Actemra

• Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients, except those with COVID-19, should be tested for latent tuberculosis before ACTEMRA use and during therapy. Treatment for latent infection should be initiated prior to ACTEMRA 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.

ACTEMRA^® (tocilizumab) is an interleukin-6 (IL-6) receptor antagonist indicated for 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 giant cell arteritis.

• Slowing the rate of decline in pulmonary function in adult patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD)

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

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

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

• Hospitalized adult and pediatric patients aged 2 years and older 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, ACTEMRA may be used alone or in combination with methotrexate: and in RA, other non-biologic DMARDs may be used. (

• RA, GCA, SSc-ILD, PJIA and SJIA
  – It is recommended that ACTEMRA 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 ACTEMRA. 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. 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 ACTEMRA was associated with a higher incidence of transaminase elevations

  [see Adverse Reactions (6.1, 6.2, 6.6, 6.8)].

  Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with ACTEMRA.

  For RA, GCA and SSc-ILD patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating ACTEMRA, 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 ACTEMRA treatment in RA, GCA or SSc-ILD 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 ACTEMRA. For recommended modifications based upon increase in transaminases

  see Dosage and Administration (2.11)

  .

  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 ACTEMRA should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with ACTEMRA. It is not recommended to initiate ACTEMRA 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), ACTEMRA treatment should be interrupted and investigation done to establish the probable cause. ACTEMRA 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 ACTEMRA 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, Systemic Sclerosis-Associated Interstitial Lung Disease and Coronavirus Disease 2019

  Neutropenia

  Treatment with ACTEMRA 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 ACTEMRA treatment in RA, GCA and SSc-ILD patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm³. In patients who develop an absolute neutrophil count less than 500 per mm³treatment 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 (2.11)
    .
  • –It is not recommended to initiate ACTEMRA treatment in COVID-19 patients with an ANC less than 1000 per mm³. Neutrophils should be monitored.

  Thrombocytopenia

  Treatment with ACTEMRA 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 ACTEMRA treatment in RA, GCA and SSc-ILD 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 (2.11)
    .
  • –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 5.3 Hepatotoxicity. For recommended modifications

  [see Dosage and Administration (2.11)]

  Lipid Abnormalities

  Treatment with ACTEMRA 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 ACTEMRA 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 ACTEMRA 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 (2.11)]

  .

  )
  .
• COVID-19
  – It is recommended that ACTEMRA 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
  (

  5.3 Hepatotoxicity

  Serious cases of hepatic injury have been observed in patients taking intravenous or subcutaneous ACTEMRA. 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. 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 ACTEMRA was associated with a higher incidence of transaminase elevations

  [see Adverse Reactions (6.1, 6.2, 6.6, 6.8)].

  Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with ACTEMRA.

  For RA, GCA and SSc-ILD patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating ACTEMRA, 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 ACTEMRA treatment in RA, GCA or SSc-ILD 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 ACTEMRA. For recommended modifications based upon increase in transaminases

  see Dosage and Administration (2.11)

  .

  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 ACTEMRA should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with ACTEMRA. It is not recommended to initiate ACTEMRA 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), ACTEMRA treatment should be interrupted and investigation done to establish the probable cause. ACTEMRA 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 ACTEMRA 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, Systemic Sclerosis-Associated Interstitial Lung Disease and Coronavirus Disease 2019

  Neutropenia

  Treatment with ACTEMRA 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 ACTEMRA treatment in RA, GCA and SSc-ILD patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm³. In patients who develop an absolute neutrophil count less than 500 per mm³treatment 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 (2.11)
    .
  • –It is not recommended to initiate ACTEMRA treatment in COVID-19 patients with an ANC less than 1000 per mm³. Neutrophils should be monitored.

  Thrombocytopenia

  Treatment with ACTEMRA 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 ACTEMRA treatment in RA, GCA and SSc-ILD 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 (2.11)
    .
  • –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 5.3 Hepatotoxicity. For recommended modifications

  [see Dosage and Administration (2.11)]

  Lipid Abnormalities

  Treatment with ACTEMRA 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 ACTEMRA 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 ACTEMRA 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 (2.11)]

  .

