Tyenne Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes .................................................................................................... 2

Table of Contents .................................................................................................................... 2

Part 1: Healthcare Professional Information ............................................................................ 4

1 Indications ................................................................................................................... 4

1.1 Pediatrics ........................................................................................................... 4

1.2 Geriatrics ........................................................................................................... 5

2 Contraindications ......................................................................................................... 5

3 Serious Warnings and Precautions Box ........................................................................ 5

4 Dosage and Administration .......................................................................................... 6

4.1 Dosing Considerations ....................................................................................... 6

4.2 Recommended Dose and Dosage Adjustment .................................................. 6

4.4 Administration ................................................................................................ 11

5 Overdose.................................................................................................................... 14

6 Dosage Forms, Strengths, Composition, and Packaging .............................................. 14

7 Warnings and Precautions .......................................................................................... 15

7.1 Special Populations ......................................................................................... 22

7.1.1 Pregnancy ........................................................................................................ 22

7.1.2 Breastfeeding .................................................................................................. 22

8 Adverse Reactions ...................................................................................................... 22

8.1 Adverse Reaction Overview ............................................................................ 22

8.2 Clinical Trial Adverse Reactions ....................................................................... 27

8.2.1 Clinical Trial Adverse Reactions - Pediatrics ..................................................... 89

8.3 Less Common Clinical Trial Adverse Reactions ................................................ 94

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data .......................................................................................................... 103

8.5 Post-Market Adverse Reactions .................................................................... 112

9 Drug Interactions ...................................................................................................... 112

9.2 Drug Interactions Overview ........................................................................... 112

9.4 Drug-Drug Interactions .................................................................................. 113

10 Clinical Pharmacology ............................................................................................... 114

10.1 Mechanism of Action .................................................................................... 114

10.2 Pharmacodynamics ....................................................................................... 114

10.3 Pharmacokinetics .......................................................................................... 114

11 Storage, Stability, and Disposal ................................................................................. 121

12 Special Handling Instructions .................................................................................... 121

Part 2: Scientific Information ................................................................................................ 122

13 Pharmaceutical Information ...................................................................................... 122

14 Clinical Trials ............................................................................................................. 123

14.4 Clinical Trials - Reference Biologic Drug ........................................................ 123

15 Microbiology ............................................................................................................. 147

16 Non-Clinical Toxicology ............................................................................................. 147

17 Supporting Product Monographs .............................................................................. 156

Patient Medication Information ........................................................................................... 157

Instructions for Use .............................................................................................................. 166

Instructions for Use .............................................................................................................. 174

Part 1: Healthcare Professional Information

Tyenne^® (tocilizumab) is a biosimilar to Actemra (tocilizumab). A biosimilar is a biologic drug that was granted authorization based on a demonstration of similarity to a version previously authorized in Canada, known as the reference biologic drug.

1 Indications

Rheumatoid Arthritis (RA) [Intravenous or subcutaneous formulations]

TYENNE (tocilizumab) is indicated for:

• reducing signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis.

Tyenne (Intravenous only) in combination with methotrexate (MTX) has been shown to reduce the rate of progression of radiographic joint damage at Week 52.

Tyenne is to be given in combination with MTX or other DMARDs; however, in cases of intolerance to MTX or where treatment with MTX is not appropriate Tyenne may also be given as monotherapy.

Giant Cell Arteritis (GCA) [Subcutaneous formulation only]

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

Polyarticular Juvenile Idiopathic Arthritis (pJIA) [Intravenous or subcutaneous formulations]

Tyenne is indicated for the treatment of signs and symptoms of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older who have responded inadequately to previous therapy with DMARDs.

Systemic Juvenile Idiopathic Arthritis (sJIA) [Intravenous or subcutaneous formulations]

Tyenne is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older, who have responded inadequately to previous therapy with one or more non-steroidal anti-inflammatory drugs and systemic corticosteroids.

