute neutrophil count (ANC) below 2,000 cells/mm³. For the treatment of COVID-19, it is recommended tocilizumab not be used in patients with an ANC less than 1,000 cells/mm³ or platelet count less than 50,000 cells/mm³; however, the National Institutes of Health (NIH) COVID-19 guidelines recommend caution in patients with an ANC less than 500 cells/mm³ or platelet count less than 50,000 cells/mm³.[65314] Thrombocytopenia and neutropenia have been noted with tocilizumab, and drug interruption or discontinuation may be needed. Check platelet count and ANC before tocilizumab receipt, 4 to 8 weeks after tocilizumab initiation, and every 3 months thereafter for adult patients. For pediatric patients with either polyarticular or systemic juvenile idiopathic arthritis (JIA), monitor neutrophils and platelets at the time of the second infusion and then every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. In patients with severe or life-threatening cytokine release syndrome (CRS) who also have cytopenias due to lymphodepleting chemotherapy or the CRS, consider the potential benefit of treating the CRS versus the risks of short-term treatment with tocilizumab.[38283]

Use tocilizumab with caution in patients with active hepatic disease or hepatic impairment. For treatment of COVID-19, it is recommended tocilizumab not be used if ALT or AST are greater than 10-times the upper limit of normal (ULN); however, the National Institutes of Health (NIH) COVID-19 guidelines recommend caution in patients with an ALT greater than 5-times the ULN.[65314] Patients hospitalized with COVID-19 may have elevated ALT or AST levels, and multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19. Consider the benefits and risk of treating COVID-19 with tocilizumab and monitor ALT and AST during treatment. For all other indications, initiation of tocilizumab is not recommended in patients who have ALT or AST above 1.5-times the ULN. Hepatotoxicity, including hepatic injury, hepatic failure, liver transplant, and death have been reported with tocilizumab therapy. Following tocilizumab initiation, the time to onset of hepatic injury ranged from months to years, and a majority of the patients presented with transaminases levels greater than 5-times the ULN. However, some patients had mild transaminase elevations along with signs and symptoms of liver impairment. Persistent hepatic enzyme elevations during therapy may require dose interruption or consideration of drug discontinuation, depending on the clinical abnormality and severity. Check liver function tests before tocilizumab receipt, 4 to 8 weeks after the start of therapy for the first 6 months, and then every 3 months after that in adult patients. For pediatric patients with either polyarticular or systemic juvenile idiopathic arthritis (JIA), monitor liver function tests at the time of the second infusion and then every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Liver function tests (LFTs) should also be measured in any patient displaying signs and symptoms of liver dysfunction, such as fatigue, anorexia, dark urine, jaundice, or right upper abdominal pain. If elevated LFTs are detected, then tocilizumab should be stopped and only restarted once liver enzymes have normalized and an alternative cause identified. In patients with severe or life-threatening cytokine release syndrome (CRS) who also have elevated hepatic enzymes due to lymphodepleting chemotherapy or the CRS, consider the potential benefit of treating the CRS versus the risks of short-term treatment with tocilizumab. The safety and efficacy of tocilizumab have not been studied in patients with positive hepatitis B virus (HBV) or hepatitis C virus (HCV) serology. Tocilizumab may cause HBV or HCV reactivation in patients who are HBV or HCV carriers, which may lead to hepatitis C or hepatitis B exacerbation. Consider evaluating patients at risk for HBV and HCV infection for prior evidence of infection before tocilizumab initiation. If tocilizumab is initiated in an HBV or HCV carrier, carefully monitor the patient for clinical and laboratory signs of active HBV or HCV infection.[38283]

Cautious use of tocilizumab may be warranted by patients with neurological disease such as preexisting or recent onset demyelinating disorders. The impact of tocilizumab on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in clinical studies. Closely monitor patients for signs and symptoms potentially indicative of demyelinating disorders.[38283]

Tocilizumab is an immunosuppressant and treatment with immunosuppressants may result in an increased risk of cancer. The impact of tocilizumab on the development of a new primary malignancy is unknown, but malignancies were observed in clinical studies. Consider the risks and benefits of tocilizumab before treatment initiation in patients with a history of neoplastic disease. Also, consider the risks and benefits of tocilizumab continuation in patients who develop a malignancy.[38283]