  )
  .
• In
  RA, CRS or COVID-19
  patients, ACTEMRA doses exceeding 800 mg per infusion are not recommended. (
  2.2 Recommended Dosage for Rheumatoid Arthritis

  ACTEMRA 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 ACTEMRA 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 (2.11), 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 ACTEMRA 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 (2.11), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.2)].
  ,
  2.7 Recommended Dosage for Cytokine Release Syndrome (CRS)

  Use only the intravenous route for treatment of CRS. The recommended dose of ACTEMRA for treatment of CRS given as a 60-minute intravenous 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 ACTEMRA 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.
  ,
  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 AUC_tau, since for dosing regimens with different inter-dose intervals, the mean concentration over the dosing period characterizes the comparative exposure better than AUC_tau.

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

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

  The accumulation ratios for AUC and C_maxafter multiple doses of 4 and 8 mg/kg IV Q4W are low, while the accumulation ratios for C_troughare higher (2.62 and 2.47, respectively). For C_max, greater than 90% of the steady-state value was reached after the 1st IV infusion. For AUC_tauand C_mean, 90% of the steady-state value was reached after the 1st and 3rd infusion for 4 mg/kg and 8 mg/kg IV, while for C_trough, approximately 90% of the steady-state value was reached after the 4th IV infusion after both doses.

  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 AUC_tauand 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 AUC_tau, 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 AUC_tau, 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)]

  .

  Systemic Sclerosis-Associated Interstitial Lung Disease – Subcutaneous Administration

  The pharmacokinetics of tocilizumab in SSc-ILD patients was determined using a population pharmacokinetic analysis on a dataset composed of 66 SSc-ILD patients treated with 162 mg tocilizumab SC every week.

  The estimated median (range) steady-state C_max, C_troughand C_meanof tocilizumab were 52.5 (14.8-121) mcg/mL, 47.2 (10.8-114) mcg/mL, and 50.4 (13.4-119) mcg/mL, respectively. The accumulation ratios for C_meanor AUC_tau, C_trough, and C_maxwere 7.11, 6.56, and 5.89, respectively. Steady-state was reached after 13 weeks.

  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 adult 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 (14.11)]

  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.

  Based on PK-sIL-6R modeling and simulation, the recommended dosing regimen for ACTEMRA is expected to result in comparable plasma exposures of tocilizumab in pediatric patients aged 2 years and older with COVID-19 as observed in adults with COVID-19

  [see Use in Specific Populations (8.4)]

  .

  Absorption

  Following subcutaneous dosing, the absorption half-life was around 4 days in RA and GCA patients and 3 days in SSc-ILD 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.

  In SSc-ILD patients, the median value of T_maxwas 2.8 days after the tocilizumab every 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 SSc-ILD patients, the central volume of distribution was 4.16 L, the peripheral volume of distribution was 2.58 L resulting in a volume of distribution at steady state of 6.74 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 adult 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

  ACTEMRA 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 ACTEMRA 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, 8.8 mL per h in SSc-ILD patients, 5.8 mL per h in pediatric patients with PJIA, and 5.7 mL per h in pediatric patients with SJIA. In adult 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 ACTEMRA serum concentrations, the half-life of ACTEMRA is also concentration-dependent and varies depending on the serum concentration level.

  For intravenous administration in RA patients, the concentration-dependent apparent t_1/2is 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.

  In SSc-ILD patients at steady state, the effective t_1/2of tocilizumab varied between 12.1 and 13.0 days for the 162 mg subcutaneous every week dosing regimen.

  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 ACTEMRA-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, GCA, and SSc-ILD 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 ACTEMRA-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 ACTEMRA, 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 ACTEMRA 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 ACTEMRA, 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 ACTEMRA (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 ACTEMRA 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 ACTEMRA (due to normalization of CYP3A4) or higher exposures after discontinuation of ACTEMRA.

  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 ACTEMRA infusion (8 mg per kg), the omeprazole AUC_infdecreased 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 ACTEMRA (8 mg per kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after ACTEMRA infusion.
  )
• In
  GCA
  patients, ACTEMRA doses exceeding 600 mg per infusion are not recommended. (
  2.3 Recommended Dosage for Giant Cell Arteritis

  Recommended Intravenous Dosage Regimen:

  The recommended dosage of ACTEMRA 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.

