What is mechanism of action?

mechanism of action is Interleukin 6 Receptor Antagonists [MoA]

Tocilizumab-anoh

(Tocilizumab)

Check Drug InteractionsCheck known drug interactions.

Tocilizumab-Anoh Prescribing Information

Patients treated with tocilizumab products including Tocilizumab-anoh are at increased risk for developing serious infections that may lead to hospitalization or death

[see

5.1 Serious Infections

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 tocilizumab products. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis

[see Adverse Reactions (6.1)]

. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with tocilizumab products. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections.

Do not administer Tocilizumab-anoh in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating Tocilizumab-anoh in patients:

with chronic or recurrent infection;
who have been exposed to tuberculosis;
with a history of serious or an opportunistic infection;
who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
with underlying conditions that may predispose them to infection.

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

[see Dosage and Administration (2.6), Adverse Reactions (6.1), and Patient Counseling Information (17)]

Hold Tocilizumab-anoh if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with Tocilizumab-anoh should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient.

COVID-19

In patients with COVID-19, monitor for signs and symptoms of new infections during and after treatment with Tocilizumab-anoh. 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 Tocilizumab-anoh 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 Tocilizumab-anoh. In patients with COVID-19, testing for latent infection is not necessary prior to initiating treatment with Tocilizumab-anoh.

Consider anti-tuberculosis therapy prior to initiation of Tocilizumab-anoh 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 Tocilizumab-anoh.

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.

6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV)

The tocilizumab-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of tocilizumab-IV 8 mg per kg monotherapy (288 patients), tocilizumab- IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or tocilizumab-IV 4 mg per kg in combination with methotrexate (774 patients).

The all exposure population includes all patients in registration studies who received at least one dose of tocilizumab-IV. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years.

All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian.

The most common serious adverse reactions were serious infections

[see Warnings and Precautions (5.1)]

. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with tocilizumab-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.

The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking tocilizumab-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of tocilizumab-IV were increased hepatic transaminase values (per protocol requirement) and serious infections.

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

Neutropenia

In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm³occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm³occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm³occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm³and the occurrence of serious infections.

In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies

[see Warnings and Precautions (5.4)]

Thrombocytopenia

In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm³occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events.

In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies

[see Warnings and Precautions (5.4)]

Elevated Liver Enzymes

Liver enzyme abnormalities are summarized in

Table 1

. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of tocilizumab-IV, or reduction in tocilizumab-IV dose, resulted in decrease or normalization of liver enzymes

[see Dosage and Administration (2.10)]

. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency

[see Warnings and Precautions (5.3, 5.4)]

Table 1 Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to VFor a description of these studies, see Section 14, Clinical Studies.
	Tocilizumab 8 mg per kg MONOTHERAPY	Methotrexate	Tocilizumab 4 mg per kg + DMARDs	Tocilizumab 8 mg per kg + DMARDs	Placebo + DMARDs
	N = 288 (%)	N = 284 (%)	N = 774 (%)	N = 1582 (%)	N = 1170 (%)
ULN = Upper Limit of Normal
AST (U/L)
> ULN to 3× ULN	22	26	34	41	17
> 3× ULN to 5× ULN	0.3	2	1	2	0.3
> 5× ULN	0.7	0.4	0.1	0.2	< 0.1
ALT (U/L)
> ULN to 3× ULN	36	33	45	48	23
> 3× ULN to 5× ULN	1	4	5	5	1
> 5× ULN	0.7	1	1.3	1.5	0.3

In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials.

In Study WA25204, of the 1538 patients with moderate to severe RA

[see Clinical Studies (14.1)]

and treated with tocilizumab, elevations in ALT or AST >3 × ULN occurred in 5.3% and 2.2% patients, respectively. One serious event of drug induced hepatitis with hyperbilirubinemia was reported in association with tocilizumab.

Lipids

Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of tocilizumab-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below:

–Mean LDL increased by 13 mg per dL in the tocilizumab 4 mg per kg+DMARD arm, 20 mg per dL in the tocilizumab 8 mg per kg+DMARD, and 25 mg per dL in tocilizumab 8 mg per kg monotherapy.–Mean HDL increased by 3 mg per dL in the tocilizumab 4 mg per kg+DMARD arm, 5 mg per dL in the tocilizumab 8 mg per kg+DMARD, and 4 mg per dL in tocilizumab 8 mg per kg monotherapy.–Mean LDL/HDL ratio increased by an average of 0.14 in the tocilizumab 4 mg per kg+DMARD arm, 0.15 in the tocilizumab 8 mg per kg+DMARD, and 0.26 in tocilizumab 8 mg per kg monotherapy.–ApoB/ApoA1 ratios were essentially unchanged in tocilizumab-treated patients.

Elevated lipids responded to lipid lowering agents.

In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials.

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.

Table 2 Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg per kg Tocilizumab plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD
24 Week Phase 3 Controlled Study Population
	Tocilizumab 8 mg per kg MONOTHERAPY	Methotrexate	Tocilizumab 4 mg per kg + DMARDs	Tocilizumab 8 mg per kg + DMARDs	Placebo + DMARDs
Preferred Term	N = 288 (%)	N = 284 (%)	N = 774 (%)	N = 1582 (%)	N = 1170 (%)
Upper Respiratory Tract Infection	7	5	6	8	6
Nasopharyngitis	7	6	4	6	4
Headache	7	2	6	5	3
Hypertension	6	2	4	4	3
ALT increased	6	4	3	3	1
Dizziness	3	1	2	3	2
Bronchitis	3	2	4	3	3
Rash	2	1	4	3	1
Mouth Ulceration	2	2	1	2	1
Abdominal Pain Upper	2	2	3	3	2
Gastritis	1	2	1	2	1
Transaminase increased	1	5	2	2	1

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

]

. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt Tocilizumab-anoh until the infection is controlled. Reported infections include:

Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients, except those with COVID-19, should be tested for latent tuberculosis before Tocilizumab-anoh use and during therapy. Treatment for latent infection should be initiated prior to Tocilizumab-anoh use.
Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
Bacterial, viral and other infections due to opportunistic pathogens.

The risks and benefits of treatment with Tocilizumab-anoh should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Tocilizumab-anoh, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy

[see

5.1 Serious Infections

[see Adverse Reactions (6.1)]

with chronic or recurrent infection;
who have been exposed to tuberculosis;
with a history of serious or an opportunistic infection;
who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
with underlying conditions that may predispose them to infection.

[see Dosage and Administration (2.6), Adverse Reactions (6.1), and Patient Counseling Information (17)]

COVID-19

Tuberculosis

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.

Viral Reactivation

]

Indications and Usage (

1.5 Cytokine Release Syndrome (CRS)

Tocilizumab-anoh is indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome in adults and pediatric patients 2 years of age and older.

) 07/2025

Dosage and Administration (

2.1 General Considerations for Administration

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 Tocilizumab-anoh 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 Tocilizumab-anoh not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm³, platelet count below 100,000 per mm³, or ALT or AST above 1.5 times the upper limit of normal (ULN)
[see Warnings and Precautions (5.3, 5.4)]
.
CRS -
Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or AST due to the lymphodepleting chemotherapy or the CRS. The decision to administer Tocilizumab-anoh should take in to account the potential benefit of treating the CRS versus the risks of short-term treatment with Tocilizumab-anoh.
COVID-19
– It is recommended that Tocilizumab-anoh 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)]
.

2.6 Recommended Dosage for Cytokine Release Syndrome (CRS)

Use only the intravenous route for treatment of CRS. The recommended dose of Tocilizumab-anoh for treatment of CRS given as a 60-minute intravenous infusion is:

Recommended Intravenous Dosage Regimen:

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

Recommended Intravenous CRS Dosage
Patients less than 30 kg weight	12 mg per kg
Patients at or above 30 kg weight	8 mg per kg
Alone or in combination with corticosteroids

• If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, up to 3 additional doses of Tocilizumab-anoh may be administered. The interval between consecutive doses should be at least 8 hours.

• Doses exceeding 800 mg per infusion are not recommended in CRS patients.

• Subcutaneous administration is not approved for CRS.

) 07/2025

Tocilizumab-anoh is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of:

Rheumatoid Arthritis (RA) (

1.1 Rheumatoid Arthritis (RA)

Tocilizumab-anoh is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

)

Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

Giant Cell Arteritis (GCA) (

1.2 Giant Cell Arteritis (GCA)

Tocilizumab-anoh is indicated for the treatment of giant cell arteritis (GCA) in adult patients.

)

Adult patients with giant cell arteritis.

Polyarticular Juvenile Idiopathic Arthritis (PJIA) (

1.3 Polyarticular Juvenile Idiopathic Arthritis (PJIA)

Tocilizumab-anoh is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.

)

Patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis.

Systemic Juvenile Idiopathic Arthritis (SJIA) (

1.4 Systemic Juvenile Idiopathic Arthritis (SJIA)

Tocilizumab-anoh is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older.

)

Patients 2 years of age and older with active systemic juvenile idiopathic arthritis.

Cytokine Release Syndrome (CRS)

(

1.5 Cytokine Release Syndrome (CRS)

)

Adults and pediatric patients with 2 years of age and older with chimeric antigen receptor (CAR) T-cell-induced severe or life-threatening cytokine release syndrome.

Coronavirus Disease 2019 (COVID-19) (

1.6 Coronavirus Disease 2019 (COVID-19)

Tocilizumab-anoh is indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adult patients who are receiving systemic corticosteroids and require supplemental oxygen, non- invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

)

Hospitalized adult patients with coronavirus disease 2019 (COVID-19) who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

For RA, pJIA and sJIA, Tocilizumab-anoh may be used alone or in combination with methotrexate: and in RA, other non-biologic DMARDs may be used. (

2 DOSAGE AND ADMINISTRATION

For RA, pJIA and sJIA, Tocilizumab-anoh may be used alone or in combination with methotrexate: and in RA, other non-biologic DMARDs may be used.

