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Tocilizumab is a recombinant humanized monoclonal antibody IL-6 receptor inhibitor used to treat inflammatory and autoimmune conditions.

It was first described in the literature in 2003 when Chugai, a subsidiary of Roche began developing IL-6 inhibiting monoclonal antibodies.

Tocilizumab was granted

FDA approval on 8 January to treat a number of inflammatory and autoimmune disorders, such as different types of arthritis and cytokine release syndrome.

It was later approved by Health

Canada on 30 April 2010.

After being investigated to treat severely ill patients with COVID-19, 1, 7, 8 tocilizumab was approved by the European Commission in December to treat COVID-19 in adults receiving systemic corticosteroids and supplemental oxygen or mechanical ventilation.

Subsequently, it was granted approval by Health Canada and the FDA in October and December 2022, respectively.

Tocilizumab-bavi, a biosimilar drug, was approved by the FDA in September 2023. 13.

Two biosimilar versions of tocilizumab have since been approved by the FDA: tocilizumab-bavi, in September and Tyenne® (tocilizumab), in June 2024.

Tyenne is the first tocilizumab biosimilar approved in both intravenous and subcutaneous formulations and is authorized to treat several inflammatory conditions, including rheumatoid arthritis and juvenile idiopathic arthritis.

Tocilizumab is indicated to treat moderate to severe rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. 6, 11, 13 Tocilizumab is also used to treat coronavirus disease 2019 (COVID-19) in adults who are receiving systemic corticosteroids and require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). 10, 11,

Tocilizumab is an

IL-6 inhibiting monoclonal antibody used to treat autoimmune and inflammatory conditions.

Tocilizumab has a long duration of action as it is generally given every 4 weeks and has a wide therapeutic index.

Patients should be counselled regarding the risk of infections, GI perforation, and hepatotoxicity.

A 162 mg subcutaneous dose given weekly has a C max of 51.3±23.2 µg/mL and an AUC of 8254±3833 µg*h/mL.

A 162 mg subcutaneous dose given every 2 weeks has a C max of 13±8.3 µg/mL and an AUC of 3460±2530 µg*h/mL.

A 162 mg subcutaneous dose given every 4 weeks has a C max of 154±42 µg/mL and an AUC of 39216±14304 µg*h/mL.

In rheumatoid arthritis patients, the central volume of distribution is 3.5 L, the peripheral volume of distribution is 2.9 L, and the volume of distribution at steady state is 6.4 L.

In giant cell arteritis patients, the central volume of distribution is 4.09 L, the peripheral volume of distribution if 3.37 L, and the volume of distribution at steady state is 7.46 L.

In pediatric patients with polyarticular juvenile arthritis, the central volume of distribution is 1.98 L, the peripheral volume of distribution is 2.1 L, and the volume of distribution at steady state is 4.08 L.

In pediatric patients with systemic juvenile idiopathic arthritis, the central volume of distribution is 1.87 L, the peripheral volume of distribution is 2.14 L, and the volume of distribution at steady state is 4.01 L.

Tocilizumab, like other monoclonal antibodies, is expected to be metabolized to smaller proteins and amino acids by proteolytic enzymes.

Data regarding the exact route of elimination of monoclonal antibodies is not readily available. 3, 6.

The half life of tocilizumab is concentration dependent.

The terminal half life in rheumatoid arthritis patients is 21.5 days.

The absorption half life in rheumatoid arthritis and giant cell arteritis patients was 4 days, and in polyarticular juvenile idiopathic arthritis patients and systemic juvenile idiopathic arthritis patients was 2 days.

The linear clearance in rheumatoid arthritis patients is 12.5 mL/h, in giant cell arteritis patients is 6.7 mL/h, in polyarticular juvenile idiopathic arthritis patients is 5.8 mL/h, and in systemic juvenile idiopathic arthritis is 5.7 mL/h.

Clearance is dose dependent and changes from non linear at low doses to linear at higher doses.

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Data regarding overdoses of tocilizumab are not readily available.

Patients experiencing an overdose may develop neutropenia.

In case of overdose, monitor patients for signs of adverse reactions and provide symptomatic and supportive treatment.

is contraindicated in patients with known hypersensitivity to tocilizumab products.

Known hypersensitivity to tocilizumab products.

RA, pJIA and sJIA, TOFIDENCE may be used alone or in combination with methotrexate; and in RA, other non-biologic DMARDs may be used.

• It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm 3, platelet count below 100,000 per mm 3, or ALT or AST above 1.5 times the upper limit of normal (ULN).

• It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 1000 per mm3, platelet count below 50,000 mm3, or ALT or AST above 10 times ULN.

