Actemra ACTPen Dailymed

Recent Major Changes Section

Indications and Usage (1.7)	12/2022
Dosage and Administration (2.1, 2.3, 2.9, 2.11)	02/2022
Dosage and Administration (2.1, 2.8, 2.9)	12/2022
Warnings and Precautions (5.1, 5.3, 5.4)	12/2022

1 Indications And Usage

ACTEMRA^® (tocilizumab) is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of:

Rheumatoid Arthritis (RA) (1.1)

• 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)

• Adult patients with giant cell arteritis.

Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD) (1.3)

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

Polyarticular Juvenile Idiopathic Arthritis (PJIA) (1.4)

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

Systemic Juvenile Idiopathic Arthritis (SJIA) (1.5)

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

Cytokine Release Syndrome (CRS) (1.6)

• 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.

Coronavirus Disease 2019 (COVID-19) (1.7)

• 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).

1.1Rheumatoid Arthritis (RA)

ACTEMRA^® (tocilizumab) 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).

1.2Giant Cell Arteritis (GCA)

ACTEMRA^® (tocilizumab) is indicated for the treatment of giant cell arteritis (GCA) in adult patients.

1.3Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD)

ACTEMRA^® (tocilizumab) is indicated for slowing the rate of decline in pulmonary function in adult patients with systemic sclerosis-associated interstitial lung disease.

1.4Polyarticular Juvenile Idiopathic Arthritis (PJIA)

ACTEMRA^® (tocilizumab) is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.

1.5Systemic Juvenile Idiopathic Arthritis (SJIA)

ACTEMRA^® (tocilizumab) is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older.

1.6Cytokine Release Syndrome (CRS)

ACTEMRA^® (tocilizumab) 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.

1.7 Coronavirus Disease 2019 (COVID-19)

ACTEMRA® (tocilizumab) 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).

2 Dosage And Administration

For RA, pJIA and sJIA, ACTEMRA may be used alone or in combination with methotrexate: and in RA, other DMARDs may be used. (2)

General Administration and Dosing Information (2.1)

• 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, 5.4).
• 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, 5.4).
• In RA, CRS or COVID-19 patients, ACTEMRA doses exceeding 800 mg per infusion are not recommended. (2.2, 2.7, 12.3)
• In GCA patients, ACTEMRA doses exceeding 600 mg per infusion are not recommended. (2.3, 12.3)

Rheumatoid Arthritis (2.2)

Recommended Adult Intravenous Dosage:

When used in combination with 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 (2.3)

Recommended Adult Intravenous Dosage:

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.

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.

ACTEMRA can be used alone following discontinuation of glucocorticoids.

Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD) (2.4)

Recommended Adult Subcutaneous Dosage:

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

Polyarticular Juvenile Idiopathic Arthritis (2.5)

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 (2.6)

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)

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.

Coronavirus Disease 2019 (2.8)

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

Administration of Intravenous formulation (2.9)

• 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 and CRS 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 (2.10)

• Follow the Instructions for Use for prefilled syringe and prefilled ACTPen^® autoinjector

Dose Modifications (2.11)

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

2.1General Considerations for Administration

Not Recommended for Concomitant Use with Biological DMARDs

ACTEMRA has 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 ACTEMRA 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, 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) [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 ACTEMRA should take into account the potential benefit of treating the CRS versus the risks of short-term treatment with ACTEMRA.
• 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 [see Warnings and Precautions (5.3, 5.4)].

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)].

2.3Recommended 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)].

2.4 Recommended Dosage for Systemic Sclerosis-Associated Interstitial Lung Disease

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

• 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)].
• Subcutaneous administration with the prefilled ACTPen^® autoinjector has not been studied in SSc-ILD.
• Intravenous administration is not approved for SSc-ILD.

2.5 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis

ACTEMRA 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 ACTEMRA 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 ACTEMRA 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 (2.11].

2.6Recommended Dosage for Systemic Juvenile Idiopathic Arthritis

ACTEMRA 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 ACTEMRA 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	12 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 ACTEMRA 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 (2.11)].

2.7Recommended 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.

2.8 Coronavirus Disease 2019 (COVID-19)

Administer ACTEMRA by intravenous infusion only.

The recommended dosage of ACTEMRA 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 ACTEMRA 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.

2.9Preparation and Administration Instructions for Intravenous Infusion

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

• Use a sterile needle and syringe to prepare ACTEMRA.
• 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 ACTEMRA injection required for the patient's dose from the infusion bag or bottle [see Dosage and Administration (2.2, 2.5, 2.6, 2.7)].

For Intravenous Use: Volume of ACTEMRA Injection per kg of Body Weight
Dosage	Indication	Volume of ACTEMRA 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 RAAdult COVID-19SJIA, 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 ACTEMRA 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 ACTEMRA solutions for infusion using 0.9% Sodium Chloride Injection, USP may be stored at 36°F to 46°F (2°C to 8°C) or room temperature for up to 24 hours and should be protected from light.
• The fully diluted ACTEMRA 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 24 hours or room temperature for up to 4 hours and should be protected from light.
• ACTEMRA solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used.
• Allow the fully diluted ACTEMRA 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.
• ACTEMRA 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 ACTEMRA 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 ACTEMRA solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and polypropylene, polyethylene and glass infusion bottles.