Gastrointestinal (GI) perforations and other GI adverse reactions have been reported in clinical studies of tocilizumab. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroid therapy. Promptly evaluate patients presenting with fever, new onset abdominal symptoms, and changes in bowel habits. Cautious tocilizumab use is warranted by patients with diverticulitis.[38283]

Cautious use of tocilizumab may be warranted for patients with hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia. Increased total cholesterol, increased HDL-C, increased LDL-C, and increased triglycerides may occur with tocilizumab. Assess lipid parameters approximately 4 to 8 weeks after tocilizumab initiation. Subsequently, it is recommended to manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.[38283]

Avoid use of live vaccines concurrently with tocilizumab as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. No data are available on the effectiveness of vaccination in patients receiving tocilizumab. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all treated patients, particularly pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating tocilizumab therapy. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.[38283]

In clinical trials for rheumatoid arthritis, the frequency of serious infections among geriatric patients was higher than younger adults. As there is a higher incidence of infections in the geriatric population in general, caution should be used when treating the elderly. Clinical studies for cytokine release syndrome did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. For COVID-19, no overall difference in safety or efficacy of tocilizumab were observed between patients 65 years and older and those under 65 years.[38283]

Available data from a pregnancy exposure registry, retrospective cohort study, pharmacovigilance, and published literature are not sufficient to determine whether the use of tocilizumab during human pregnancy is associated with a risk for major birth defects, miscarriages, or other adverse maternal or fetal outcomes. Animal reproduction studies indicate there may be a potential fetal risk. Intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis resulted in abortion/embryo-fetal death at doses 1.25-times or more of the maximum recommended human dose (MRHD). Monoclonal antibodies, like tocilizumab, are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. This may affect the immune response in the in utero exposed infant; consider risks and benefits before administering live or live-attenuated vaccines to neonates or infants exposed to tocilizumab in utero.[38283] Due to limited data during pregnancy, guidelines state that tocilizumab should be replaced before conception by another medication, if possible. The drug should be used during pregnancy only when no other pregnancy-compatible drug can effectively control the maternal disease.[62180] For COVID-19, the National Institutes of Health (NIH) states that the decision to administer tocilizumab to a pregnant patient must be shared between the patient and their healthcare providers, and that potential maternal benefit and fetal risks must be considered.[65314] Tocilizumab may affect labor and obstetric delivery. Inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity, leading to potential delays in parturition.[38283]

The lack of clinical data during lactation precludes clear determination of the risk of tocilizumab to the breast-feeding infant; therefore the developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for tocilizumab and the potential adverse effects on the breastfed child from exposure to the drug or the underlying maternal condition. There is no information available on the presence of tocilizumab in human milk or its effects on the breast-fed infant or milk production. Maternal immunoglobulin G (IgG) is present in human milk. If tocilizumab is transferred into human milk, the effects of local exposure in the gastrointestinal (GI) tract and potential limited systemic exposure in the infant to tocilizumab are unknown.[38283] Until more data are available, guidelines state that tocilizumab should generally be avoided during breast-feeding if another therapy is available to control the maternal disease. The drug has a large molecular weight, and experts suggest the oral bioavailability of any drug exposure to the infant through the GI tract is likely low. Breast-feeding should not be discouraged, however, when using the drug if no other options are available.[62180] For COVID-19, the National Institutes of Health (NIH) states that tocilizumab should be offered to lactating patients who qualify for therapy, and that breast-feeding can continue without interruption.[65314]

Tocilizumab is indicated in pediatric patients 2 years of age and older for the treatment of active systemic or polyarticular juvenile idiopathic arthritis (JIA) or cytokine release syndrome (CRS). The safety and efficacy of tocilizumab in infants and young children less than 2 years of age have not been established. It is recommended that all pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating tocilizumab therapy. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.[38283]

Patients who undergo surgery while taking biologic therapy, such as tocilizumab, may be at greater risk for postoperative infections. For elective surgeries, balance the risk of postoperative infection against the risk of developing a severe or unstable disease by stopping the biologic therapy. The American College of Rheumatology recommends holding tocilizumab for one full dosing interval before undergoing total knee or total hip arthroplasties.[71153]