Not Recommended for Concomitant Use with Biological DMARDs

Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection. Avoid using TOFIDENCE with biological DMARDs.

Baseline Laboratory Evaluation Prior to Treatment

Obtain and assess baseline complete blood count (CBC) and liver function tests prior to treatment.

• RA, GCA, PJIA and SJIA – It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm ³, platelet count below 100,000 per mm ³, or ALT or AST above 1.5 times the upper limit of normal (ULN) [see Warnings and Precautions (5.3, 5.4)] .
• COVID-19- It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 1000 per mm3 , platelet count below 50,000 mm3 , or ALT or AST above 10 times ULN [see Warnings and Precautions (5.3, 5.4)]

Recommended Intravenous Dosage Regimen:

The recommended dosage of TOFIDENCE for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.

• Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.1)].
• Doses exceeding 800 mg per infusion are not recommended in RA patients [see Clinical Pharmacology (12.3)].

When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Interruption of dose is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)and Warnings and Precautions (5.3, 5.4).

Recommended Intravenous Dosage Regimen:

The recommended dosage of TOFIDENCE for adult patients given as a 60-minute single intravenous drip infusion is 6 mg per kg every 4 weeks in combination with tapering course of glucocorticoids.

TOFIDENCE can be used alone following discontinuation of glucocorticoids.

• Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)].
• Doses exceeding 600 mg per infusion are not recommended in GCA patients [see Clinical Pharmacology (12.3)].

When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Recommended Intravenous Dosage Regimen:

The recommended dosage of TOFIDENCE for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is:

When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)].

Recommended Intravenous Dosage Regimen:

The recommended dose of TOFIDENCE for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is:

When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)].

Serious Infections

Hold TOFIDENCE treatment if a patient develops a serious infection until the infection is controlled.

Laboratory Abnormalities

COVID-19

In patients with COVID-19, monitor for signs and symptoms of new infections during and after treatment with TOFIDENCE. There is limited information regarding the use of tocilizumab products in patients with COVID-19 and concomitant active serious infections. The risks and benefits of treatment with TOFIDENCE in COVID-19 patients with other concurrent infections should be considered.

Tuberculosis

Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating TOFIDENCE. In patients with COVID-19, testing for latent infection is not necessary prior to initiating treatment with TOFIDENCE.

Consider anti-tuberculosis therapy prior to initiation of TOFIDENCE in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Closely monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating TOFIDENCE.

Viral Reactivation

Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with tocilizumab. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded.

Patients with Rheumatoid Arthritis, Giant Cell Arteritis and Coronavirus Disease 2019

Patients with Polyarticular and Systemic Juvenile Idiopathic Arthritis

A similar pattern of liver enzyme elevation, low neutrophil count, low platelet count and lipid elevations is noted with tocilizumab products treatment in the PJIA and SJIA populations. Monitor neutrophils, platelets, ALT and AST at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Monitor lipids as above for approved adult indications [see Dosage and Administration (2.8)].

Overall Infections

In the 24 week, controlled clinical studies, the rate of infections in the tocilizumab-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group was 133 and 127 events per 100 patient-years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis.

The overall rate of infections with tocilizumab-IV in the all exposure population remained consistent with rates in the controlled periods of the studies.

Serious Infections

In the 24 week, controlled clinical studies, the rate of serious infections in the tocilizumab-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group.

In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported [see Warnings and Precautions (5.1)].

In the cardiovascular outcomes Study WA25204, the rate of serious infections in the tocilizumab 8 mg/kg IV every 4 weeks group, with or without DMARD, was 4.5 per 100 patient-years, and the rate in the etanercept 50 mg weekly SC group, with or without DMARD, was 3.2 per 100 patient-years [see Clinical Studies (14.1)].

Gastrointestinal Perforations

During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with tocilizumab-IV therapy.

In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroids, or methotrexate [see Warnings and Precautions (5.2)]. The relative contribution of these concomitant medications versus tocilizumab-IV to the development of GI perforations is not known.

Infusion Reactions

In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria. These events were not treatment limiting.

Anaphylaxis

Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with tocilizumab-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of tocilizumab-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction [see Warnings and Precautions (5.6)].