General Administration and Dosing Information

RA, GCA, PJIA and SJIA
It is recommended that Tocilizumab-anoh not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm³, platelet count below 100,000 per mm³, or ALT or AST above 1.5 times the upper limit of normal (ULN)
.
COVID-19
It is recommended that Tocilizumab-anohnot 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
.
In
RA, CRS, or COVID-19
patients, Tocilizumab-anohdoses exceeding 800 mg per infusion are not recommended.
In
GCA
patients, Tocilizumab-anohdoses exceeding 600 mg per infusion are not recommended.

Rheumatoid Arthritis

(

2.2)

Recommended Adult Intravenous Dosage:

When used in combination with non-biologic DMARDs or as monotherapy the recommended starting dose is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.

Recommended Adult Subcutaneous Dosage:

Patients less than 100 kg weight	162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response
Patients at or above 100 kg weight	162 mg administered subcutaneously every week

Giant Cell Arteritis

Recommended Adult Intravenous Dosage:

The recommended dose is 6 mg per kg every 4 weeks in combination with a tapering course of glucocorticoids. Tocilizumab-anohcan be used alone following discontinuation of glucocorticoids.

Recommended Adult Subcutaneous Dosage:

The recommended dose is 162 mg given once every week as a subcutaneous injection, in combination with a tapering course of glucocorticoids.

A dose of 162 mg given once every other week as a subcutaneous injection, in combination with a tapering course of glucocorticoids, may be prescribed based on clinical considerations.

Tocilizumab-anoh can be used alone following discontinuation of glucocorticoids.

Polyarticular Juvenile Idiopathic Arthritis

Recommended Intravenous PJIA Dosage Every 4 Weeks
Patients less than 30 kg weight	10 mg per kg
Patients at or above 30 kg weight	8 mg per kg

Recommended Subcutaneous PJIA Dosage
Patients less than 30 kg weight	162 mg once every three weeks
Patients at or above 30 kg weight	162 mg once every two weeks

Systemic Juvenile Idiopathic Arthritis

Recommended Intravenous SJIA Dosage Every 2 Weeks
Patients less than 30 kg weight	12 mg per kg
Patients at or above 30 kg weight	8 mg per kg

Recommended Subcutaneous SJIA Dosage
Patients less than 30 kg weight	162 mg every two weeks
Patients at or above 30 kg weight	162 mg every week

Cytokine Release Syndrome (

2.6

)

Recommened Intravenous CRS Dosage
Patients less than 30 kg weight	12 mg per kg
Patients at or above 30 kg weight	8 mg per kg
Alone or in combination with corticosteroids

Coronavirus Disease 2019

The recommended dosage of Tocilizumab-anohfor adult patients with COVID-19 is 8 mg per kg administered by a 60-minute intravenous infusion.

Administration of Intravenous Formulation

For patients with RA, GCA, COVID-19, CRS, PJIA, and SJIA patients at or above 30 kg, dilute to 100 mL in 0.9% or 0.45% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique.
For PJIA, CRS and SJIA patients less than 30 kg, dilute to 50 mL in 0.9% or 0.45% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique.
Administer as a single intravenous drip infusion over 1 hour; do not administer as bolus or push.

Administration of Subcutaneous Formulation

Follow the Instructions for Use for prefilled syringe and prefilled autoinjector

Dose Modifications

Recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.

2.1 General Considerations for Administration

Not Recommended for Concomitant Use 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 Tocilizumab-anoh not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm³, platelet count below 100,000 per mm³, or ALT or AST above 1.5 times the upper limit of normal (ULN)
[see Warnings and Precautions (5.3, 5.4)]
.
CRS -
Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or AST due to the lymphodepleting chemotherapy or the CRS. The decision to administer Tocilizumab-anoh should take in to account the potential benefit of treating the CRS versus the risks of short-term treatment with Tocilizumab-anoh.
COVID-19
– It is recommended that Tocilizumab-anoh 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)]
.

2.2 Recommended Dosage for Rheumatoid Arthritis

Tocilizumab-anoh may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion or as a subcutaneous injection.

Recommended Intravenous Dosage Regimen:

The recommended dosage of Tocilizumab-anoh 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 (2.9), 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)]
.

Recommended Subcutaneous Dosage Regimen:

Patients less than 100 kg weight	162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response
Patients at or above 100 kg weight	162 mg administered subcutaneously every week

When transitioning from Tocilizumab-anoh intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia

[see Dosage and Administration (2.9), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.2)].

2.3 Recommended Dosage for Giant Cell Arteritis

Recommended Intravenous Dosage Regimen:

The recommended dosage of Tocilizumab-anoh 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.

Tocilizumab-anoh 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 (2.9)]
.
Doses exceeding 600 mg per infusion are not recommended in GCA patients
[see Clinical Pharmacology (12.3)].

Recommended Subcutaneous Dosage Regimen:

The recommended dose of Tocilizumab-anoh for adult patients with GCA is 162 mg given once every week as a subcutaneous injection in combination with a tapering course of glucocorticoids.

A dose of 162 mg given once every other week as a subcutaneous injection in combination with a tapering course of glucocorticoids may be prescribed based on clinical considerations.

Tocilizumab-anoh can be used alone following discontinuation of glucocorticoids.

When transitioning from Tocilizumab-anoh intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia

[see Dosage and Administration (2.9)].

2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis

Tocilizumab-anoh may be used as an intravenous infusion or as a subcutaneous injection alone or in combination with methotrexate. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate.

Recommended Intravenous Dosage Regimen:

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

Recommended Intravenous PJIA Dosage Every 4 Weeks
Patients less than 30 kg weight	10 mg per kg
Patients at or above 30 kg weight	8 mg per kg

Recommended Subcutaneous Dosage Regimen:

Recommended Subcutaneous PJIA Dosage
Patients less than 30 kg weight	162 mg once every 3 weeks
Patients at or above 30 kg weight	162 mg once every 2 weeks

When transitioning from Tocilizumab-anoh intravenous therapy to subcutaneous administration, 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 (2.9]

2.5 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis

Tocilizumab-anoh may be used as an intravenous infusion or as a subcutaneous injection alone or in combination with methotrexate. Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate.

Recommended Intravenous Dosage Regimen:

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

Recommended Intravenous SJIA Dosage Every 2 weeks
Patients less than 30 kg weight	162 mg per kg
Patients at or above 30 kg weight	8 mg per kg

Recommended Subcutaneous Dosage Regimen:

Recommended Subcutaneous SJIA Dosage
Patients less than 30 kg weight	162 mg once every two weeks
Patients at or above 30 kg weight	162 mg once every week

When transitioning from Tocilizumab-anoh intravenous therapy to subcutaneous administration, administer the first subcutaneous dose when the next scheduled intravenous dose is due.

Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia

[see Dosage and Administration (2.9)]

2.6 Recommended Dosage for Cytokine Release Syndrome (CRS)

Use only the intravenous route for treatment of CRS. The recommended dose of Tocilizumab-anoh for treatment of CRS given as a 60-minute intravenous infusion is:

Recommended Intravenous Dosage Regimen:

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

Recommended Intravenous CRS Dosage
Patients less than 30 kg weight	12 mg per kg
Patients at or above 30 kg weight	8 mg per kg
Alone or in combination with corticosteroids

2.7 Coronavirus Disease 2019 (COVID-19)

Administer Tocilizumab-anoh by intravenous infusion only.

The recommended dosage of Tocilizumab-anoh for treatment of adult patients with COVID-19 is 8 mg per kg administered as a single 60-minute intravenous infusion. If clinical signs or symptoms worsen or do not improve after the first dose, one additional infusion of Tocilizumab-anoh may be administered at least 8 hours after the initial infusion.

Doses exceeding 800 mg per infusion are not recommended in patients with COVID-19.
Subcutaneous administration is not approved for COVID-19.

2.8 Preparation and Administration Instructions for Intravenous Infusion

Tocilizumab-anoh for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows:

Use a sterile needle and syringe to prepare Tocilizumab-anoh.
Patients
less than 30 kg
: use a
50 mL
infusion bag or bottle of 0.9% or 0.45% Sodium Chloride Injection, USP, and then follow steps 1 and 2 below.
Patients
at or above 30 kg weight
: use a
100 mL
infusion bag or bottle, and then follow steps 1 and 2 below.
Step 1. Withdraw a volume of 0.9% or 0.45% Sodium Chloride Injection, USP, equal to the volume of the Tocilizumab-anoh injection required for the patient's dose from the infusion bag or bottle
[see Dosage and Administration (2.2, 2.4, 2.5, 2.6)]
.

For Intravenous Use: Volume of Tocilizumab-anoh Injection per kg of Body Weight
Dosage	Indication	Volume of Tocilizumab-anoh injection per kg of body weight
4 mg/kg	Adult RA	0.2 mL/kg
6 mg/kg	Adult GCA	0.3 mL/kg
8 mg/kg	Adult RA Adult COVID-19 SJIA,PJIA and CRS (greater than or equal to 30 kg of body weight)	0.4 mL/kg
10 mg/kg	PJIA (less than 30 kg of body weight)	0.5 mL/kg
12 mg/kg	SJIA and CRS (less than 30 kg of body weight)	0.6 mL/kg

Step 2. Withdraw the amount of Tocilizumab-anoh for intravenous infusion from the vial(s) and add slowly into the 0.9% or 0.45% Sodium Chloride Injection, USP infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming.
The fully diluted Tocilizumab-anoh solutions for infusion using 0.9% Sodium Chloride Injection, USP may be stored at 36°F to 46°F (2°C to 8°C) for up to 48 hours or room temperature up to 86°F (30°C) for up to 4 hours and should be protected from light.
The fully diluted Tocilizumab-anoh solutions for infusion using 0.45% Sodium Chloride Injection, USP may be stored at 36°F to 46°F (2°C to 8°C) for up to 48 hours or room temperature up to 86°F (30°C) for up to 4 hours and should be protected from light.
Tocilizumab-anoh solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used.
Allow the fully diluted Tocilizumab-anoh solution to reach room temperature prior to infusion.
The infusion should be administered over 60 minutes, and must be administered with an infusion set. Do not administer as an intravenous push or bolus.
Tocilizumab-anoh should not be infused concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of Tocilizumab-anoh with other drugs.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulates and discolorations are noted, the product should not be used.
Fully diluted Tocilizumab-anoh solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and polypropylene, polyethylene and glass infusion bottles.