2.10Preparation and Administration Instructions for Subcutaneous Injection

• ACTEMRA 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. ACTEMRA 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 ACTEMRA or the patient's caregiver may administer ACTEMRA if a healthcare practitioner determines that it is appropriate. PJIA and SJIA patients may self-inject with the ACTEMRA prefilled syringe or ACTPen^® autoinjector, or the patient's caregiver may administer ACTEMRA 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 ACTEMRA prefilled syringes (PFS) or prefilled ACTPen^® autoinjectors exhibiting particulate matter, cloudiness, or discoloration. ACTEMRA for subcutaneous administration should be clear and colorless to pale yellow. Do not use if any part of the PFS or ACTPen^® autoinjector appears to be damaged.
• Patients using ACTEMRA for subcutaneous administration should be instructed to inject the full amount in the syringe (0.9 mL) or full amount in the ACTPen^® autoinjector (0.9 mL), which provides 162 mg of ACTEMRA, 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.

2.11Dosage Modifications due to Serious Infections or Laboratory Abnormalities

Serious Infections

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

Laboratory Abnormalities

Rheumatoid Arthritis, Giant Cell Arteritis and Systemic Sclerosis-Associated Interstitial Lung Disease

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

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

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

Polyarticular and Systemic Juvenile Idiopathic Arthritis

Dose reduction of ACTEMRA has not been studied in the PJIA and SJIA populations. Dose interruptions of ACTEMRA 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 ACTEMRA dosing until the clinical situation has been evaluated. In PJIA and SJIA the decision to discontinue ACTEMRA for a laboratory abnormality should be based upon the medical assessment of the individual patient.

• Serious Infections – do not administer ACTEMRA during an active infection, including localized infections. If a serious infection develops, interrupt ACTEMRA until the infection is controlled. (5.1)
• Gastrointestinal (GI) perforation—use with caution in patients who may be at increased risk. (5.2)
• Hepatotoxicity- Monitor patients for signs and symptoms of hepatic injury. Modify or discontinue ACTEMRA if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (2.10, 5.3)
• Laboratory monitoring—recommended due to potential consequences of treatment-related changes in neutrophils, platelets, lipids, and liver function tests. (2.10, 5.4)
• Hypersensitivity reactions, including anaphylaxis and death have occurred. (5.6)
• Live vaccines—Avoid use with ACTEMRA. (5.9, 7.3)

5.1Serious 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 ACTEMRA. 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 ACTEMRA. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, uleriosis). 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 ACTEMRA in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating ACTEMRA 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 ACTEMRA, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see Dosage and Administration (2.8), Adverse Reactions (6.1), and Patient Counseling Information (17)].

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

COVID-19

In patients with COVID-19, monitor for signs and symptoms of new infections during and after treatment with ACTEMRA. There is limited information regarding the use of ACTEMRA in patients with COVID-19 and concomitant active serious infections. The risks and benefits of treatment with ACTEMRA 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 ACTEMRA. In patients with COVID-19, testing for latent infection is not necessary prior to initiating treatment with ACTEMRA.

Consider anti-tuberculosis therapy prior to initiation of ACTEMRA 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 ACTEMRA.

Viral Reactivation

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

5.2Gastrointestinal Perforations

Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with ACTEMRA. Use ACTEMRA with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation [see Adverse Reactions (6.1)].

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.

5.4Changes 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 mm³ 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 (2.11) .
• – 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 mm³ treatment 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)].

5.5Immunosuppression

The impact of treatment with ACTEMRA on the development of malignancies is not known but malignancies were observed in clinical studies [see Adverse Reactions (6.1)]. ACTEMRA is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies.

5.6Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have been reported in association with ACTEMRA [see Adverse Reactions (6)] and anaphylactic events with a fatal outcome have been reported with intravenous infusion of ACTEMRA. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials of intravenous ACTEMRA, 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population, 0.7% (8 out of 1068) in the subcutaneous 6-month controlled RA trials, and in 0.7% (10 out of 1465) of patients in the subcutaneous all-exposure population. In the SJIA controlled trial with intravenous ACTEMRA, 1 out of 112 patients (0.9%) experienced hypersensitivity reactions that required treatment discontinuation. In the PJIA controlled trial with intravenous ACTEMRA, 0 out of 188 patients (0%) in the ACTEMRA all-exposure population experienced hypersensitivity reactions that required treatment discontinuation. Reactions that required treatment discontinuation included generalized erythema, rash, and urticaria. Injection site reactions were categorized separately [see Adverse Reactions (6)].

In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and death have occurred in patients treated with a range of doses of intravenous ACTEMRA, with or without concomitant therapies. Events have occurred in patients who received premedication. Hypersensitivity, including anaphylaxis events, have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of ACTEMRA [see Adverse Reactions (6.8)]. ACTEMRA for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. For ACTEMRA subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of ACTEMRA immediately and discontinue ACTEMRA permanently. Do not administer ACTEMRA to patients with known hypersensitivity to ACTEMRA [see Contraindications (4) and Adverse Reactions (6)].

5.7Demyelinating Disorders

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

5.8Active Hepatic Disease and Hepatic Impairment

Treatment with ACTEMRA is not recommended in patients with active hepatic disease or hepatic impairment [see Adverse Reactions (6.1), Use in Specific Populations (8.6)].

5.9Vaccinations

Avoid use of live vaccines concurrently with ACTEMRA as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ACTEMRA.

No data are available on the effectiveness of vaccination in patients receiving ACTEMRA. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, particularly pediatric or elderly patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ACTEMRA therapy. The interval between live vaccinations and initiation of ACTEMRA therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.