Laboratory Abnormalities

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of tocilizumab or of other tocilizumab products.

In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies.

Malignancies

During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving tocilizumab-IV, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the tocilizumab-IV 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 [see Warnings and Precautions (5.5)].

Other Adverse Reactions

Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg tocilizumab-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2 .

Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with tocilizumab-IV in controlled trials were:

Infections and Infestations:oral herpes simplex
Gastrointestinal disorders:stomatitis, gastric ulcer
Investigations:weight increased, total bilirubin increased
Blood and lymphatic system disorders:leukopenia
General disorders and administration site conditions:edema peripheral
Respiratory, thoracic, and mediastinal disorders:dyspnea, cough
Eye disorders:conjunctivitis
Renal disorders:nephrolithiasis
Endocrine disorders:hypothyroidism

Infections

The rate of infections in the tocilizumab-IV all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (8%).

Infusion Reactions

In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the tocilizumab-IV all exposure population, 11 patients (6%) experienced an event during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and SJIA patients [see Adverse Reactions (6.1and 6.4)].

No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported.

Immunogenicity

One patient, in the 10 mg/kg less than 30 kg group, developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.

Laboratory Abnormalities

Infections

In the 12 week controlled phase, the rate of all infections in the tocilizumab-IV group was 345 per 100 patient-years and 287 per 100 patient-years in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years.

In the 12 week controlled phase, the rate of serious infections in the tocilizumab-IV group was 11.5 per 100 patient years. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 per 100 patient years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media.

Macrophage Activation Syndrome

In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with tocilizumab-IV. One patient in the placebo group escaped to tocilizumab-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had tocilizumab-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae. Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the tocilizumab-IV SJIA clinical development experience; however no definitive conclusions can be made.

Infusion Reactions

Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA. Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion. In the 12 week controlled phase, 4% of tocilizumab-IV and 0% of placebo treated patients experienced events occurring during infusion. One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment.

Within 24 hours after infusion, 16% of patients in the tocilizumab-IV treatment group and 5% of patients in the placebo group experienced an event. In the tocilizumab-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious.

Anaphylaxis

Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with tocilizumab-IV during the controlled and open label extension study [see Warnings and Precautions (5.6)].

Immunogenicity

All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti-tocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage activation syndrome while on escape therapy and was discontinued from the study.

Laboratory Abnormalities

Laboratory Abnormalities

In the pooled safety population of EMPACTA, COVACTA, and REMDACTA, neutrophil counts <1000 cells/mcl occurred in 3.4% of patients who received tocilizumab and 0.5% of patients who received placebo. Platelet counts <50,000 cells/mcl occurred in 3.2% of patients who received tocilizumab and 1.5% of patients who received placebo. ALT or AST at or above 5× ULN occurred in 11.7% of patients who received tocilizumab and 9.9% of patients who received placebo.

Risk Summary

The limited available data with tocilizumab products in pregnant women are not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies, such as tocilizumab products, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in uteroexposed infant [see Clinical Considerations]. In animal reproduction studies, intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at doses 1.25 times and higher than the maximum recommended human dose by the intravenous route of 8 mg per kg every 2 to 4 weeks. The literature in animals suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition [see Data]. Based on the animal data, there may be a potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Data

Risk Summary

No information is available on the presence of tocilizumab products in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal immunoglobulin G (IgG) is present in human milk. If tocilizumab products are transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to tocilizumab products are unknown.

The lack of clinical data during lactation precludes clear determination of the risk of tocilizumab products to an infant during lactation; therefore the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TOFIDENCE and the potential adverse effects on the breastfed child from Tofidence or from the underlying maternal condition.

Systemic Juvenile Idiopathic Arthritis – Intravenous Use

A multicenter, open-label, single arm study to evaluate the PK, safety and exploratory PD and efficacy of tocilizumab over 12-weeks in SJIA patients (N=11) under 2 years of age was conducted. Patients received intravenous tocilizumab 12 mg/kg every two weeks. Concurrent use of stable background treatment with corticosteroids, MTX, and/or non-steroidal anti-inflammatory drugs was permitted. Patients who completed the 12-week period could continue to the optional extension period (a total of 52-weeks or until the age of 2 years, whichever was longer).