2.9 Preparation and Administration Instructions for Subcutaneous Injection

Tocilizumab-anoh for subcutaneous injection is not intended for intravenous drip infusion.

Assess suitability of patient for subcutaneous home use and instruct patients to inform a healthcare professional before administering the next dose if they experience any symptoms of allergic reaction. Patients should seek immediate medical attention if they develop symptoms of serious allergic reactions. Tocilizumab-anoh subcutaneous injection is intended for use under the guidance of a healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject Tocilizumab-anoh or the patient's caregiver may administer Tocilizumab-anoh if a healthcare practitioner determines that it is appropriate. PJIA and SJIA patients may self-inject with the Tocilizumab-anoh prefilled syringe or prefilled autoinjector, or the patient's caregiver may administer Tocilizumab-anoh if both the healthcare practitioner and the parent/legal guardian determines it is appropriate
[see Use in Specific Populations (8.4)]
. Patients, or patient caregivers, should be instructed to follow the directions provided in the Instructions for Use (IFU) for additional details on medication administration.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use Tocilizumab-anoh prefilled syringes (PFS) or prefilled autoinjector (AI) exhibiting particulate matter, cloudiness, or discoloration. Tocilizumab-anoh for subcutaneous administration should be clear to slightly opalescent and colorless to yellow. Do not use if any part of the PFS or AI appears to be damaged.
Patients using Tocilizumab-anoh for subcutaneous administration should be instructed to inject the full amount in the syringe (0.9 mL) or full amount in the autoinjector (0.9 mL), which provides 162 mg of Tocilizumab-anoh, according to the directions provided in the IFU.
Injection sites should be rotated with each injection and should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

2.10 Dosage Modifications due to Serious Infections or Laboratory Abnormalities

Serious Infections

Hold Tocilizumab-anoh treatment if a patient develops a serious infection until the infection is controlled.

Laboratory Abnormalities

Rheumatoid Arthritis and Giant Cell Arteritis

Liver Enzyme Abnormalities [see Warnings and Precautions (5.3, 5.4)]
Lab Value	Recommendation for RA	Recommendation for GCA
Greater than 1 to 3× ULN	Dose modify concomitant DMARDs if appropriate For persistent increases in this range: For patients receiving intravenous Tocilizumab-anoh, reduce dose to 4 mg per kg or hold Tocilizumab-anoh until ALT or AST have normalized For patients receiving subcutaneous Tocilizumab-anoh, reduce injection frequency to every other week or hold dosing until ALT or AST have normalized. Resume Tocilizumab-anoh at every other week and increase frequency to every week as clinically appropriate.	Dose modify immunomodulatory agents if appropriate For persistent increases in this range: For patients receiving intravenous Tocilizumab-anoh, hold Tocilizumab-anoh until ALT or AST have normalized For patients receiving subcutaneous Tocilizumab-anoh, reduce injection frequency to every other week or hold dosing until ALT or AST have normalized. Resume Tocilizumab-anoh at every other week and increase frequency to every week as clinically appropriate.
Greater than 3 to 5× ULN (confirmed by repeat testing)	Hold Tocilizumab-anoh dosing until less than 3× ULN and follow recommendations above for greater than 1 to 3× ULN For persistent increases greater than 3× ULN, discontinue Tocilizumab-anoh	Hold Tocilizumab-anoh dosing until less than 3× ULN and follow recommendations above for greater than 1 to 3× ULN For persistent increases greater than 3× ULN, discontinue Tocilizumab-anoh
Greater than 5× ULN	Discontinue Tocilizumab-anoh	Discontinue Tocilizumab-anoh

Low Absolute Neutrophil Count (ANC) [see Warnings and Precautions (5.4)]
Lab Value (cells per mm³)	Recommendation for RA	Recommendation for GCA
ANC greater than 1000	Maintain dose	Maintain dose
ANC 500 to 1000	Hold Tocilizumab-anoh dosing When ANC greater than 1000 cells per mm³: For patients receiving intravenous Tocilizumab-anoh, resume Tocilizumab-anoh at 4 mg per kg and increase to 8 mg per kg as clinically appropriate For patients receiving subcutaneous Tocilizumab-anoh, resume Tocilizumab-anoh at every other week and increase frequency to every week as clinically appropriate	Hold Tocilizumab-anoh dosing When ANC greater than 1000 cells per mm³: For patients receiving intravenous Tocilizumab-anoh, resume Tocilizumab-anoh at 6 mg per kg For patients receiving subcutaneous Tocilizumab-anoh, resume Tocilizumab-anoh at every other week and increase frequency to every week as clinically appropriate
ANC less than 500	Discontinue Tocilizumab-anoh	Discontinue Tocilizumab-anoh

Low Platelet Count [see Warnings and Precautions (5.4)]
Lab Value (cells per mm³)	Recommendation for RA	Recommendation for GCA
50,000 to 100,000	Hold Tocilizumab-anoh dosing When platelet count is greater than 100,000 cells per mm³: For patients receiving intravenous Tocilizumab-anoh, resume Tocilizumab-anoh at 4 mg per kg and increase to 8 mg per kg as clinically appropriate For patients receiving subcutaneous Tocilizumab-anoh, resume Tocilizumab-anoh at every other week and increase frequency to every week as clinically appropriate	Hold Tocilizumab-anoh dosing When platelet count is greater than 100,000 cells per mm³: For patients receiving intravenous Tocilizumab-anoh, resume Tocilizumab-anoh at 6 mg per kg For patients receiving subcutaneous Tocilizumab-anoh, resume Tocilizumab-anoh at every other week and increase frequency to every week as clinically appropriate
Less than 50,000	Discontinue Tocilizumab-anoh	Discontinue Tocilizumab-anoh

Polyarticular and Systemic Juvenile Idiopathic Arthritis

Dose reduction of tocilizumab products has not been studied in the PJIA and SJIA populations. Dose interruptions of Tocilizumab-anoh are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with PJIA and SJIA at levels similar to what is outlined above for patients with RA and GCA. If appropriate, dose modify or stop concomitant methotrexate and/or other medications and hold Tocilizumab-anoh dosing until the clinical situation has been evaluated. In PJIA and SJIA the decision to discontinue Tocilizumab-anoh for a laboratory abnormality should be based upon the medical assessment of the individual patient.

)

General Administration and Dosing Information (

2.1 General Considerations for Administration

Not Recommended for Concomitant Use 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 Tocilizumab-anoh not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm³, platelet count below 100,000 per mm³, or ALT or AST above 1.5 times the upper limit of normal (ULN)
[see Warnings and Precautions (5.3, 5.4)]
.
CRS -
Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or AST due to the lymphodepleting chemotherapy or the CRS. The decision to administer Tocilizumab-anoh should take in to account the potential benefit of treating the CRS versus the risks of short-term treatment with Tocilizumab-anoh.
COVID-19
– It is recommended that Tocilizumab-anoh 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)]
.

)