Cytokine release syndrome (CRS) [Intravenous formulation only]

Tyenne is indicated for the treatment of patients with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS), in accordance with patient populations specified for authorized CAR T cell products.

Coronavirus disease 2019 (COVID-19) [Intravenous formulation only]:

Tyenne is indicated for the treatment of 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.

1.1 Pediatrics

Pediatrics (<18 years of age): The safety and efficacy in patients aged less than 2 years in sJIA and pJIA have not been established.

The safety and efficacy of Tyenne for treating CAR T cell-induced CRS in children under the age of 3 has not been established.

1.2 Geriatrics

Geriatrics (>65 years of age): Of the 2644 patients who received tocilizumab in studies, 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. There is a higher incidence of infections in the elderly population in general, therefore, caution should be used when treating the elderly with tocilizumab.

2 Contraindications

Tyenne (tocilizumab) should not be administered to patients with known hypersensitivity to tocilizumab or any of its components. For a complete listing, see 6 Dosage Forms, Strengths, Composition and Packaging section of the product monograph.

Patients with active infections, with the exception of COVID-19, as indicated (see also 7 Warnings and Precautions).

3 Serious Warnings and Precautions Box

Serious Warnings and Precautions

4 Dosage and Administration

4.1 Dosing Considerations

General

• For adult patients with RA, Tyenne may be administered as an intravenous infusion or a subcutaneous injection.
• For adult patients with GCA, Tyenne is administered as a subcutaneous injection.
• For patients with pJIA and sJIA, Tyenne is administered as an intravenous infusion or a subcutaneous injection.
• For patients with CRS, Tyenne is administered as an intravenous infusion.
• For adult patients with COVID-19, Tyenne is administered as an intravenous infusion.
• For adult patients with COVID-19, Tyenne should not be administered in patients who are not receiving corticosteroids.
• Intravenous infusion: Use a sterile needle and syringe to prepare Tyenne.

See below for indication specific details.

RHEUMATOID ARTHRITIS [INTRAVENOUS OR SUBCUTANEOUS FORMULATIONS]

Dosing Considerations

• It would be prudent not to use Tyenne in patients who are using azathioprine or cyclophosphamide.
• Tocilizumab has not been studied in combination with biological DMARDs such as TNF antagonists.
• Treatment with biological DMARDs such as TNF inhibitors has been associated with reactivation of Hepatitis B and C. Therefore, screening for viral hepatitis should be performed in accordance with published guidelines before starting therapy with Tyenne. In clinical studies with tocilizumab, patients who screened positive for hepatitis were excluded from the study
• Tyenne treatment should be interrupted if a patient develops a serious infection until the infection is controlled.
• Continuing therapy beyond 16 weeks should be carefully reconsidered in a patient not responding within this time period.

4.2 Recommended Dose and Dosage Adjustment

RHEUMATOID ARTHRITIS [INTRAVENOUS OR SUBCUTANEOUS FORMULATIONS]

Tyenne is to be given in combination with MTX or other DMARDs; however, in cases of intolerance to MTX or where treatment with MTX is not appropriate Tyenne may also be given as monotherapy.

Recommended Intravenous Dose

The recommended intravenous dose of Tyenne for adult patients with rheumatoid arthritis is 4 mg/kg followed by an increase to 8 mg/kg based on clinical response, given once every 4 weeks as an intravenous infusion over 1 hour.

In clinical trials with tocilizumab, patients with the following laboratory parameter were not initiated: Platelet count below 100,000/mm³, hemoglobin (Hb) below 8.5 g/dL, WBC below 3000/mm³, ANC below 2.0x10⁹/L, absolute lymphocyte count below 500/mm³, ALT or AST above 1.5 x upper limit of normal (ULN), total bilirubin above ULN, Triglycerides (TG) above 10 mmol/L (above 900 mg/dL), Serum creatinine above 1.4 mg/dL in female patients and above 1.6 mg/dL in male patients.