The primary PK endpoints (C _max, C _troughand AUC _2weeks) of tocilizumab at steady-state in this study were within the ranges of these parameters observed in patients with SJIA aged 2 to 17 years.

The safety and immunogenicity of tocilizumab for patients with SJIA under 2 years of age was assessed descriptively. SAEs, AEs leading to discontinuation, and infectious AEs were reported by 27.3%, 36.4%, and 81.8% of patients. Six patients (54.5%) experienced hypersensitivity reactions, defined as all adverse events occurring during or within 24 hours after an infusion considered related to tocilizumab. Three of these patients experienced serious hypersensitivity reactions and were withdrawn from the study. Three patients with hypersensitivity reactions (two with serious hypersensitivity reactions) developed treatment induced anti-tocilizumab antibodies after the event. There were no cases of MAS based on the protocol-specified criteria, but 2 cases of suspected MAS based on Ravelli criteria Ravelli A, Minoia F, Davì S on behalf of the Paediatric Rheumatology International Trials Organisation, the Childhood Arthritis and Rheumatology Research Alliance, the Pediatric Rheumatology Collaborative Study Group, and the Histiocyte Society, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis. Annals of the Rheumatic Diseases 2016;75:481-489. .

Rheumatoid Arthritis - Intravenous Administration

The pharmacokinetics in healthy subjects and RA patients suggest that PK is similar between the two populations.

The population PK model was developed from an analysis dataset composed of an IV dataset of 1793 patients from Study I, Study III, Study IV, and Study V. C _meanis included in place of AUC _tau, since for dosing regimens with different inter-dose intervals, the mean concentration over the dosing period characterizes the comparative exposure better than AUC _tau.

At high serum concentrations, when total clearance of tocilizumab is dominated by linear clearance, a terminal half-life of approximately 21.5 days was derived from the population parameter estimates.

For doses of 4 mg/kg tocilizumab given every 4 weeks intravenously, the estimated median (range) C _max, C _trough, and C _meanof tocilizumab at steady state were 86.1 (44.8–202) mcg/mL, 0.1 (0.0–14.6) mcg/mL, and 18.0 (8.9–50.7) mcg/mL, respectively. For doses of 8 mg/kg tocilizumab given every 4 weeks intravenously, the estimated median (range) C _max, C _trough, and C _meanof tocilizumab were 176 (75.4–557) mcg/mL, 13.4 (0.1–154) mcg/mL, and 54.0 (17–260) mcg/mL, respectively. C _maxincreased dose-proportionally between doses of 4 and 8 mg/kg IV every 4 weeks, while a greater than dose-proportional increase was observed in C _meanand C _trough. At steady-state, C _meanand C _troughwere 3.0 and 134 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively.

The accumulation ratios for AUC and C _maxafter multiple doses of 4 and 8 mg/kg IV Q4W are low, while the accumulation ratios for C _troughare higher (2.62 and 2.47, respectively). For C _max, greater than 90% of the steady-state value was reached after the 1st IV infusion. For AUC _tauand C _mean, 90% of the steady-state value was reached after the 1st and 3rd infusion for 4 mg/kg and 8 mg/kg IV, while for C _trough, approximately 90% of the steady-state value was reached after the 4th IV infusion after both doses.

Population PK analysis identified body weight as a significant covariate impacting the pharmacokinetics of tocilizumab. When given IV on a mg/kg basis, individuals with body weight ≥ 100 kg are predicted to have mean steady-state exposures higher than mean values for the patient population. Therefore, tocilizumab doses exceeding 800 mg per infusion are not recommended in patients with RA [see Dosage and Administration (2.1)].

Giant Cell Arteritis – Intravenous Administration

The pharmacokinetics of tocilizumab IV in GCA patients was characterized by a non-compartmental pharmacokinetic analysis which included 22 patients treated with 6 mg/kg intravenously every 4 weeks for 20 weeks. The median (range) C _max, C _troughand C _meanof tocilizumab at steady state were 178 (115-320) mcg/mL, 22.7 (3.38-54.5) mcg/mL and 57.5 (32.9-110) mcg/mL, respectively. Steady state trough concentrations were within the range observed in GCA patients treated with tocilizumab by another route of administration.