In RA or

COVID-19 patients, TOFIDENCE doses exceeding 800 mg per infusion are not recommended.

In GCA patients, TOFIDENCE doses exceeding 600 mg per infusion are not recommended.

Rheumatoid Arthritis Recommended Adult Intravenous Dosage

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

Giant Cell Arteritis Recommended Adult Intravenous Dosage: The recommended dose is 6 mg per kg every 4 weeks in combination with a tapering course of glucocorticoids.

TOFIDENCE can be used alone following discontinuation of glucocorticoids.

Polyarticular Juvenile Idiopathic Arthritis Recommended Intravenous

PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg Systemic Juvenile Idiopathic Arthritis Recommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg Coronavirus Disease The recommended dosage of TOFIDENCE for adult patients with COVID-19 is 8 mg per kg administered by a 60-minute intravenous infusion.

Administration of Intravenous Formulation For patients with RA, GCA, COVID-19, PJIA, and SJIA patients at or above 30 kg, dilute to 100 mL in 0.9% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique.

For PJIA and

SJIA patients less than 30 kg, dilute to 50 mL in 0.9% 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.

Recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia. 2.1 General Considerations for Administration Not Recommended for Concomitant Use with Biological DMARDs Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection.

Avoid using TOFIDENCE with biological

Baseline Laboratory Evaluation Prior to Treatment

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

RA, GCA, PJIA and SJIA – It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm 3, platelet count below 100,000 per mm 3, or ALT or AST above 1.5 times the upper limit of normal (ULN) .

• It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 1000 per mm3, platelet count below 50,000 mm3, or ALT or AST above 10 times ULN 2.2 Recommended Dosage for Rheumatoid Arthritis TOFIDENCE may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion.

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

Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.

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

When transitioning from intravenous therapy with

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

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

Doses exceeding 600 mg per infusion are not recommended in GCA patients.

TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose. 2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis TOFIDENCE may be used as an intravenous infusion alone or in combination with methotrexate.

Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate.

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

Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia. 2.5 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis TOFIDENCE may be used as an intravenous infusion or in combination with methotrexate.

Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate.

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

Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia. 2.6 Coronavirus Disease 2019 (COVID-19) Administer TOFIDENCE by intravenous infusion only.

The recommended dosage of

TOFIDENCE 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 TOFIDENCE 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. 2.7 Preparation and Administration Instructions for Intravenous Infusion TOFIDENCE for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows: Use a sterile needle and syringe to prepare TOFIDENCE.

Patients less than 30 kg: use a 50 mL infusion bag or bottle of 0.9% Sodium Chloride Injection, USP, and then follow steps and 2 below.

Patients at or above 30 kg weight: use a 100 mL infusion bag or bottle, and then follow steps and 2 below.

Step 1.

Withdraw a volume of 0.9% Sodium Chloride Injection, USP, equal to the volume of the TOFIDENCE injection required for the patient's dose from the infusion bag or bottle.

Volume of TOFIDENCE Injection per kg of Body Weight Dosage Indication Volume of TOFIDENCE injection per kg of body weight 4 mg/kg Adult RA 0.2 mL/kg 6 mg/kg Adult GCA 0.3 mL/kg 8 mg/kg Adult RA Adult COVID-19 SJIA and PJIA (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 (less than 30 kg of body weight) 0.6 mL/kg Step 2.

Withdraw the amount of

TOFIDENCE for intravenous infusion from the vial(s) and add slowly into the 0.9% Sodium Chloride Injection, USP infusion bag or bottle.

To mix the solution, gently invert the bag to avoid foaming.

The fully diluted

TOFIDENCE solutions for infusion using 0.9% Sodium Chloride Injection, USP may be stored refrigerated at 36°F to 46°F (2°C to 8°C) for up to 24 hours or room temperature at 68°F to 77°F (20°C to 25°C) for up to 12 hours and should be protected from light.

TOFIDENCE solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used.

Allow the fully diluted

TOFIDENCE 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.

TOFIDENCE 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 TOFIDENCE 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

TOFIDENCE solutions are compatible with infusion bags and/or infusion sets with the following materials: polypropylene, polyethylene, polyolefin, polyvinyl chloride, polyethersulfone, polyurethane, nylon and stainless steel. 2.8 Dosage Modifications due to Serious.

Infections or Laboratory Abnormalities Serious.

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

Laboratory Abnormalities Rheumatoid Arthritis and Giant Cell Arteritis Liver Enzyme Abnormalities Lab Value Recommendation for RA Recommendation for GCA Greater than to 3× ULN Dose modify concomitant DMARDs if appropriate.