RA, GCA, PJIA and SJIA
It is recommended that Tocilizumab-anoh not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm³, platelet count below 100,000 per mm³, or ALT or AST above 1.5 times the upper limit of normal (ULN)
(
5.3 Hepatotoxicity
Serious cases of hepatic injury have been observed in patients taking intravenous or subcutaneous tocilizumab products. Some of these cases have resulted in liver transplant or death. Time to onset for cases ranged from months to years after treatment initiation with tocilizumab products. While most cases presented with marked elevations of transaminases (> 5 times ULN), some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases.
During randomized controlled studies, treatment with tocilizumab was associated with a higher incidence of transaminase elevations
[see Adverse Reactions (6.1, 6.2, 6.5, 6.7)].
Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with tocilizumab.
For RA and GCA patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating Tocilizumab-anoh, every 4 to 8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter. It is not recommended to initiate Tocilizumab-anoh treatment in RA or GCA patients with elevated transaminases ALT or AST greater than 1.5× ULN. In patients who develop elevated ALT or AST greater than 5× ULN, discontinue Tocilizumab-anoh. For recommended modifications based upon increase in transaminases
see Dosage and Administration (2.10)
.
Patients hospitalized with COVID-19 may have elevated ALT or AST levels. Multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19. The decision to administer Tocilizumab-anoh should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with Tocilizumab-anoh. It is not recommended to initiate Tocilizumab-anoh treatment in COVID-19 patients with elevated ALT or AST above 10 × ULN. Monitor ALT and AST during treatment.
Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (e.g., ALT greater than three times the upper limit of the reference range, serum total bilirubin greater than two times the upper limit of the reference range), Tocilizumab-anoh treatment should be interrupted and investigation done to establish the probable cause. Tocilizumab-anoh should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests.
A similar pattern of liver enzyme elevation is noted with tocilizumab products treatment in the PJIA and SJIA populations. Monitor liver test panel at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA.
,
5.4 Changes in Laboratory Parameters
Patients with Rheumatoid Arthritis, Giant Cell Arteritis and Coronavirus Disease 2019
Neutropenia
Treatment with tocilizumab products was associated with a higher incidence of neutropenia. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience.
-It is not recommended to initiate Tocilizumab-anoh treatment in RA and GCA patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm
³
. In patients who develop an absolute neutrophil count less than 500 per mm
³
treatment is not recommended.–Monitor neutrophils 4 to 8 weeks after start of therapy and every 3 months thereafter
[see Clinical Pharmacology (12.2)]
. For recommended modifications based on ANC results
see Dosage and Administration (2.10)
.–It is not recommended to initiate Tocilizumab-anoh treatment in COVID-19 patients with an ANC less than 1000 per mm
³
. Neutrophils should be monitored.
Thrombocytopenia
Treatment with tocilizumab products was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials
[see Adverse Reactions (6.1, 6.2)]
.
–It is not recommended to initiate Tocilizumab-anoh treatment in RA and GCA patients with a platelet count below 100,000 per mm³. In patients who develop a platelet count less than 50,000 per mm³treatment is not recommended.
–Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on platelet counts
see Dosage and Administration (2.9)
.
–In COVID-19 patients with a platelet count less than 50,000 per mm³, treatment is not recommended. Platelets should be monitored.
Elevated Liver Enzymes
Refer to 5.3Hepatotoxicity. For recommended modifications
[see Dosage and Administration (2.10)]
Lipid Abnormalities
Treatment with tocilizumab products was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol
[see Adverse Reactions (6.1, 6.2)]
.
–Assess lipid parameters approximately 4 to 8 weeks following initiation of Tocilizumab-anoh therapy.
–Subsequently, manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.
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 (2.10)]
.
)
.
COVID-19
It is recommended that Tocilizumab-anohnot 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
(
5.3 Hepatotoxicity
Serious cases of hepatic injury have been observed in patients taking intravenous or subcutaneous tocilizumab products. Some of these cases have resulted in liver transplant or death. Time to onset for cases ranged from months to years after treatment initiation with tocilizumab products. While most cases presented with marked elevations of transaminases (> 5 times ULN), some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases.
During randomized controlled studies, treatment with tocilizumab was associated with a higher incidence of transaminase elevations
[see Adverse Reactions (6.1, 6.2, 6.5, 6.7)].
Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with tocilizumab.
For RA and GCA patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating Tocilizumab-anoh, every 4 to 8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter. It is not recommended to initiate Tocilizumab-anoh treatment in RA or GCA patients with elevated transaminases ALT or AST greater than 1.5× ULN. In patients who develop elevated ALT or AST greater than 5× ULN, discontinue Tocilizumab-anoh. For recommended modifications based upon increase in transaminases
see Dosage and Administration (2.10)
.
Patients hospitalized with COVID-19 may have elevated ALT or AST levels. Multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19. The decision to administer Tocilizumab-anoh should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with Tocilizumab-anoh. It is not recommended to initiate Tocilizumab-anoh treatment in COVID-19 patients with elevated ALT or AST above 10 × ULN. Monitor ALT and AST during treatment.
Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (e.g., ALT greater than three times the upper limit of the reference range, serum total bilirubin greater than two times the upper limit of the reference range), Tocilizumab-anoh treatment should be interrupted and investigation done to establish the probable cause. Tocilizumab-anoh should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests.
A similar pattern of liver enzyme elevation is noted with tocilizumab products treatment in the PJIA and SJIA populations. Monitor liver test panel at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA.
,
5.4 Changes in Laboratory Parameters
Patients with Rheumatoid Arthritis, Giant Cell Arteritis and Coronavirus Disease 2019
Neutropenia
Treatment with tocilizumab products was associated with a higher incidence of neutropenia. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience.
-It is not recommended to initiate Tocilizumab-anoh treatment in RA and GCA patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm
³
. In patients who develop an absolute neutrophil count less than 500 per mm
³
treatment is not recommended.–Monitor neutrophils 4 to 8 weeks after start of therapy and every 3 months thereafter
[see Clinical Pharmacology (12.2)]
. For recommended modifications based on ANC results
see Dosage and Administration (2.10)
.–It is not recommended to initiate Tocilizumab-anoh treatment in COVID-19 patients with an ANC less than 1000 per mm
³
. Neutrophils should be monitored.
Thrombocytopenia
Treatment with tocilizumab products was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials
[see Adverse Reactions (6.1, 6.2)]
.
–It is not recommended to initiate Tocilizumab-anoh treatment in RA and GCA patients with a platelet count below 100,000 per mm³. In patients who develop a platelet count less than 50,000 per mm³treatment is not recommended.
–Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on platelet counts
see Dosage and Administration (2.9)
.
–In COVID-19 patients with a platelet count less than 50,000 per mm³, treatment is not recommended. Platelets should be monitored.
Elevated Liver Enzymes
Refer to 5.3Hepatotoxicity. For recommended modifications
[see Dosage and Administration (2.10)]
Lipid Abnormalities
Treatment with tocilizumab products was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol
[see Adverse Reactions (6.1, 6.2)]
.
–Assess lipid parameters approximately 4 to 8 weeks following initiation of Tocilizumab-anoh therapy.
–Subsequently, manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.
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 (2.10)]
.
)
.

RA, CRS, or COVID-19

patients, Tocilizumab-anohdoses exceeding 800 mg per infusion are not recommended. (

2.2 Recommended Dosage for Rheumatoid Arthritis

Tocilizumab-anoh may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion or as a subcutaneous injection.

Recommended Intravenous Dosage Regimen:

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 (2.9), 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)]
.

Recommended Subcutaneous Dosage Regimen:

Patients less than 100 kg weight	162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response
Patients at or above 100 kg weight	162 mg administered subcutaneously every week

When transitioning from Tocilizumab-anoh intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

[see Dosage and Administration (2.9), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.2)].

2.7 Coronavirus Disease 2019 (COVID-19)

Administer Tocilizumab-anoh by intravenous infusion only.

Doses exceeding 800 mg per infusion are not recommended in patients with COVID-19.
Subcutaneous administration is not approved for COVID-19.

12.3 Pharmacokinetics

PK of tocilizumab is characterized by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination. The nonlinear part of tocilizumab elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time. Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.

Rheumatoid Arthritis - Intravenous and Subcutaneous 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, and from an IV and SC dataset of 1759 patients from Studies SC- I and SC-II. C_meanis included in place of AUCtau, since for dosing regimens with different inter-dose intervals, the mean concentration over the dosing period characterizes the comparative exposure better than AUCtau.

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 AUCtau and 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.

For doses of 162 mg given every other week subcutaneously, the estimated median (range) steady-state C_max, C_trough, and C_meanof tocilizumab were 12.1 (0.4–49.3) mcg/mL, 4.1 (0.0–34.2) mcg/mL, and 9.2 (0.2– 43.6) mcg/mL, respectively.

For doses of 162 mg given every week subcutaneously, the estimated median (range) steady-state C_max, C_trough, and C_meanof tocilizumab were 49.8 (3–150) mcg/mL, 42.9 (1.3–144) mcg/mL, and 47.3 (2.4–147) mcg/mL, respectively. Exposures after the 162 mg SC QW regimen were greater by 5.1 (C_mean) to 10.5 fold (C_trough) compared to the 162 mg SC Q2W regimen.

Accumulation ratios after multiple doses of either SC regimen were higher than after IV regimen with the highest ratios for C_trough(6.02 and 6.30, for 162 mg SC Q2W and 162 mg SC QW, respectively). The higher accumulation for C_troughwas expected based on the nonlinear clearance contribution at lower concentrations. For C_max, greater than 90% of the steady-state value was reached after the 5th SC and the 12th SC injection with the Q2W and QW regimens, respectively. For AUCtau and C_mean, 90% of the steady-state value was reached after the 6th and 12th injections for the 162 mg SC Q2W and QW regimens, respectively. For C_trough, approximately 90% of the steady- state value was reached after the 6th and 12th injections for the 162 mg SC Q2W and QW regimens, respectively.

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 (2.2)]

. Due to the flat dosing employed for SC administration of tocilizumab, no modifications are necessary by this dosing route.

Giant Cell Arteritis – Subcutaneous and Intravenous Administration

The pharmacokinetics of tocilizumab SC in GCA patients was determined using a population pharmacokinetic analysis on a dataset composed of 149 GCA patients treated with 162 mg subcutaneously every week or with 162 mg subcutaneously every other week.

For the 162 mg every week dose, the estimated median (range) steady-state C_max, C_troughand C_meanof tocilizumab SC were 72.1 (12.2–151) mcg/mL, 67.2 (10.7–145) mcg/mL, and 70.6 (11.7–149) mcg/mL, respectively. The accumulation ratios for C_meanor AUCtau, C_trough, and C_maxwere 10.9, 9.6, and 8.9, respectively. Steady state was reached after 17 weeks. For the 162 mg every other week dose, the estimated median (range) steady-state C_max, C_trough, and C_meanof tocilizumab were 17.2 (1.1–56.2) mcg/mL, 7.7 (0.1–37.3) mcg/mL, and 13.7 (0.5– 49) mcg/mL, respectively. The accumulation ratios for C_meanor AUCtau, C_trough, and C_maxwere 2.8, 5.6, and 2.3 respectively. Steady-state was reached after 14 weeks.

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 162 mg TCZ SC administered every week or every other week.

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 and Subcutaneous 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 or 52 patients treated with TCZ SC.

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.

For doses of 162 mg tocilizumab (patients with a body weight at or above 30 kg) given every 2 weeks subcutaneously, the estimated median (range) C_max, C_trough, and C_meanof tocilizumab were 29.7 (7.56– 50.3) mcg/mL, 12.7 (0.19–23.8) mcg/mL, and 23.0 (3.86–36.9) mcg/mL, respectively. For doses of 162 mg tocilizumab (patients with a body weight less than 30 kg) given every 3 weeks subcutaneously, the estimated median (range) C_max, C_trough, and C_meanof tocilizumab were 62.4 (39.4–121) mcg/mL, 13.4 (0.21– 52.3) mcg/mL, and 35.7 (17.4–91.8) mcg/mL, respectively.

The accumulation ratios were 1.46 and 2.04 for AUC_4weeks, 2.08 and 3.58 for C_trough, and 1.32 and 1.72 for C_max, for 162 mg given every 3 weeks (BW less than 30 kg) and 162 mg given every 2 weeks (BW at or above 30 kg) subcutaneous doses, respectively. Following subcutaneous dosing, steady state C_troughwas comparable for patients in the two body weight groups, while steady-state C_maxand C_meanwere higher for patients in the less than 30 kg group compared to the group at or above 30 kg. All patients treated with TCZ SC had steady-state C_troughat or higher than that achieved with TCZ IV across the spectrum of body weights. The average and trough concentrations in patients after subcutaneous dosing were within the range of those achieved in adult patients with RA following the subcutaneous administration of the recommended regimens.

Systemic Juvenile Idiopathic Arthritis – Intravenous and Subcutaneous 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 or 51 patients treated with TCZ SC.

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 AUC_4weeks, 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.