Based on pharmacokinetic exposure and extrapolation between RA and GCA patients, when given IV on a mg/kg basis, tocilizumab doses exceeding 600 mg per infusion are not recommended in patients with GCA [see Dosage and Administration (2.3)].

Polyarticular Juvenile Idiopathic Arthritis – Intravenous Administration

The pharmacokinetics of tocilizumab (TCZ) in PJIA patients was characterized by a population pharmacokinetic analysis which included 188 patients who were treated with TCZ IV.

For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 4 weeks intravenously, the estimated median (range) C _max, C _trough, and C _meanof tocilizumab at steady state were 181 (114–331) mcg/mL, 3.28 (0.02–35.4) mcg/mL, and 38.6 (22.2–83.8) mcg/mL, respectively. For doses of 10 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 4 weeks intravenously, the estimated median (range) C _max, C _trough, and C _meanof tocilizumab were 167 (125–220) mcg/mL, 0.35 (0–11.8) mcg/mL, and 30.8 (16.0–48.0) mcg/mL, respectively.

The accumulation ratios were 1.05 and 1.16 for AUC _4weeks, and 1.43 and 2.22 for C _troughfor 10 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. No accumulation for C _maxwas observed. Following 10 mg/kg and 8 mg/kg TCZ IV every 4 weeks doses in PJIA patients (aged 2 to 17 years), steady state concentrations (trough and average) were within the range of exposures in adult RA patients following 4 mg/kg and 8 mg/kg every 4 weeks, and steady state peak concentrations in PJIA patients were comparable to those following 8 mg/kg every 4 weeks in adult RA patients.

Systemic Juvenile Idiopathic Arthritis—Intravenous Administration

The pharmacokinetics of tocilizumab (TCZ) in SJIA patients was characterized by a population pharmacokinetic analysis which included 89 patients who were treated with TCZ IV.

For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 2 weeks intravenously, the estimated median (range) C _max, C _trough, and C _meanof tocilizumab were 253 (120–404) mcg/mL, 70.7 (5.26–127) mcg/mL, and 117 (37.6–199) mcg/mL, respectively. For doses of 12 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 2 weeks intravenously, the estimated median (range) C _max, C _trough, and C _meanof tocilizumab were 274 (149–444) mcg/mL, 65.9 (19.0–135) mcg/mL, and 124 (60–194) mcg/mL, respectively.

The accumulation ratios were 1.95 and 2.01 for AUC4 _weeks, and 3.41 and 3.20 for C _troughfor 12 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. Accumulation data for C _maxwere 1.37 and 1.42 for 12 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. Following every other week dosing with tocilizumab IV, steady state was reached by 8 weeks for both body weight groups. Mean estimated tocilizumab exposure parameters were similar between the two dose groups defined by body weight.

COVID-19 -Intravenous Administration

The pharmacokinetics of tocilizumab in COVID-19 patients was characterized by a population pharmacokinetic analysis of a dataset composed of 380 adult patients treated with tocilizumab 8mg/kg intravenously (IV) in the COVACTA study [see Clinical Studies (14.5)] and another clinical study.

For one dose of 8 mg/kg tocilizumab IV, the estimated median (range) C _maxand C _day28of 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 tocilizumab IV separated by at least 8 hours, the estimated median (range) Cmax and Cday28 of tocilizumab was 290 (152-604) mcg/mL and 7.04 (0.00474-54.8) mcg/mL, respectively. The weight-tiered dosing used in RECOVERY study, 800 mg for patients >90 kg, 600 mg for patients >65 and ≤90 kg, 400 mg for patients >40 and ≤65 kg, and 8mg/kg for patients ≤40 kg, is comparable to 8 mg/kg dosing and is expected to have similar exposure.

Clinical Response

The percentages of intravenous tocilizumab-treated patients achieving ACR 20, 50 and 70 responses are shown in Table 4. In all intravenous studies, patients treated with 8 mg per kg tocilizumab had higher ACR 20, ACR 50, and ACR 70 response rates versus MTX- or placebo-treated patients at week 24.