For persistent increases in this range

For patients receiving intravenous TOFIDENCE, reduce dose to 4 mg per kg or hold TOFIDENCE until ALT or AST have normalized.

Dose modify immunomodulatory agents if appropriate

For persistent increases in this range: For patients receiving intravenous TOFIDENCE, hold TOFIDENCE until ALT or AST have normalized.

Greater than to 5× ULN (confirmed by repeat testing) Hold TOFIDENCE dosing until less than 3.

(tocilizumab-bavi) injection is a preservative-free, sterile, clear to opalescent, colorless to light yellow solution.

TOFIDENCE is supplied as 80 mg/4 mL (NDC 64406-024-01), 200 mg/10 mL (NDC 64406-022-01), and 400 mg/20 mL (NDC 64406-023-01) individually packaged 20 mg/mL single-dose vials for further dilution prior to intravenous infusion.

Do not use beyond expiration date on the container or package.

TOFIDENCE must be refrigerated at 36°F to 46°F (2°C to 8°C).

Do not freeze.

Protect the vials from light by storage in the original package until time of use.

Do not use beyond expiration date on the container or package.

TOFIDENCE must be refrigerated at 36°F to 46°F (2°C to 8°C).

Do not freeze.

Protect the vials from light by storage in the original package until time of use.

The available data with tocilizumab products from a pregnancy exposure registry, retrospective cohort study, pharmacovigilance, and published literature are insufficient to draw conclusion about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

These studies had methodological limitations, including small sample size of tocilizumab exposed groups, missing exposure and outcomes information, and lack of adjustment for cofounders.

Monoclonal antibodies, such as tocilizumab products, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant.

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 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.

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 to 4% and to 20%, respectively.

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 TOFIDENCE in utero.

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.

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 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.

TOFIDENCE by intravenous use is indicated for the treatment of pediatric patients with: Active systemic juvenile idiopathic arthritis in patients 2 years of age and older Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older The safety and effectiveness of TOFIDENCE in pediatric patients with conditions other than PJIA or SJIA have not been established.

The safety and effectiveness in pediatric patients below the age of 2 have not been established in PJIA or SJIA.

Arthritis – Intravenous Use A multicenter, open-label, single arm study to evaluate the PK, safety and exploratory PD and efficacy of tocilizumab over 12-weeks in SJIA patients (N=11) under 2 years of age was conducted.

Patients received intravenous tocilizumab 12 mg/kg every two weeks.

Concurrent use of stable background treatment with corticosteroids, MTX, and/or non-steroidal anti-inflammatory drugs was permitted.

Patients who completed the 12-week period could continue to the optional extension period (a total of 52-weeks or until the age of 2 years, whichever was longer).

The primary

PK endpoints (C max, C trough and AUC 2weeks ) of tocilizumab at steady-state in this study were within the ranges of these parameters observed in patients with SJIA aged to 17 years.

The safety and immunogenicity of tocilizumab for patients with SJIA under 2 years of age was assessed descriptively.

SAEs, AEs leading to discontinuation, and infectious AEs were reported by 27.3%, 36.4%, and 81.8% of patients.

Six patients (54.5%) experienced hypersensitivity reactions, defined as all adverse events occurring during or within 24 hours after an infusion considered related to tocilizumab.

Three of these patients experienced serious hypersensitivity reactions and were withdrawn from the study.

Three patients with hypersensitivity reactions (two with serious hypersensitivity reactions) developed treatment induced anti-tocilizumab antibodies after the event.

There were no cases of

MAS based on the protocol-specified criteria, but 2 cases of suspected MAS based on Ravelli criteria Ravelli A, Minoia F, Davì S on behalf of the Paediatric Rheumatology International Trials Organisation, the Childhood Arthritis and Rheumatology Research Alliance, the Pediatric Rheumatology Collaborative Study Group, and the Histiocyte Society, et al.

Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis.

Diseases 2016;75:481-489. .

Of the 2644 patients who received tocilizumab in Studies I to V, a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older.

The frequency of serious infection among tocilizumab treated subjects 65 years of age and older was higher than those under the age of 65.

As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

In the

EMPACTA, COVACTA, and REMDACTA studies, of the 974 COVID-19 patients in the tocilizumab arm, 375 (39%) were 65 years of age or older.

No overall differences in safety or effectiveness of tocilizumab were observed between patients 65 years of age and older and those under the age of 65 years of age in these studies.

RECOVERY study, of the 2022 COVID-19 patients in the tocilizumab arm, 930 (46%) were 65 years of age or older.

No overall differences in effectiveness of tocilizumab were observed between patients 65 years of age and older and those under the age 65 years of age in this study.