  ACTEMRA 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 (2.11)]
    .
  • 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 ACTEMRA 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.

  ACTEMRA can be used alone following discontinuation of glucocorticoids.

  When transitioning from ACTEMRA 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 (2.11)]

  .
  ,
  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 AUC_tau, since for dosing regimens with different inter-dose intervals, the mean concentration over the dosing period characterizes the comparative exposure better than AUC_tau.

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

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

  The accumulation ratios for AUC and C_maxafter multiple doses of 4 and 8 mg/kg IV Q4W are low, while the accumulation ratios for C_troughare higher (2.62 and 2.47, respectively). For C_max, greater than 90% of the steady-state value was reached after the 1st IV infusion. For AUC_tauand C_mean, 90% of the steady-state value was reached after the 1st and 3rd infusion for 4 mg/kg and 8 mg/kg IV, while for C_trough, approximately 90% of the steady-state value was reached after the 4th IV infusion after both doses.

  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 AUC_tauand 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 AUC_tau, 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 AUC_tau, 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)]

  .

  Systemic Sclerosis-Associated Interstitial Lung Disease – Subcutaneous Administration

  The pharmacokinetics of tocilizumab in SSc-ILD patients was determined using a population pharmacokinetic analysis on a dataset composed of 66 SSc-ILD patients treated with 162 mg tocilizumab SC every week.

  The estimated median (range) steady-state C_max, C_troughand C_meanof tocilizumab were 52.5 (14.8-121) mcg/mL, 47.2 (10.8-114) mcg/mL, and 50.4 (13.4-119) mcg/mL, respectively. The accumulation ratios for C_meanor AUC_tau, C_trough, and C_maxwere 7.11, 6.56, and 5.89, respectively. Steady-state was reached after 13 weeks.

  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 adult 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 (14.11)]

  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.

  Based on PK-sIL-6R modeling and simulation, the recommended dosing regimen for ACTEMRA is expected to result in comparable plasma exposures of tocilizumab in pediatric patients aged 2 years and older with COVID-19 as observed in adults with COVID-19

  [see Use in Specific Populations (8.4)]

  .

  Absorption

  Following subcutaneous dosing, the absorption half-life was around 4 days in RA and GCA patients and 3 days in SSc-ILD 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.

  In SSc-ILD patients, the median value of T_maxwas 2.8 days after the tocilizumab every 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 SSc-ILD patients, the central volume of distribution was 4.16 L, the peripheral volume of distribution was 2.58 L resulting in a volume of distribution at steady state of 6.74 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 adult 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

  ACTEMRA 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 ACTEMRA 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, 8.8 mL per h in SSc-ILD patients, 5.8 mL per h in pediatric patients with PJIA, and 5.7 mL per h in pediatric patients with SJIA. In adult 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 ACTEMRA serum concentrations, the half-life of ACTEMRA is also concentration-dependent and varies depending on the serum concentration level.

  For intravenous administration in RA patients, the concentration-dependent apparent t_1/2is 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.

  In SSc-ILD patients at steady state, the effective t_1/2of tocilizumab varied between 12.1 and 13.0 days for the 162 mg subcutaneous every week dosing regimen.

  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 ACTEMRA-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, GCA, and SSc-ILD 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 ACTEMRA-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 ACTEMRA, 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 ACTEMRA 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 ACTEMRA, 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 ACTEMRA (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 ACTEMRA 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 ACTEMRA (due to normalization of CYP3A4) or higher exposures after discontinuation of ACTEMRA.

  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 ACTEMRA infusion (8 mg per kg), the omeprazole AUC_infdecreased 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 ACTEMRA (8 mg per kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after ACTEMRA infusion.
  )

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.

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

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.

ACTEMRA can be used alone following discontinuation of glucocorticoids.

The recommended dose of ACTEMRA for adult patients with SSc-ILD is 162 mg given once every week as a subcutaneous injection.

• 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, SJIA, CRS and COVID-19 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.

• Follow the
  Instructions for Use
  
  ACTEMRA^®(AC-TEM-RA)
  
  (tocilizumab)
  
  Injection, For Subcutaneous Use
  
  Single-dose Prefilled Syringe

  Read and follow the Instructions for Use that come with your ACTEMRA prefilled syringe before you start using it and each time you get a prescription refill. Before you use ACTEMRA prefilled syringe for the first time, make sure your healthcare provider shows you the right way to use it.