For doses of 162 mg tocilizumab (patients with a body weight at or above 30 kg) given every week subcutaneously, the estimated median (range) C_max, C_trough, and C_meanof tocilizumab were 89.8 (26.4– 190) mcg/mL, 72.4 (19.5–158) mcg/mL, and 82.4 (23.9–169) mcg/mL, respectively. For doses of 162 mg tocilizumab (patients with a body weight less than 30 kg) given every 2 weeks subcutaneously, the estimated median (range) C_max, C_trough, and C_meanof tocilizumab were 127 (51.7–266) mcg/mL, 64.2 (16.6–136) mcg/mL, and 92.7 (38.5–199) mcg/mL, respectively.

The accumulation ratios were 2.27 and 4.28 for AUC_4weeks, 3.21 and 4.39 for C_trough, and 1.88 and 3.66 for C_max, for 162 mg given every 2 weeks (BW less than 30 kg) and 162 mg given every week (BW at or above 30 kg) subcutaneous doses, respectively. Following subcutaneous dosing, steady state was reached by 12 weeks for both body weight groups. All patients treated with tocilizumab SC had steady-state C_maxlower than that achieved with tocilizumab IV across the spectrum of body weights. Trough and mean concentrations in patients after SC dosing were similar to those achieved with tocilizumab IV across body weights.

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 (14.10)]

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) C_maxand C_day28of 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.

Absorption

Following subcutaneous dosing, the absorption half-life was around 4 days in RA and GCA patients. The bioavailability for the subcutaneous formulation was 80%.

Following subcutaneous dosing in PJIA patients, the absorption half-life was around 2 days, and the bioavailability for the subcutaneous formulation in PJIA patients was 96%.

Following subcutaneous dosing in SJIA patients, the absorption half-life was around 2 days, and the bioavailability for the SC formulation in SJIA patients was 95%.

In RA patients the median values of T_maxwere 2.8 days after the tocilizumab every week dose and 4.7 days after the tocilizumab every other week dose.

In GCA patients, the median values of T_maxwere 3 days after the tocilizumab every week dose and 4.5 days after the tocilizumab every other week dose.

Distribution

Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L.

In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distribution was 3.37 L resulting in a volume of distribution at steady state of 7.46 L.

In pediatric patients with PJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L.

In pediatric patients with SJIA, the central volume of distribution was 1.87 L, the peripheral volume of distribution was 2.14 L resulting in a volume of distribution at steady state of 4.01 L.

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

Elimination

Tocilizumab is eliminated by a combination of linear clearance and nonlinear elimination. The concentration- dependent nonlinear elimination plays a major role at low tocilizumab concentrations. Once the nonlinear pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance. The saturation of the nonlinear elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time.

Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.

The linear clearance in the population pharmacokinetic analysis was estimated to be 12.5 mL per h in RA patients, 6.7 mL per h in GCA patients, 5.8 mL per h in pediatric patients with PJIA, and 5.7 mL per h in pediatric patients with SJIA. In COVID-19 patients, serum concentrations were below the limit of quantification after 35 days on average following one infusion of tocilizumab 8 mg/kg intravenously. The average linear clearance in the population pharmacokinetic analysis was estimated to be 17.6 mL per hour in patients with baseline ordinal scale category 3 (OS 3, patients requiring supplemental oxygen), 22.5 mL per hour in patients with baseline OS 4 (patients requiring high-flow oxygen or non-invasive ventilation), 29 mL per hour in patients with baseline OS 5 (patients requiring mechanical ventilation), and 35.4 mL per hour in patients with baseline OS 6 (patients requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support).

Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level.

For intravenous administration in RA patients, the concentration-dependent apparent t1/2 is up to 11 days for 4 mg per kg and up to 13 days for 8 mg per kg every 4 weeks in patients with RA at steady-state. For subcutaneous administration in RA patients, the concentration-dependent apparent t_1/2is up to 13 days for 162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state.

In GCA patients at steady state, the effective t_1/2of tocilizumab varied between 18.3 and 18.9 days for 162 mg subcutaneously every week dosing regimen and between 4.2 and 7.9 days for 162 mg subcutaneously every other week dosing regimen. For intravenous administration in GCA patients, the TCZ concentration-dependent apparent t_1/2was 13.2 days following 6 mg/kg every 4 weeks.

The t_1/2of tocilizumab in children with PJIA is up to 17 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg or 10 mg/kg for body weight below 30 kg) during a dosing interval at steady state. For subcutaneous administration, the t_1/2of tocilizumab in PJIA patients is up to 10 days for the two body weight categories (every other week regimen for body weight at or above 30 kg or every 3 week regimen for body weight less than 30 kg) during a dosing interval at steady state.

The t_1/2of tocilizumab intravenous in pediatric patients with SJIA is up to 16 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg and 12 mg/kg for body weight below 30 kg every other week) during a dosing interval at steady-state. Following subcutaneous administration, the effective t_1/2of tocilizumab subcutaneous in SJIA patients is up to 14 days for both the body weight categories (162 mg every week for body weight at or above 30 kg and 162 mg every two weeks for body weight below 30 kg) during a dosing interval at steady state.

Specific Populations

Population pharmacokinetic analyses in adult rheumatoid arthritis patients and GCA patients showed that age, gender and race did not affect the pharmacokinetics of tocilizumab. Linear clearance was found to increase with body size. In RA patients, the body weight-based dose (8 mg per kg) resulted in approximately 86% higher exposure in patients who are greater than 100 kg in comparison to patients who are less than 60 kg. There was an inverse relationship between tocilizumab exposure and body weight for flat dose subcutaneous regimens.

In GCA patients treated with tocilizumab-SC, higher exposure was observed in patients with lower body weight. For the 162 mg every week subcutaneous dosing regimen, the steady-state C_meanwas 51% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. For the 162 mg every other week subcutaneous regimen, the steady-state C_meanwas 129% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. There is limited data for patients above 100 kg (n=7).

In COVID-19 patients, exposure following body-weight-based intravenous dosing (8 mg per kg tocilizumab up to 100 kg body weight with a maximum dose of 800 mg) was dependent on body weight and disease severity assessed by an ordinal scale (OS). Within an OS category, compared to patients with a mean body weight of 80 kg, exposure was 20% lower in patients weighing less than 60 kg. Exposure in patients weighing more than 100 kg was in the same range as exposure in patients with a mean body weight of 80 kg. For an 80 kg patient, exposure decreases as OS category increases; for each category increase, exposure decreases by 13%.

Patients with Hepatic Impairment

No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted.

Patients with Renal Impairment

No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab was conducted.

Most of the RA and GCA patients in the population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (estimated creatinine clearance less than 80 mL per min and at or above 50 mL per min based on Cockcroft-Gault formula) did not impact the pharmacokinetics of tocilizumab.

Approximately one-third of the patients in the tocilizumab-SC GCA clinical trial had moderate renal impairment at baseline (estimated creatinine clearance of 30-59 mL/min). No impact on tocilizumab exposure was noted in these patients.

No dose adjustment is required in patients with mild or moderate renal impairment.

Drug Interaction Studies

In vitro data suggested that IL-6 reduced mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by co-incubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Its effect on CYP2C8 or transporters (e.g., P-gp) is unknown. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation of Tocilizumab-anoh, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Caution should be exercised when Tocilizumab-anoh is coadministered with drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives (CYP3A4 substrates)

[see Drug Interactions (7.2)]

Simvastatin

Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients not treated with tocilizumab, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4- to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of tocilizumab (10 mg per kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of tocilizumab in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of Tocilizumab-anoh (due to normalization of CYP3A4) or higher exposures after discontinuation of Tocilizumab-anoh.

Omeprazole

Omeprazole is a CYP2C19 and CYP3A4 substrate. In RA patients receiving 10 mg omeprazole, exposure to omeprazole was approximately 2 fold higher than that observed in healthy subjects. In RA patients receiving 10 mg omeprazole, before and one week after tocilizumab infusion (8 mg per kg), the omeprazole AUCinf decreased by 12% for poor (N=5) and intermediate metabolizers (N=5) and by 28% for extensive metabolizers (N=8) and were slightly higher than those observed in healthy subjects.

Dextromethorphan

Dextromethorphan is a CYP2D6 and CYP3A4 substrate. In 13 RA patients receiving 30 mg dextromethorphan, exposure to dextromethorphan was comparable to that in healthy subjects. However, exposure to its metabolite, dextrorphan (a CYP3A4 substrate), was a fraction of that observed in healthy subjects. One week following administration of a single infusion of tocilizumab (8 mg per kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after tocilizumab infusion.

)