For individuals whose body weight is more than 100 kg, doses exceeding 800 mg per infusion are not recommended (see 10.3 Pharmacokinetics).

Tyenne intravenous formulation is not intended for subcutaneous administration.

Recommended Subcutaneous Dose:

The recommended dose of Tyenne for adult patients with moderately to severely active rheumatoid arthritis is:

Patients transitioning from Tyenne intravenous therapy to subcutaneous administration should administer the first subcutaneous dose at the time of the next scheduled intravenous dose under the supervision of a qualified healthcare professional.

Tyenne subcutaneous formulation is not intended for intravenous administration.

Patients should be assessed for suitability for subcutaneous home use and instructed to inform a healthcare professional if they experience symptoms of allergic reaction before administering the next dose. Patients should seek immediate medical attention if they develop any symptoms of serious allergic reactions (see 7 Warnings and Precautions).

POLYARTICULAR JUVENILE IDIOPATHIC ARTHRITIS (pJIA) [INTRAVENOUS OR SUBCUTANEOUS FORMULATIONS]

Recommended Dose

Intravenous Dosing Regimen:

The recommended dose of Tyenne intravenous for patients with pJIA is:

• 10 mg/kg for patients below 30 kg
• 8 mg/kg for patients ≥30 kg

given in combination with MTX, once every four weeks as an intravenous infusion.

Subcutaneous Dosing Regimen:

The recommended dose of Tyenne subcutaneous for patients with pJIA is:

• 162 mg once every three weeks for patients below 30 kg
• 162 mg once every two weeks for patients ≥30 kg

given in combination with MTX.

The pre-filled syringe with needle safety device (PFS + NSD) can be used to treat pediatric patients of all approved ages. The autoinjector should not be used to treat pediatric patients <12 years of age.

Tyenne may also be given as monotherapy in cases of intolerance to MTX or where treatment with MTX is not appropriate. A change in dose should only be based on a consistent change in the patient’s body weight over time.

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

SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS (sJIA) [INTRAVENOUS AND SUBCUTANEOUS FORMULATIONS]

A change in dose should only be based on a consistent change in the patient’s body weight over time. Tyenne can be used alone or in combination with MTX.

Recommended Dose

Intravenous Dosing Regimen:

The recommended dose of Tyenne for patients with sJIA

• 12 mg/kg for patients below 30 kg
• 8 mg/kg for patients ≥30 kg

given once every two weeks as an intravenous infusion over 1 hour.

Subcutaneous Dosing Regimen:

The recommended dose of Tyenne subcutaneous for patients with sJIA is:

• 162 mg once every two weeks for patients below 30 kg,
• 162 mg once every week for patients ≥30 kg

The PFS + NSD can be used to treat pediatric patients of all approved ages. The autoinjector should not be used to treat pediatric patients <12 years of age.

GIANT CELL ARTERITIS (GCA) [SUBCUTANEOUS FORMULATION ONLY]

For adult patients with GCA, the recommended dose of Tyenne 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.

Tyenne can be used alone following discontinuation of glucocorticoids.

Dose adjustment may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see 4.2 Recommended Dose and Dosage Adjustment].

Intravenous administration is not approved for GCA.

CYTOKINE RELEASE SYNDROME (CRS) [INTRAVENOUS FORMULATION ONLY]

The recommended dose for treatment of CRS given as a 60-minute intravenous infusion is 8 mg/kg in patients weighing greater than or equal to 30 kg or 12 mg/kg in patients weighing less than 30 kg.

Authorized CAR T cell products may provide additional recommendations in the CRS management algorithm within that product monograph. Doses exceeding 800 mg per infusion are not recommended in CRS patients whose body weight is more than 100 kg (see 10.3 Pharmacokinetics). Tyenne can be given 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 Tyenne may be administered. Recommended dosing intervals may differ between CAR T cell products. Consult the CRS management algorithm in the appropriate CAR T cell therapy product monograph for information on dosing intervals.

Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or AST due to the underlying malignancy, preceding lymphodepleting chemotherapy or the CRS. The decision to administer Tyenne should take into account the potential benefit of treating the CRS versus the risks of short-term treatment with Tyenne.

COVID-19 [Intravenous formulation only]

The recommended dose of Tyenne for the treatment of adult patients with COVID-19 is a single intravenous infusion of 8 mg/kg administered over 60 minutes. Doses exceeding 800 mg per infusion are not recommended in patients with COVID-19.

If clinical signs or symptoms worsen or do not improve after the first dose, one additional intravenous infusion of Tyenne 8 mg/kg may be administered at least 8 hours after the initial infusion.

Administration of Tyenne is not recommended in patients with COVID-19 who have any of the following laboratory abnormalities:

DOSE ADJUSTMENTS FOR RA AND GCA

The following dose adjustments are recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.

Liver enzyme abnormalities

Low absolute neutrophil count (ANC)

Low platelet count

DOSE ADJUSTMENTS FOR pJIA AND sJIA

Dose reduction of Tyenne has not been studied in the pJIA or sJIA population. Dose interruptions of Tyenne for laboratory abnormalities are recommended in patients with pJIA or sJIA and are similar to what is outlined above for patients with RA and GCA (see 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic). If appropriate, concomitant MTX and/or other medications should be dose modified or interrupted and Tyenne dosing interrupted until the clinical situation has been evaluated. In pJIA or sJIA the decision to discontinue Tyenne for a laboratory abnormality should be based upon the medical assessment of the individual patient.

Special Dosage Instructions

Pediatric: The safety and efficacy of Tyenne in children with conditions other than pJIA or sJIA have not been established. Children under the age of two have not been studied. The safety and efficacy of Tyenne for treating CAR T cell-induced CRS in children under the age of three has not been established.

Geriatric: As with all biologics, there is a higher incidence of infections in the elderly population in general, therefore, caution should be used when treating the elderly.

Renal impairment: No dose adjustment is required in patients with mild renal impairment (see 10 Clinical Pharmacology, Special Populations and Conditions, Renal Insufficiency). Tyenne has not been studied in patients with moderate to severe renal impairment.

Hepatic impairment: The safety and efficacy of Tyenne has not been studied in patients with hepatic impairment (see 7 Warnings and Precautions). Therefore, no dose recommendations can be made.

4.4 Administration

The KabiCare clinic Network has been established to facilitate the administration of Tyenne. This network consists of clinics located across Canada that are staffed by qualified healthcare professionals specially trained in the administration of Tyenne. Contact your doctor if you have any questions. Information about the KabiCare Infusion Network can be obtained by contacting KabiCare® at: 1-888-304-2034 or info@kabicare.ca.

Intravenous Tyenne

RHEUMATOID ARTHRITIS:

Tyenne concentrate for intravenous infusion should be diluted to 100 mL by a healthcare professional using aseptic technique as follows:

• Withdraw the required amount of Tyenne for a dose of 4 mg/kg or 8 mg/kg (equivalent to 0.2 mL/kg or 0.4 mL/kg, respectively).
• Withdraw the same amount of sterile, non-pyrogenic 0.9% or 0.45% w/v sodium chloride solution from the infusion bag and discard.
• Slowly add the withdrawn Tyenne concentrate into the infusion bag. The final volume in the infusion bag should total 100 mL.
• To mix the solution, gently invert the bag to avoid foaming.
• Allow the fully diluted Tyenne 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.