During the 24 week controlled portions of Studies I to V, patients treated with tocilizumab at a dose of 4 mg per kg in patients with inadequate response to DMARDs or TNF antagonist therapy had lower response rates compared to patients treated with tocilizumab 8 mg per kg.

In study II, a greater proportion of patients treated with 4 mg per kg and 8 mg per kg tocilizumab + MTX achieved a low level of disease activity as measured by a DAS 28-ESR less than 2.6 compared with placebo +MTX treated patients at week 52. The proportion of tocilizumab-treated patients achieving DAS 28-ESR less than 2.6, and the number of residual active joints in these responders in Study II are shown in Table 5.

The results of the components of the ACR response criteria for Studies III and V are shown in Table 6. Similar results to Study III were observed in Studies I, II and IV.

The percent of ACR 20 responders by visit for Study III is shown in Figure 1. Similar response curves were observed in studies I, II, IV, and V.

Figure 1 Percent of ACR 20 Responders by Visit for Study III (Inadequate Response to MTX) The same patients may not have responded at each timepoint.

Figure 1

Radiographic Response

In Study II, structural joint damage was assessed radiographically and expressed as change in total Sharp-Genant score and its components, the erosion score and joint space narrowing score. Radiographs of hands/wrists and forefeet were obtained at baseline, 24 weeks, 52 weeks, and 104 weeks and scored by readers unaware of treatments group and visit number. The results from baseline to week 52 are shown in Table 7. tocilizumab 4 mg per kg slowed (less than 75% inhibition compared to the control group) and tocilizumab 8 mg per kg inhibited (at least 75% inhibition compared to the control group) the progression of structural damage compared to placebo plus MTX at week 52.

The mean change from baseline to week 104 in Total Sharp-Genant Score for the tocilizumab 4 mg per kg groups was 0.47 (SD = 1.47) and for the 8 mg per kg groups was 0.34 (SD = 1.24). By the week 104, most patients in the control (placebo + MTX) group had crossed over to active treatment, and results are therefore not included for comparison. Patients in the active groups may have crossed over to the alternate active dose group, and results are reported per original randomized dose group.

In the placebo group, 66% of patients experienced no radiographic progression (Total Sharp-Genant Score change ≤ 0) at week 52 compared to 78% and 83% in the tocilizumab 4 mg per kg and 8 mg per kg, respectively. Following 104 weeks of treatment, 75% and 83% of patients initially randomized to tocilizumab 4 mg per kg and 8 mg per kg, respectively, experienced no progression of structural damage compared to 66% of placebo treated patients.

Health Related Outcomes

In Study II, physical function and disability were assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI). Both dosing groups of tocilizumab demonstrated a greater improvement compared to the placebo group in the AUC of change from baseline in the HAQ-DI through week 52. The mean change from baseline to week 52 in HAQ-DI was 0.6, 0.5, and 0.4 for tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, and placebo treatment groups, respectively. Sixty-three percent (63%) and sixty percent (60%) of patients in the tocilizumab 8 mg per kg and tocilizumab 4 mg per kg treatment groups, respectively, achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) at week 52 compared to 53% in the placebo treatment group.

Cardiovascular Outcomes

Study WA25204 (NCT01331837) was a randomized, open-label (sponsor-blinded), 2-arm parallel-group, multi-center, non-inferiority, cardiovascular (CV) outcomes trial in patients with a diagnosis of moderate to severe RA. This CV safety study was designed to exclude a moderate increase in CV risk in patients treated with tocilizumab compared with a TNF inhibitor standard of care (etanercept).

The study included 3,080 seropositive RA patients with active disease and an inadequate response to non-biologic disease-modifying anti-rheumatic drugs, who were aged ≥50 years with at least one additional CV risk factor beyond RA. Patients were randomized 1:1 to IV tocilizumab 8 mg/kg Q4W or SC etanercept 50 mg QW and followed for an average of 3.2 years. The primary endpoint was the comparison of the time-to-first occurrence of any component of a composite of major adverse CV events (MACE; non-fatal myocardial infarction, non-fatal stroke, or CV death), with the final intent-to-treat analysis based on a total of 161 confirmed CV events (83/1538 [5.4%] for tocilizumab; 78/1542 [5.1%] for etanercept) reviewed by an independent and blinded adjudication committee.