In
GCA
patients, Tocilizumab-anohdoses exceeding 600 mg per infusion are not recommended. (
2.3 Recommended Dosage for Giant Cell Arteritis
Recommended Intravenous Dosage Regimen:
The recommended dosage of Tocilizumab-anoh 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.
Tocilizumab-anoh 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 (2.9)]
.
Doses exceeding 600 mg per infusion are not recommended in GCA patients
[see Clinical Pharmacology (12.3)].
Recommended Subcutaneous Dosage Regimen:
The recommended dose of Tocilizumab-anoh for adult patients with GCA is 162 mg given once every week as a subcutaneous injection in combination with a tapering course of glucocorticoids.
A dose of 162 mg given once every other week as a subcutaneous injection in combination with a tapering course of glucocorticoids may be prescribed based on clinical considerations.
Tocilizumab-anoh can be used alone following discontinuation of glucocorticoids.
When transitioning from Tocilizumab-anoh intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.
Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia
[see Dosage and Administration (2.9)].
,
12.3 Pharmacokinetics
PK of tocilizumab is characterized by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination. The nonlinear part of tocilizumab elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time. Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.
Rheumatoid Arthritis - Intravenous and Subcutaneous 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, and from an IV and SC dataset of 1759 patients from Studies SC- I and SC-II. C_meanis included in place of AUCtau, since for dosing regimens with different inter-dose intervals, the mean concentration over the dosing period characterizes the comparative exposure better than AUCtau.
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 AUCtau and 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.
For doses of 162 mg given every other week subcutaneously, the estimated median (range) steady-state C_max, C_trough, and C_meanof tocilizumab were 12.1 (0.4–49.3) mcg/mL, 4.1 (0.0–34.2) mcg/mL, and 9.2 (0.2– 43.6) mcg/mL, respectively.
For doses of 162 mg given every week subcutaneously, the estimated median (range) steady-state C_max, C_trough, and C_meanof tocilizumab were 49.8 (3–150) mcg/mL, 42.9 (1.3–144) mcg/mL, and 47.3 (2.4–147) mcg/mL, respectively. Exposures after the 162 mg SC QW regimen were greater by 5.1 (C_mean) to 10.5 fold (C_trough) compared to the 162 mg SC Q2W regimen.
Accumulation ratios after multiple doses of either SC regimen were higher than after IV regimen with the highest ratios for C_trough(6.02 and 6.30, for 162 mg SC Q2W and 162 mg SC QW, respectively). The higher accumulation for C_troughwas expected based on the nonlinear clearance contribution at lower concentrations. For C_max, greater than 90% of the steady-state value was reached after the 5th SC and the 12th SC injection with the Q2W and QW regimens, respectively. For AUCtau and C_mean, 90% of the steady-state value was reached after the 6th and 12th injections for the 162 mg SC Q2W and QW regimens, respectively. For C_trough, approximately 90% of the steady- state value was reached after the 6th and 12th injections for the 162 mg SC Q2W and QW regimens, respectively.
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 (2.2)]
. Due to the flat dosing employed for SC administration of tocilizumab, no modifications are necessary by this dosing route.
Giant Cell Arteritis – Subcutaneous and Intravenous Administration
The pharmacokinetics of tocilizumab SC in GCA patients was determined using a population pharmacokinetic analysis on a dataset composed of 149 GCA patients treated with 162 mg subcutaneously every week or with 162 mg subcutaneously every other week.
For the 162 mg every week dose, the estimated median (range) steady-state C_max, C_troughand C_meanof tocilizumab SC were 72.1 (12.2–151) mcg/mL, 67.2 (10.7–145) mcg/mL, and 70.6 (11.7–149) mcg/mL, respectively. The accumulation ratios for C_meanor AUCtau, C_trough, and C_maxwere 10.9, 9.6, and 8.9, respectively. Steady state was reached after 17 weeks. For the 162 mg every other week dose, the estimated median (range) steady-state C_max, C_trough, and C_meanof tocilizumab were 17.2 (1.1–56.2) mcg/mL, 7.7 (0.1–37.3) mcg/mL, and 13.7 (0.5– 49) mcg/mL, respectively. The accumulation ratios for C_meanor AUCtau, C_trough, and C_maxwere 2.8, 5.6, and 2.3 respectively. Steady-state was reached after 14 weeks.
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 162 mg TCZ SC administered every week or every other week.
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 and Subcutaneous 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 or 52 patients treated with TCZ SC.
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.
For doses of 162 mg tocilizumab (patients with a body weight at or above 30 kg) given every 2 weeks subcutaneously, the estimated median (range) C_max, C_trough, and C_meanof tocilizumab were 29.7 (7.56– 50.3) mcg/mL, 12.7 (0.19–23.8) mcg/mL, and 23.0 (3.86–36.9) mcg/mL, respectively. For doses of 162 mg tocilizumab (patients with a body weight less than 30 kg) given every 3 weeks subcutaneously, the estimated median (range) C_max, C_trough, and C_meanof tocilizumab were 62.4 (39.4–121) mcg/mL, 13.4 (0.21– 52.3) mcg/mL, and 35.7 (17.4–91.8) mcg/mL, respectively.
The accumulation ratios were 1.46 and 2.04 for AUC_4weeks, 2.08 and 3.58 for C_trough, and 1.32 and 1.72 for C_max, for 162 mg given every 3 weeks (BW less than 30 kg) and 162 mg given every 2 weeks (BW at or above 30 kg) subcutaneous doses, respectively. Following subcutaneous dosing, steady state C_troughwas comparable for patients in the two body weight groups, while steady-state C_maxand C_meanwere higher for patients in the less than 30 kg group compared to the group at or above 30 kg. All patients treated with TCZ SC had steady-state C_troughat or higher than that achieved with TCZ IV across the spectrum of body weights. The average and trough concentrations in patients after subcutaneous dosing were within the range of those achieved in adult patients with RA following the subcutaneous administration of the recommended regimens.
Systemic Juvenile Idiopathic Arthritis – Intravenous and Subcutaneous 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 or 51 patients treated with TCZ SC.
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 AUC_4weeks, 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.
For doses of 162 mg tocilizumab (patients with a body weight at or above 30 kg) given every week subcutaneously, the estimated median (range) C_max, C_trough, and C_meanof tocilizumab were 89.8 (26.4– 190) mcg/mL, 72.4 (19.5–158) mcg/mL, and 82.4 (23.9–169) mcg/mL, respectively. For doses of 162 mg tocilizumab (patients with a body weight less than 30 kg) given every 2 weeks subcutaneously, the estimated median (range) C_max, C_trough, and C_meanof tocilizumab were 127 (51.7–266) mcg/mL, 64.2 (16.6–136) mcg/mL, and 92.7 (38.5–199) mcg/mL, respectively.
The accumulation ratios were 2.27 and 4.28 for AUC_4weeks, 3.21 and 4.39 for C_trough, and 1.88 and 3.66 for C_max, for 162 mg given every 2 weeks (BW less than 30 kg) and 162 mg given every week (BW at or above 30 kg) subcutaneous doses, respectively. Following subcutaneous dosing, steady state was reached by 12 weeks for both body weight groups. All patients treated with tocilizumab SC had steady-state C_maxlower than that achieved with tocilizumab IV across the spectrum of body weights. Trough and mean concentrations in patients after SC dosing were similar to those achieved with tocilizumab IV across body weights.
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 (14.10)]
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) C_maxand C_day28of 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.
Absorption
Following subcutaneous dosing, the absorption half-life was around 4 days in RA and GCA patients. The bioavailability for the subcutaneous formulation was 80%.
Following subcutaneous dosing in PJIA patients, the absorption half-life was around 2 days, and the bioavailability for the subcutaneous formulation in PJIA patients was 96%.
Following subcutaneous dosing in SJIA patients, the absorption half-life was around 2 days, and the bioavailability for the SC formulation in SJIA patients was 95%.
In RA patients the median values of T_maxwere 2.8 days after the tocilizumab every week dose and 4.7 days after the tocilizumab every other week dose.
In GCA patients, the median values of T_maxwere 3 days after the tocilizumab every week dose and 4.5 days after the tocilizumab every other week dose.
Distribution
Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L.
In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distribution was 3.37 L resulting in a volume of distribution at steady state of 7.46 L.
In pediatric patients with PJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L.
In pediatric patients with SJIA, the central volume of distribution was 1.87 L, the peripheral volume of distribution was 2.14 L resulting in a volume of distribution at steady state of 4.01 L.
In COVID-19 patients treated with one or two infusions of tocilizumab 8 mg/kg intravenously separated by 8 hours, the estimated central volume of distribution was 4.52 L, and the estimated peripheral volume of distribution was 4.23 L, resulting in a volume of distribution of 8.75 L.
Elimination
Tocilizumab is eliminated by a combination of linear clearance and nonlinear elimination. The concentration- dependent nonlinear elimination plays a major role at low tocilizumab concentrations. Once the nonlinear pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance. The saturation of the nonlinear elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time.
Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.
The linear clearance in the population pharmacokinetic analysis was estimated to be 12.5 mL per h in RA patients, 6.7 mL per h in GCA patients, 5.8 mL per h in pediatric patients with PJIA, and 5.7 mL per h in pediatric patients with SJIA. In COVID-19 patients, serum concentrations were below the limit of quantification after 35 days on average following one infusion of tocilizumab 8 mg/kg intravenously. The average linear clearance in the population pharmacokinetic analysis was estimated to be 17.6 mL per hour in patients with baseline ordinal scale category 3 (OS 3, patients requiring supplemental oxygen), 22.5 mL per hour in patients with baseline OS 4 (patients requiring high-flow oxygen or non-invasive ventilation), 29 mL per hour in patients with baseline OS 5 (patients requiring mechanical ventilation), and 35.4 mL per hour in patients with baseline OS 6 (patients requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support).
Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level.
For intravenous administration in RA patients, the concentration-dependent apparent t1/2 is up to 11 days for 4 mg per kg and up to 13 days for 8 mg per kg every 4 weeks in patients with RA at steady-state. For subcutaneous administration in RA patients, the concentration-dependent apparent t_1/2is up to 13 days for 162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state.
In GCA patients at steady state, the effective t_1/2of tocilizumab varied between 18.3 and 18.9 days for 162 mg subcutaneously every week dosing regimen and between 4.2 and 7.9 days for 162 mg subcutaneously every other week dosing regimen. For intravenous administration in GCA patients, the TCZ concentration-dependent apparent t_1/2was 13.2 days following 6 mg/kg every 4 weeks.
The t_1/2of tocilizumab in children with PJIA is up to 17 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg or 10 mg/kg for body weight below 30 kg) during a dosing interval at steady state. For subcutaneous administration, the t_1/2of tocilizumab in PJIA patients is up to 10 days for the two body weight categories (every other week regimen for body weight at or above 30 kg or every 3 week regimen for body weight less than 30 kg) during a dosing interval at steady state.
The t_1/2of tocilizumab intravenous in pediatric patients with SJIA is up to 16 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg and 12 mg/kg for body weight below 30 kg every other week) during a dosing interval at steady-state. Following subcutaneous administration, the effective t_1/2of tocilizumab subcutaneous in SJIA patients is up to 14 days for both the body weight categories (162 mg every week for body weight at or above 30 kg and 162 mg every two weeks for body weight below 30 kg) during a dosing interval at steady state.
Specific Populations
Population pharmacokinetic analyses in adult rheumatoid arthritis patients and GCA patients showed that age, gender and race did not affect the pharmacokinetics of tocilizumab. Linear clearance was found to increase with body size. In RA patients, the body weight-based dose (8 mg per kg) resulted in approximately 86% higher exposure in patients who are greater than 100 kg in comparison to patients who are less than 60 kg. There was an inverse relationship between tocilizumab exposure and body weight for flat dose subcutaneous regimens.
In GCA patients treated with tocilizumab-SC, higher exposure was observed in patients with lower body weight. For the 162 mg every week subcutaneous dosing regimen, the steady-state C_meanwas 51% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. For the 162 mg every other week subcutaneous regimen, the steady-state C_meanwas 129% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. There is limited data for patients above 100 kg (n=7).
In COVID-19 patients, exposure following body-weight-based intravenous dosing (8 mg per kg tocilizumab up to 100 kg body weight with a maximum dose of 800 mg) was dependent on body weight and disease severity assessed by an ordinal scale (OS). Within an OS category, compared to patients with a mean body weight of 80 kg, exposure was 20% lower in patients weighing less than 60 kg. Exposure in patients weighing more than 100 kg was in the same range as exposure in patients with a mean body weight of 80 kg. For an 80 kg patient, exposure decreases as OS category increases; for each category increase, exposure decreases by 13%.
Patients with Hepatic Impairment
No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted.
Patients with Renal Impairment
No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab was conducted.
Most of the RA and GCA patients in the population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (estimated creatinine clearance less than 80 mL per min and at or above 50 mL per min based on Cockcroft-Gault formula) did not impact the pharmacokinetics of tocilizumab.
Approximately one-third of the patients in the tocilizumab-SC GCA clinical trial had moderate renal impairment at baseline (estimated creatinine clearance of 30-59 mL/min). No impact on tocilizumab exposure was noted in these patients.
No dose adjustment is required in patients with mild or moderate renal impairment.
Drug Interaction Studies
In vitro data suggested that IL-6 reduced mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by co-incubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Its effect on CYP2C8 or transporters (e.g., P-gp) is unknown. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation of Tocilizumab-anoh, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Caution should be exercised when Tocilizumab-anoh is coadministered with drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives (CYP3A4 substrates)
[see Drug Interactions (7.2)]
.
Simvastatin
Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients not treated with tocilizumab, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4- to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of tocilizumab (10 mg per kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of tocilizumab in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of Tocilizumab-anoh (due to normalization of CYP3A4) or higher exposures after discontinuation of Tocilizumab-anoh.
Omeprazole
Omeprazole is a CYP2C19 and CYP3A4 substrate. In RA patients receiving 10 mg omeprazole, exposure to omeprazole was approximately 2 fold higher than that observed in healthy subjects. In RA patients receiving 10 mg omeprazole, before and one week after tocilizumab infusion (8 mg per kg), the omeprazole AUCinf decreased by 12% for poor (N=5) and intermediate metabolizers (N=5) and by 28% for extensive metabolizers (N=8) and were slightly higher than those observed in healthy subjects.
Dextromethorphan
Dextromethorphan is a CYP2D6 and CYP3A4 substrate. In 13 RA patients receiving 30 mg dextromethorphan, exposure to dextromethorphan was comparable to that in healthy subjects. However, exposure to its metabolite, dextrorphan (a CYP3A4 substrate), was a fraction of that observed in healthy subjects. One week following administration of a single infusion of tocilizumab (8 mg per kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after tocilizumab infusion.
)