POLYARTICULAR JUVENILE IDIOPATHIC ARTHRITIS (PJIA), SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS (SJIA), CYTOKINE RELEASE SYNDROME (CRS) AND ADULT COVID-19 PATIENTS:

Tyenne concentrate for intravenous infusion should be diluted by a healthcare professional using aseptic technique as outlined below.

pJIA, sJIA and CRS Patients ≥30 kg and Adult COVID-19 Patients:

• Withdraw the required amount of Tyenne for a dose of 8 mg/kg (equivalent to 0.4 mL/kg) for patients weighing <100 kg. For patients who weigh ≥100 kg, withdraw 40 mL of Tyenne for an 800 mg dose.
• From a 100 mL infusion bag containing 0.9% or 0.45% w/v sterile, non-pyrogenic sodium chloride solution, withdraw the volume equivalent to the volume of Tyenne needed to provide an 8 mg/kg dose (or 800 mg in patients weighing >100 kg) and discard.
• Slowly inject the previously withdrawn Tyenne concentrate into the infusion bag. The final volume in the infusion bag should total 100 mL.

pJIA Patients below 30 kg:

• Withdraw the required amount of Tyenne for a dose of 10 mg/kg (equivalent to 0.5 mL/kg).
• From a 50 mL infusion bag, withdraw the same amount of sterile, non-pyrogenic 0.9% or 0.45% w/v sodium chloride solution from the infusion bag and discard.
• Slowly add the withdrawn Tyenne concentrate into the infusion bag. The final volume in the infusion bag should total 50 mL.

sJIA and CRS Patients below 30 kg:

• Withdraw the required amount of Tyenne for a dose of 12 mg/kg (equivalent to 0.6 mL/kg).
• From a 50 mL infusion bag, withdraw the same amount of sterile, non-pyrogenic 0.9% or 0.45% w/v sodium chloride solution from the infusion bag and discard.
• Slowly add the withdrawn Tyenne concentrate into the infusion bag. The final volume in the infusion bag should total 50 mL.

For all pJIA, sJIA, CRS and Adult COVID-19 Patients:

• To mix the solution, gently invert the bag to avoid foaming.
• Allow the fully diluted Tyenne 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.

For All Prepared Infusion Solutions: Tyenne does not contain preservatives, therefore reconstitution and dilution of the product should be performed under aseptic conditions. The prepared infusion solution of tocilizumab is physically and chemically stable in 0.9% or 0.45% w/v sodium chloride solution. Following dilution in 0.9% or 0.45% sodium chloride, the prepared solution for infusion may be stored in the infusion bag for up to 48 hours up to 30 °C followed by 14 days at 2-8 °C, protected from light. From a microbiological point of view, the prepared infusion should be used immediately (see 11 Storage, Stability, and Disposal).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Tyenne is a colorless to pale yellow liquid. If particulates and discolorations are noted, the product should not be used. Fully diluted Tyenne solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and polypropylene, polyethylene and glass infusion bottles.

Tyenne 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 Tyenne with other drugs.

Subcutaneous Tyenne

Tyenne subcutaneous formulation is not intended for intravenous administration.

Tyenne subcutaneous formulation is administered with a single-use pre-filled syringe with needle safety device (PFS + NSD) or autoinjector. The autoinjector should not be used to treat pediatric patients <12 years of age since there is a potential risk of intramuscular injection due to thinner subcutaneous tissue layer.

Tyenne subcutaneous injection is intended for use under the guidance and supervision of a physician. After proper training in subcutaneous injection technique, a patient (or parent/caregiver) may inject Tyenne if a physician determines that it is appropriate and with medical follow-up as necessary. The first injection should be performed under the supervision of a qualified healthcare professional. The recommended injection sites (abdomen, thigh and upper arm) should be rotated and injections should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

Patients who transition from Tyenne intravenous administration to subcutaneous administration should administer the first subcutaneous dose at the time of the next scheduled intravenous dose under the supervision of a qualified health care professional.

Patients (or parent/caregiver) using Tyenne for subcutaneous administration should be instructed to inject the full amount in the syringe or autoinjector (0.9 mL) which provides 162 mg of Tyenne, according to the directions provided in the Consumer Information Leaflet.

Do not use if the medicine is cloudy or contains particles, is any color besides colorless to yellowish, or any part of the PFS + NSD or autoinjector appears to be damaged.