  • Do not remove the needle cap until you are ready to inject ACTEMRA.
  • Do not try to take apart the syringe at any time.
  • Do not reuse the same syringe.

  Parts of your ACTEMRA Prefilled Syringe

  (See Figure A).

  Figure A

  Supplies needed for your ACTEMRA Prefilled Syringe Injection (See Figure B):

  • ACTEMRA prefilled syringe
  • alcohol pad
  • sterile cotton ball or gauze
  • puncture-resistant container or sharps container for safe disposal of needle cap and used syringe
    (See Step 4 "Dispose of the syringe")
    Figure B

  Step 1. Preparing for an ACTEMRA Injection

  Find a comfortable space with a clean, flat, working surface.

  • Take the box containing the syringe out of the refrigerator and open the box.
    Do not
    touch the trigger fingers on the syringe as this may damage the syringe.
  • Remove 1 single-use ACTEMRA prefilled syringe from the box and let it warm up for 30 minutes to allow it to reach room temperature. If the syringe does not reach room temperature, this could cause your injection to feel uncomfortable and make it difficult to push the plunger in.
  • Do not
    speed up the warming process in any way, such as using the microwave or placing the syringe in warm water.
  • Check the expiration date on the ACTEMRA prefilled syringe
    (See Figure A). Do not
    use it if the expiration date has passed because it may not be safe to use. If the expiration date has passed safely dispose of the syringe in a sharps container and get a new one.

  Do not remove the needle cap while allowing your ACTEMRA prefilled syringe to reach room temperature.

  • Keep your unused syringes in the original carton and keep in the refrigerator at 36°F to 46°F (2°C to 8°C).
    Do not
    freeze.
  • Once removed from the refrigerator, your prefilled syringe can be stored up to 2 weeks at or below 86°F (30°C). Your prefilled syringe must always be kept in the original carton in order to protect from light and moisture. Hold your ACTEMRA prefilled syringe with the covered needle pointing down
    (See Figure C).
    Figure C
  • Check the liquid in the ACTEMRA prefilled syringe. It should be clear and colorless to pale yellow. Do not inject ACTEMRA if the liquid is cloudy, discolored, or has lumps or particles in it because it may not be safe to use. Safely dispose of the syringe in a sharps container and get a new one.
  • Wash your hands well with soap and water.

  Step 2. Choose and Prepare an Injection Site

  Choose an Injection Site

  • The front of your thigh and your abdomen except for the 2-inch area around your navel are the recommended injection sites
    (See Figure D).
  • The outer area of the upper arms may also be used only if the injection is being given by a caregiver. Do not attempt to use the upper arm area by yourself
    (See Figure D).

  Rotate Injection Site

  • Choose a different injection site for each new injection at least 1-inch from the last area you injected.
  • Do not inject into moles, scars, bruises, or areas where the skin is tender, red, hard or not intact.Figure D

  Prepare the Injection Site

  • Wipe the injection site with an alcohol pad in a circular motion and let it air dry to reduce the chance of getting an infection.
    Do not
    touch the injection site again before giving the injection.
  • Do not
    fan or blow on the clean area.