Rheumatoid Arthritis

(

2.2 Recommended Dosage for Rheumatoid Arthritis

Tocilizumab-anoh may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion or as a subcutaneous injection.

Recommended Intravenous Dosage Regimen:

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 (2.9), 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)]
.

Recommended Subcutaneous Dosage Regimen:

Patients less than 100 kg weight	162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response
Patients at or above 100 kg weight	162 mg administered subcutaneously every week

When transitioning from Tocilizumab-anoh intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

[see Dosage and Administration (2.9), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.2)].

)

Recommended Adult Intravenous Dosage:

Recommended Adult Subcutaneous Dosage:

Patients less than 100 kg weight	162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response
Patients at or above 100 kg weight	162 mg administered subcutaneously every week

Giant Cell Arteritis (

2.3 Recommended Dosage for Giant Cell Arteritis

Recommended Intravenous Dosage Regimen:

Tocilizumab-anoh 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 (2.9)]
.
Doses exceeding 600 mg per infusion are not recommended in GCA patients
[see Clinical Pharmacology (12.3)].

Recommended Subcutaneous Dosage Regimen:

The recommended dose of Tocilizumab-anoh for adult patients with GCA is 162 mg given once every week as a subcutaneous injection in combination with a tapering course of glucocorticoids.

A dose of 162 mg given once every other week as a subcutaneous injection in combination with a tapering course of glucocorticoids may be prescribed based on clinical considerations.

Tocilizumab-anoh can be used alone following discontinuation of glucocorticoids.

When transitioning from Tocilizumab-anoh intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

[see Dosage and Administration (2.9)].

)

Recommended Adult Intravenous Dosage:

The recommended dose is 6 mg per kg every 4 weeks in combination with a tapering course of glucocorticoids. Tocilizumab-anohcan be used alone following discontinuation of glucocorticoids.

Recommended Adult Subcutaneous Dosage:

The recommended dose is 162 mg given once every week as a subcutaneous injection, in combination with a tapering course of glucocorticoids.

A dose of 162 mg given once every other week as a subcutaneous injection, in combination with a tapering course of glucocorticoids, may be prescribed based on clinical considerations.

Tocilizumab-anoh can be used alone following discontinuation of glucocorticoids.

Polyarticular Juvenile Idiopathic Arthritis (

2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis

Recommended Intravenous Dosage Regimen:

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

Recommended Intravenous PJIA Dosage Every 4 Weeks
Patients less than 30 kg weight	10 mg per kg
Patients at or above 30 kg weight	8 mg per kg

Recommended Subcutaneous Dosage Regimen:

Recommended Subcutaneous PJIA Dosage
Patients less than 30 kg weight	162 mg once every 3 weeks
Patients at or above 30 kg weight	162 mg once every 2 weeks

When transitioning from Tocilizumab-anoh intravenous therapy to subcutaneous administration, 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 (2.9]

)

Recommended Intravenous PJIA Dosage Every 4 Weeks
Patients less than 30 kg weight	10 mg per kg
Patients at or above 30 kg weight	8 mg per kg

Recommended Subcutaneous PJIA Dosage
Patients less than 30 kg weight	162 mg once every three weeks
Patients at or above 30 kg weight	162 mg once every two weeks

Systemic Juvenile Idiopathic Arthritis (

2.5 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis

Recommended Intravenous Dosage Regimen:

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

Recommended Intravenous SJIA Dosage Every 2 weeks
Patients less than 30 kg weight	162 mg per kg
Patients at or above 30 kg weight	8 mg per kg

Recommended Subcutaneous Dosage Regimen:

Recommended Subcutaneous SJIA Dosage
Patients less than 30 kg weight	162 mg once every two weeks
Patients at or above 30 kg weight	162 mg once every week

When transitioning from Tocilizumab-anoh intravenous therapy to subcutaneous administration, administer the first subcutaneous dose when the next scheduled intravenous dose is due.

Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia

[see Dosage and Administration (2.9)]

)

Recommended Intravenous SJIA Dosage Every 2 Weeks
Patients less than 30 kg weight	12 mg per kg
Patients at or above 30 kg weight	8 mg per kg

Recommended Subcutaneous SJIA Dosage
Patients less than 30 kg weight	162 mg every two weeks
Patients at or above 30 kg weight	162 mg every week

Cytokine Release Syndrome (

2.7 Coronavirus Disease 2019 (COVID-19)

Administer Tocilizumab-anoh by intravenous infusion only.

Doses exceeding 800 mg per infusion are not recommended in patients with COVID-19.
Subcutaneous administration is not approved for COVID-19.

)

Recommened Intravenous CRS Dosage
Patients less than 30 kg weight	12 mg per kg
Patients at or above 30 kg weight	8 mg per kg
Alone or in combination with corticosteroids

Coronavirus Disease 2019 (

2.7 Coronavirus Disease 2019 (COVID-19)

Administer Tocilizumab-anoh by intravenous infusion only.

Doses exceeding 800 mg per infusion are not recommended in patients with COVID-19.
Subcutaneous administration is not approved for COVID-19.

)

The recommended dosage of Tocilizumab-anohfor adult patients with COVID-19 is 8 mg per kg administered by a 60-minute intravenous infusion.

Administration of Intravenous Formulation (

2.8 Preparation and Administration Instructions for Intravenous Infusion

Tocilizumab-anoh for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows:

Use a sterile needle and syringe to prepare Tocilizumab-anoh.
Patients
less than 30 kg
: use a
50 mL
infusion bag or bottle of 0.9% or 0.45% Sodium Chloride Injection, USP, and then follow steps 1 and 2 below.
Patients
at or above 30 kg weight
: use a
100 mL
infusion bag or bottle, and then follow steps 1 and 2 below.
Step 1. Withdraw a volume of 0.9% or 0.45% Sodium Chloride Injection, USP, equal to the volume of the Tocilizumab-anoh injection required for the patient's dose from the infusion bag or bottle
[see Dosage and Administration (2.2, 2.4, 2.5, 2.6)]
.

For Intravenous Use: Volume of Tocilizumab-anoh Injection per kg of Body Weight
Dosage	Indication	Volume of Tocilizumab-anoh injection per kg of body weight
4 mg/kg	Adult RA	0.2 mL/kg
6 mg/kg	Adult GCA	0.3 mL/kg
8 mg/kg	Adult RA Adult COVID-19 SJIA,PJIA and CRS (greater than or equal to 30 kg of body weight)	0.4 mL/kg
10 mg/kg	PJIA (less than 30 kg of body weight)	0.5 mL/kg
12 mg/kg	SJIA and CRS (less than 30 kg of body weight)	0.6 mL/kg

Step 2. Withdraw the amount of Tocilizumab-anoh for intravenous infusion from the vial(s) and add slowly into the 0.9% or 0.45% Sodium Chloride Injection, USP infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming.
The fully diluted Tocilizumab-anoh solutions for infusion using 0.9% Sodium Chloride Injection, USP may be stored at 36°F to 46°F (2°C to 8°C) for up to 48 hours or room temperature up to 86°F (30°C) for up to 4 hours and should be protected from light.
The fully diluted Tocilizumab-anoh solutions for infusion using 0.45% Sodium Chloride Injection, USP may be stored at 36°F to 46°F (2°C to 8°C) for up to 48 hours or room temperature up to 86°F (30°C) for up to 4 hours and should be protected from light.
Tocilizumab-anoh solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used.
Allow the fully diluted Tocilizumab-anoh solution to reach room temperature prior to infusion.
The infusion should be administered over 60 minutes, and must be administered with an infusion set. Do not administer as an intravenous push or bolus.
Tocilizumab-anoh should not be infused concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of Tocilizumab-anoh with other drugs.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulates and discolorations are noted, the product should not be used.
Fully diluted Tocilizumab-anoh solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and polypropylene, polyethylene and glass infusion bottles.