5 Overdose

There are limited data available on overdosage with Tyenne (tocilizumab). One case of accidental overdose was reported in which a patient with multiple myeloma received a single dose of 40 mg/kg intravenous. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received a single dose up to 28 mg/kg intravenous, although dose-limiting neutropenia was observed.

In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate symptomatic treatment.

6 Dosage Forms, Strengths, Composition, and Packaging

Table – Dosage Forms, Strengths, Composition, and Packaging

For Intravenous Infusion

Tyenne (tocilizumab for injection) is supplied in single-use vials as a preservative-free, sterile concentrate (20 mg/mL) solution for intravenous infusion. The following packaging configurations are available:

• Type I glass single use vial with a stopper (butyl rubber) containing 80 mg of tocilizumab in 4 mL (20 mg/mL). Packs of 1 and 4 vials.
• Type I glass single use vial with a stopper (butyl rubber) containing 200 mg of tocilizumab in 10 mL (20 mg/mL). Packs of 1 and 4 vials.
• Type I glass single use vial with a stopper (butyl rubber) containing 400 mg of tocilizumab in 20 mL (20 mg/mL). Packs of 1 and 4 vials.

*Not all pack sizes may be marketed.

For Subcutaneous Injection

Tyenne (tocilizumab injection) for subcutaneous administration is supplied as a sterile preservative-free liquid solution in either a ready-to-use single-use pre-filled syringe (PFS) with needle safety device or single-use autoinjector. Each device delivers 0.9 mL (162 mg) of tocilizumab per injection. The PFS and autoinjector are not made with natural rubber latex. The following packaging configurations are available:

• Pre-filled syringes with needle safety device (PFS with NSD) containing 162 mg tocilizumab. Packs of 1, 4 and 12 pre-filled syringes.
• Autoinjector containing 162 mg tocilizumab. Packs of 1 and 4 autoinjectors.

*Not all pack sizes may be marketed.

7 Warnings and Precautions

Please see 3 Serious Warnings and Precautions Box.

General

In order to improve the traceability of biological medicinal products, the trade name, the non-proprietary (active ingredient) name, as well as other product-specific identifiers such as the Drug Identification Number (DIN) and batch/lot number of the administered product should be clearly recorded (or stated) in the patient file.

Carcinogenesis and Genotoxicity

The impact of treatment with tocilizumab on the development of malignancies is not known but malignancies were observed in clinical studies (see 8.1 Adverse Reaction Overview, Malignancies). Tyenne is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies (see 8.1 Adverse Reaction Overview, Malignancies).

Cardiovascular

RA patients have an increased risk for cardiovascular disorders and should have risk factors (e.g. hypertension, hyperlipidaemia) managed as part of usual standard of care. Adverse events of hypertension have been observed with tocilizumab treated patients in clinical trials, 21 hypertension serious adverse events (SAEs) (0.13 per 100 patient years intravenous all-exposure RA population) in long-term trials occurred in patients receiving tocilizumab, all at the higher dose (8 mg/kg) (see 8 Adverse Reactions). Most events were transitory.

Dependence,Tolerance and/or Abuse Liability

No studies on the effects on the potential for tocilizumab to cause dependence have been performed. However, there is no evidence from the available data that tocilizumab treatment results in dependence.

Driving and Operating Machinery

No studies on the effects on the ability to drive and use machinery have been performed. However, there is no evidence from the available data that treatment with tocilizumab affects the ability to drive and use machines. However, given that dizziness has been reported, patients who experience this adverse reaction should be advised not to drive or use machines until it has been resolved.

Gastrointestinal

Gastrointestinal perforations have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with tocilizumab. Tocilizumab should be used with caution in patients at increased risk for gastrointestinal perforation, including those with a history of gastrointestinal ulceration, diverticulitis, concomitant corticosteroid use and age >65 years. These medically confirmed GI perforations occurred at a higher rate following treatment with 8 mg/kg tocilizumab compared to 4 mg/kg tocilizumab 0.22 (95% CI: 0.14, 0.31) vs. 0.14 (95% CI: 0.00, 0.77) per 100 patient years in the intravenous all-exposure RA population] (see 8 Adverse Reactions).