  Step 3. Inject ACTEMRA

  • Hold the ACTEMRA prefilled syringe with 1 hand and pull the needle cap straight off with your other hand
    (See Figure E). Do not
    hold the plunger while you remove the needle cap. If you cannot remove the needle cap you should ask a caregiver for help or contact your healthcare provider.Figure E
  • Throw away the needle cap in a sharps container.
  • There may be a small air bubble in the ACTEMRA prefilled syringe. You do not need to remove it.
  • You may see a drop of liquid at the end of the needle. This is normal and will not affect your dose.
  • Do not
    touch the needle or let it touch any surfaces.
  • Do not
    use the prefilled syringe if it is dropped.
  • If it is not used within 5 minutes of needle cap removal, the syringe should be disposed of in the puncture resistant container or sharps container and a new syringe should be used.
  • Never reattach the needle cap after removal.
  • Hold the ACTEMRA prefilled syringe in 1 hand between the thumb and index finger
    (See Figure F).
    Figure F
  • Do not
    pull back on the plunger of the syringe.
  • Use your other hand and gently pinch the area of skin you cleaned. Hold the pinched skin firmly. Pinching the skin is important to make sure that you inject under the skin (into fatty tissue) but not any deeper (into muscle). Injection into muscle could cause the injection to feel uncomfortable.
  • Do not
    hold or push on the plunger while inserting the needle into the skin.
  • Use a quick, dart-like motion to insert the needle all the way into the pinched skin at an angle between 45° to 90°
    (See Figure G).
    It is important to use the correct angle to make sure the medicine is delivered under the skin (into fatty tissue), or the injection could be painful and the medicine may not work.Figure G
  • Keep the syringe in position and let go of the pinch of skin.
  • Slowly inject all of the medicine by gently pushing the plunger all the way down
    (See Figure H).
    You must press the plunger all the way down to get the full dose of medicine and to ensure the trigger fingers are completely pushed to the side. If the plunger is not fully depressed the needle shield will not extend to cover the needle when it is removed. If the needle is not covered, carefully place the syringe into the puncture resistant container to avoid injury with the needle.Figure H
  • After the plunger is pushed all the way down, keep pressing down on the plunger to be sure all of the medicine is injected before taking the needle out of the skin.
  • Keep pressing down on the plunger while you take the needle out of the skin at the same angle as inserted
    (See Figure I).
    Figure I
  • After the needle is removed completely from the skin, release the plunger, allowing the needle-shield to protect the needle
    (See Figure J).
    Figure J

  After the Injection

  • There may be a little bleeding at the injection site. You can press a cotton ball or gauze over the injection site.
  • Do not
    rub the injection site.
  • If needed, you may cover the injection site with a small bandage.

  Step 4. Dispose of the syringe

  • The ACTEMRA prefilled syringe should not be reused.
  • Put the used syringe into your puncture resistant container
    (See " How do I throw away used syringes?")
  • Do not
    put the needle cap back on the needle.
  • If your injection is given by another person, this person must also be careful when removing the syringe and disposing of the syringe to prevent accidental needle stick injury and passing infection.

  How do I throw away used syringes?

  • Put your used needles and syringes including ACTEMRA in a FDA-cleared sharps disposal container right away after use
    (See Figure K). Do not throw away (dispose of) loose needles and syringes in your household trash.
    Figure K
  • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
    • made of a heavy-duty plastic
    • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out
    • upright stable during use
    • leak-resistant
    • properly labeled to warn of hazardous waste inside the container
      • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at:
        http://www.fda.gov/safesharpsdisposal
        .
      • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.
  • Keep ACTEMRA prefilled syringes and the disposal container out of the reach of children.

  Record your Injection

  • Write the date, time, and specific part of your body where you injected yourself. It may also be helpful to write any questions or concerns about the injection so you can ask your healthcare provider.

  If you have questions or concerns about your ACTEMRA prefilled syringe, please contact your healthcare provider familiar with ACTEMRA or call 1-800-ACTEMRA.

  This Medication Guide and Instructions for Use has been approved by the U.S. Food and Drug Administration.
  
  Medication Guide Revised: 08/2025
  
  ACTEMRA is a registered trademark of Chugai Seiyaku Kabushiki Kaisha Corp., a member of the Roche Group.

  Genentech, Inc.

  
  
  A Member of the Roche Group
  
  1 DNA Way
  
  South San Francisco, CA 94080-4990

  U.S. License No.: 1048
  
  © 2025 Genentech, Inc. All rights reserved.

  Figure A

  Figure B

  Figure C

  Figure D

  Figure E

  Figure F

  Figure G

  Figure H

  Figure I

  Figure J

  Figure K

  for prefilled syringe and prefilled ACTPen^® autoinjector

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

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 (

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

• Pregnancy:
  Based on animal data, may cause fetal harm. (
  8.1 Pregnancy

  Risk Summary

  The available data with ACTEMRA 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 confounders. Monoclonal antibodies, such as tocilizumab, 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 ACTEMRA

  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 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 is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to tocilizumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of ACTEMRA to an infant during lactation; therefore the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ACTEMRA and the potential adverse effects on the breastfed child from tocilizumab or from the underlying maternal condition.
  )