)

For patients with RA, GCA, COVID-19, CRS, PJIA, and SJIA patients at or above 30 kg, dilute to 100 mL in 0.9% or 0.45% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique.
For PJIA, CRS and SJIA patients less than 30 kg, dilute to 50 mL in 0.9% or 0.45% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique.
Administer as a single intravenous drip infusion over 1 hour; do not administer as bolus or push.

Administration of Subcutaneous Formulation (

2.9 Preparation and Administration Instructions for Subcutaneous Injection

Tocilizumab-anoh for subcutaneous injection is not intended for intravenous drip infusion.

Assess suitability of patient for subcutaneous home use and instruct patients to inform a healthcare professional before administering the next dose if they experience any symptoms of allergic reaction. Patients should seek immediate medical attention if they develop symptoms of serious allergic reactions. Tocilizumab-anoh subcutaneous injection is intended for use under the guidance of a healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject Tocilizumab-anoh or the patient's caregiver may administer Tocilizumab-anoh if a healthcare practitioner determines that it is appropriate. PJIA and SJIA patients may self-inject with the Tocilizumab-anoh prefilled syringe or prefilled autoinjector, or the patient's caregiver may administer Tocilizumab-anoh if both the healthcare practitioner and the parent/legal guardian determines it is appropriate
[see Use in Specific Populations (8.4)]
. Patients, or patient caregivers, should be instructed to follow the directions provided in the Instructions for Use (IFU) for additional details on medication administration.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use Tocilizumab-anoh prefilled syringes (PFS) or prefilled autoinjector (AI) exhibiting particulate matter, cloudiness, or discoloration. Tocilizumab-anoh for subcutaneous administration should be clear to slightly opalescent and colorless to yellow. Do not use if any part of the PFS or AI appears to be damaged.
Patients using Tocilizumab-anoh for subcutaneous administration should be instructed to inject the full amount in the syringe (0.9 mL) or full amount in the autoinjector (0.9 mL), which provides 162 mg of Tocilizumab-anoh, according to the directions provided in the IFU.
Injection sites should be rotated with each injection and should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

)

Follow the Instructions for Use for prefilled syringe and prefilled autoinjector

Dose Modifications (

2.10 Dosage Modifications due to Serious Infections or Laboratory Abnormalities

Serious Infections

Hold Tocilizumab-anoh treatment if a patient develops a serious infection until the infection is controlled.

Laboratory Abnormalities

Rheumatoid Arthritis and Giant Cell Arteritis

Liver Enzyme Abnormalities [see Warnings and Precautions (5.3, 5.4)]
Lab Value	Recommendation for RA	Recommendation for GCA
Greater than 1 to 3× ULN	Dose modify concomitant DMARDs if appropriate For persistent increases in this range: For patients receiving intravenous Tocilizumab-anoh, reduce dose to 4 mg per kg or hold Tocilizumab-anoh until ALT or AST have normalized For patients receiving subcutaneous Tocilizumab-anoh, reduce injection frequency to every other week or hold dosing until ALT or AST have normalized. Resume Tocilizumab-anoh at every other week and increase frequency to every week as clinically appropriate.	Dose modify immunomodulatory agents if appropriate For persistent increases in this range: For patients receiving intravenous Tocilizumab-anoh, hold Tocilizumab-anoh until ALT or AST have normalized For patients receiving subcutaneous Tocilizumab-anoh, reduce injection frequency to every other week or hold dosing until ALT or AST have normalized. Resume Tocilizumab-anoh at every other week and increase frequency to every week as clinically appropriate.
Greater than 3 to 5× ULN (confirmed by repeat testing)	Hold Tocilizumab-anoh dosing until less than 3× ULN and follow recommendations above for greater than 1 to 3× ULN For persistent increases greater than 3× ULN, discontinue Tocilizumab-anoh	Hold Tocilizumab-anoh dosing until less than 3× ULN and follow recommendations above for greater than 1 to 3× ULN For persistent increases greater than 3× ULN, discontinue Tocilizumab-anoh
Greater than 5× ULN	Discontinue Tocilizumab-anoh	Discontinue Tocilizumab-anoh

Low Absolute Neutrophil Count (ANC) [see Warnings and Precautions (5.4)]
Lab Value (cells per mm³)	Recommendation for RA	Recommendation for GCA
ANC greater than 1000	Maintain dose	Maintain dose
ANC 500 to 1000	Hold Tocilizumab-anoh dosing When ANC greater than 1000 cells per mm³: For patients receiving intravenous Tocilizumab-anoh, resume Tocilizumab-anoh at 4 mg per kg and increase to 8 mg per kg as clinically appropriate For patients receiving subcutaneous Tocilizumab-anoh, resume Tocilizumab-anoh at every other week and increase frequency to every week as clinically appropriate	Hold Tocilizumab-anoh dosing When ANC greater than 1000 cells per mm³: For patients receiving intravenous Tocilizumab-anoh, resume Tocilizumab-anoh at 6 mg per kg For patients receiving subcutaneous Tocilizumab-anoh, resume Tocilizumab-anoh at every other week and increase frequency to every week as clinically appropriate
ANC less than 500	Discontinue Tocilizumab-anoh	Discontinue Tocilizumab-anoh

Low Platelet Count [see Warnings and Precautions (5.4)]
Lab Value (cells per mm³)	Recommendation for RA	Recommendation for GCA
50,000 to 100,000	Hold Tocilizumab-anoh dosing When platelet count is greater than 100,000 cells per mm³: For patients receiving intravenous Tocilizumab-anoh, resume Tocilizumab-anoh at 4 mg per kg and increase to 8 mg per kg as clinically appropriate For patients receiving subcutaneous Tocilizumab-anoh, resume Tocilizumab-anoh at every other week and increase frequency to every week as clinically appropriate	Hold Tocilizumab-anoh dosing When platelet count is greater than 100,000 cells per mm³: For patients receiving intravenous Tocilizumab-anoh, resume Tocilizumab-anoh at 6 mg per kg For patients receiving subcutaneous Tocilizumab-anoh, resume Tocilizumab-anoh at every other week and increase frequency to every week as clinically appropriate
Less than 50,000	Discontinue Tocilizumab-anoh	Discontinue Tocilizumab-anoh

Polyarticular and Systemic Juvenile Idiopathic Arthritis

)

Recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.

Intravenous Infusion

Injection: 80 mg/4 mL (20 mg/mL), 200 mg/10 mL (20 mg/mL), 400 mg/20 mL (20 mg/mL) in single-dose vials for further dilution prior to intravenous infusion (

3 DOSAGE FORMS AND STRENGTHS

Intravenous Infusion

Injection: 80 mg/4 mL (20 mg/mL), 200 mg/10 mL (20 mg/mL), 400 mg/20 mL (20 mg/mL) in single-dose vials for further dilution prior to intravenous infusion

Subcutaneous Injection

Injection: 162 mg/0.9 mL in a single-dose prefilled syringe or single-dose prefilled autoinjector

Intravenous Infusion

Injection: 80 mg/4 mL, 200 mg/10 mL, 400 mg/20 mL as a clear to slightly opalescent, colorless to pale yellow solution in 20 mg/mL single-dose vials for further dilution prior to intravenous infusion.

Subcutaneous Injection

Injection: 162 mg/0.9 mL clear to slightly opalescent, colorless to yellow solution in a single-dose prefilled syringe or single-dose prefilled autoinjector.

)

Subcutaneous Injection

Injection: 162 mg/0.9 mL in a single-dose prefilled syringe or single-dose prefilled autoinjector (

3 DOSAGE FORMS AND STRENGTHS

Intravenous Infusion

Injection: 80 mg/4 mL (20 mg/mL), 200 mg/10 mL (20 mg/mL), 400 mg/20 mL (20 mg/mL) in single-dose vials for further dilution prior to intravenous infusion

Subcutaneous Injection

Injection: 162 mg/0.9 mL in a single-dose prefilled syringe or single-dose prefilled autoinjector

Intravenous Infusion

Subcutaneous Injection

Injection: 162 mg/0.9 mL clear to slightly opalescent, colorless to yellow solution in a single-dose prefilled syringe or single-dose prefilled autoinjector.

)

Pregnancy:
Based on animal data, may cause fetal harm. (
8.1 Pregnancy
Risk Summary
The available data with tocilizumab products from a pregnancy exposure registry, retrospective cohort study, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. These studies had methodological limitations, including small sample size of tocilizumab exposed groups, missing exposure and outcomes information, and lack of adjustment for cofounders. 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 utero
exposed 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
Fetal/Neonatal adverse reactions
Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to Tocilizumab-anoh
in utero [see Warnings and Precautions 5.9)].
Disease-associated Maternal Risk
Published data suggest that the risk of adverse pregnancy outcomes in women with rheumatoid arthritis is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.
Data
Animal Data
An embryo-fetal developmental toxicity study was performed in which pregnant Cynomolgus monkeys were treated intravenously with tocilizumab at daily doses of 2, 10, or 50 mg/ kg during organogenesis from gestation day (GD) 20-50. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by the intravenous route at maternal intravenous doses of 10 and 50 mg/ kg. Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring.
Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (ll6^-/-null mice), parturition was delayed relative to wild-type (ll6^+/+) mice. Administration of recombinant IL-6 to ll6^-/-null mice restored the normal timing of delivery.
)
Lactation:
Discontinue drug or nursing taking into consideration importance of drug to mother. (
8.2 Lactation
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 Tocilizumab-anoh and the potential adverse effects on the breastfed child from Tocilizumab-anoh or from the underlying maternal condition.
)

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