Non-inferiority of tocilizumab to etanercept for cardiovascular risk was determined by excluding >80% relative increase in the risk of MACE. The estimated hazard ratio (HR) for the risk of MACE comparing tocilizumab to etanercept was 1.05; 95% CI (0.77, 1.43).

Systemic Features

Of patients with fever or rash at baseline, those treated with tocilizumab had fewer systemic features; 35 out of 41 (85%) became fever free (no temperature recording at or above 37.5°C in the preceding 14 days) compared to 5 out of 24 (21%) of placebo-treated patients, and 14 out of 22 (64%) became free of rash compared to 2 out of 18 (11%) of placebo-treated patients. Responses were consistent in the open label extension (data available through 44 weeks).

Corticosteroid Tapering

Of the patients receiving oral corticosteroids at baseline, 8 out of 31 (26%) placebo and 48 out of 70 (69%), tocilizumab patients achieved a JIA ACR 70 response at week 6 or 8 enabling corticosteroid dose reduction. Seventeen (24%) tocilizumab patients versus 1 (3%) placebo patient were able to reduce the dose of corticosteroid by at least 20% without experiencing a subsequent JIA ACR 30 flare or occurrence of systemic symptoms to week 12. In the open label portion of the study, by week 44, there were 44 out of 103 (43%) tocilizumab patients off oral corticosteroids. Of these 44 patients 50% were off corticosteroids 18 weeks or more.

Health Related Outcomes

Physical function and disability were assessed using the Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI). Seventy-seven percent (58 out of 75) of patients in the tocilizumab treatment group achieved a minimal clinically important improvement in CHAQ-DI (change from baseline of ≥ 0.13 units) at week 12 compared to 19% (7 out of 37) in the placebo treatment group.

RECOVERY (Randomised Evaluation of COVID-19 Therapy) Collaborative Group Study in Hospitalized Adults Diagnosed with COVID-19

RECOVERY was a randomized, controlled, open-label, multicenter platform study conducted in the United Kingdom to evaluate the efficacy and safety of potential treatments in hospitalized adult patients with severe COVID-19 pneumonia. Eligible patients for the tocilizumab portion of the study had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical contraindications to any of the treatments and had clinical evidence of progressive COVID-19 (defined as oxygen saturation <92% on room air or receiving oxygen therapy, and CRP ≥75 mg/L). Patients were then randomized to receive either standard of care (SoC) or intravenous tocilizumab at a weight-tiered dosing comparable to the recommended dosage [see Clinical Pharmacology (12.3)] in addition to SoC.

Efficacy analyses were performed in the intent-to-treat (ITT) population comprising 4116 adult patients who were randomized to the tocilizumab + SoC arm (n=2022) or to the SoC arm (n=2094). The mean age of participants was 64 years (range: 20 to 101), and patients were 67% male, 76% White, 11% Asian, 3% Black or African American, and 1% mixed race. At baseline, 0.2% of patients were not on supplemental oxygen, 45% of patients required low flow oxygen, 41% of patients required non-invasive ventilation or high-flow oxygen, and 14% of patients required invasive mechanical ventilation; 82% of patients were reported to be receiving systemic corticosteroids.

The primary efficacy endpoint was time to death through Day 28. The results for the overall population and the subgroups of patients who were or were not receiving systemic corticosteroids at time of randomization are summarized in Table 9.

EMPACTA

EMPACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous tocilizumab 8 mg/kg in combination with SoC in hospitalized, non-ventilated adult patients with COVID-19 pneumonia. Eligible patients were at least 18 years of age, had confirmed SARS-CoV-2 infection by a positive reverse-transcriptase polymerase chain reaction (RT-PCR) result, had pneumonia confirmed by radiography, and had SpO2 < 94% on ambient air.

Of the 389 patients randomized, efficacy analyses were performed in the modified intent-to-treat (mITT) population comprising 377 patients who were randomized and received study medication (249 in the tocilizumab arm; 128 in the placebo arm). The mean age of participants was 56 years (range: 20 to 95); 59% of patients were male, 56% were of Hispanic or Latino ethnicity, 53% were White, 20% were American Indian/Alaska Native, 15% were Black/African American and 2% were Asian. At baseline, 9% patients were not on supplemental oxygen, 64% patients required low flow oxygen, 27% patients required high-flow oxygen, and 73% were on corticosteroids.

The primary efficacy endpoint evaluated time to progression to mechanical ventilation or death through Day 28. The hazard ratio comparing tocilizumab to placebo was 0.56 (95% CI, 0.33 to 0.97), a statistically significant result (log-rank, p-value = 0.036). The cumulative proportion of patients who required mechanical ventilation or died by Day 28 was 12.0% (95% CI, 8.5% to 16.9%) in the tocilizumab arm and 19.3% (95% CI, 13.3% to 27.4%) in the placebo arm.

Mortality at Day 28 was 10.4% in the tocilizumab arm versus 8.6% in the placebo arm (weighted difference (tocilizumab arm - placebo arm): 2.0% [95% CI, -5.2% to 7.8%]).

COVACTA

COVACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous tocilizumab 8 mg/kg in combination with SoC for the treatment of adult patients hospitalized with severe COVID-19 pneumonia. The study randomized 452 patients who were at least 18 years of age with confirmed SARS-CoV-2 infection by a positive RT-PCR result, had pneumonia confirmed by radiography, and had oxygen saturation of 93% or lower on ambient air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mmHg or less. At baseline, 3% of patients were not on supplemental oxygen, 28% were on low flow oxygen, 30% were on non-invasive ventilation or high flow oxygen, 38% were on invasive mechanical ventilation, and 22% were on corticosteroids. The primary efficacy endpoint was clinical status on Day 28 assessed on a 7-category ordinal scale that ranged from "discharged" to "death." There were no statistically significant differences observed in the distributions of clinical status on the 7-category ordinal scale at Day 28 when comparing the tocilizumab arm to the placebo arm.

Mortality at Day 28 was 19.7% in the tocilizumab arm versus 19.4% in the placebo arm (weighted difference (tocilizumab arm - placebo arm): 0.3% [95% CI, -7.6 to 8.2]).

REMDACTA

REMDACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous tocilizumab 8 mg/kg in combination with intravenous remdesivir (RDV) 200 mg on Day 1 followed by 100 mg once daily for a total of 10 days in hospitalized patients with severe COVID-19 pneumonia. The study randomized 649 adult patients with SARS-CoV-2 infection confirmed by a positive polymerase chain reaction (PCR) result, pneumonia confirmed by radiography, and who required supplemental oxygen > 6 L/min to maintain SpO2 >93%. At baseline, 7% of patients were on low flow oxygen, 80% were on non-invasive ventilation or high flow oxygen, 14% were on invasive mechanical ventilation, and 84% were on corticosteroids.

The primary efficacy endpoint was time from randomization to hospital discharge or 'ready for discharge' up to Day 28. There was no statistically significant difference between the treatment arms with respect to time to hospital discharge or "ready for discharge" through Day 28.

Mortality at Day 28 was 18.1% in the tocilizumab + RDV arm versus 19.5% in the placebo +RDV arm (weighted difference (tocilizumab arm - placebo arm): -1.3% [95% CI, -7.8% to 5.2%]).

Mortality Across Studies in Patients Receiving Baseline Corticosteroids

A study-level meta-analysis was conducted on EMPACTA, COVACTA, REMDACTA and RECOVERY studies. For each of the four studies, the risk difference through Day 28 was estimated by the Kaplan-Meier method in the subgroup of patients receiving baseline corticosteroids, summarized in Figure 2. Patients from the RECOVERY trial represent 78.8% of the total sample size in this meta-analysis. The combined risk difference showed that tocilizumab treatment (n=2261) resulted in a 4.61% absolute reduction in the risk of death at Day 28 (risk difference=-4.6%; 95% CI: -7.3% to -1.9%) compared to SoC (n=2034).

Figure 2 Risk Differences Through Day 28 for Baseline Corticosteroid Use Subpopulation in RECOVERY, EMPACTA, COVACTA and REMDACTA studies

Figure 2