Patients should be evaluated promptly for early identification of gastrointestinal perforation, especially since typical symptoms of diverticulitis or perforation such as pain, fever or leukocytosis may be attenuated or absent in immunocompromised patients.

In clinical studies with tocilizumab, patients with a history of diverticulitis, chronic ulcerative lower GI disease such as Crohn’s disease, ulcerative colitis or other symptomatic lower GI conditions were excluded.

Hepatic/Biliary/Pancreatic

Serious cases of hepatic injury have been observed in patients taking intravenous or subcutaneous tocilizumab. Some of these cases have resulted in liver transplant or death. Time to onset for cases ranged from 2 weeks to over 5 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 tocilizumab was associated with a higher incidence of transaminase elevations. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with tocilizumab (see 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data, Liver Enzyme Elevations).

For RA, GCA, pJIA, and sJIA patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating tocilizumab, every 4 to 8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter. It is not recommended to initiate tocilizumab treatment in RA or GCA patients with elevated transaminases ALT or AST greater than 1.5x ULN. In RA, GCA, pJIA and sJIA patients who develop elevated ALT or AST greater than 5x ULN, discontinue tocilizumab. For recommended modifications based upon increase in transaminases (see 4.2 Recommended Dose and Dosage Adjustment, Dose Adjustments for RA and GCA).

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (e.g., ALT greater than three times the upper limit of the reference range, serum total bilirubin greater than two times the upper limit of the reference range), tocilizumab treatment should be interrupted and investigation done to establish the probable cause.

tocilizumab should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests.

A similar pattern of liver enzyme elevation is noted with tocilizumab treatment in the pJIA and sJIA populations. Monitor liver test panel prior to the initiation of treatment at the time of the second administration and thereafter every 2 to 4 weeks for pJIA and sJIA. For recommended dose modifications, see 4.2 Recommended Dose and Dosage Adjustment, Dose Adjustments for pJIA and sJIA.

Treatment with Tyenne is not recommended in patients with active hepatic disease or hepatic impairment.

Immune

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis have been reported in association with tocilizumab (see 8.1 Adverse Reaction Overview, Infusion Reactions). Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.7 % (19 out of 2644) of patients in the 6-month controlled intravenous trials, and in 1.4% (60 out of 4171) of patients in the intravenous all-exposure RA population, after 2 and 5 years of follow-up, respectively, 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 RA population after 2 years of follow-up.

In the post marketing setting, serious hypersensitivity AEs and anaphylaxis occurred during treatment with tocilizumab, both with or without premedication; and with or without previous hypersensitivity reactions. These SAEs occurred in patients treated with a range of doses of tocilizumab, and with or without other treatments for arthritis. These events were associated with the first infusion of tocilizumab and as late as the 20th infusion, although the majority (66/86, 77%) of cases were reported between the 2nd and 4th doses (in cases where the infusion number was reported). In the post marketing setting, cases with a fatal outcome have been reported with intravenous tocilizumab.

Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during infusion with Tyenne. Tyenne intravenous should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction after the administration of Tyenne infusion or subcutaneous injection. If an anaphylactic reaction or other serious hypersensitivity reaction occurs, administration of Tyenne should be stopped immediately and Tyenne should be permanently discontinued. Do not administer Tyenne to patients with known hypersensitivity to Tyenne. Patients with clinically significant hypersensitivity should not be rechallenged with additional doses of Tyenne (see 2 Contraindications and 8 Adverse Reactions).

Immunization

Live and live attenuated vaccines should not be given concurrently with tocilizumab 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 tocilizumab.

In a randomized open-label study, adult RA patients aged 25-65 years treated with tocilizumab and MTX mounted a similar immunological response to the tetanus toxoid vaccine as adult patients receiving MTX only.

An effective response to the 23-valent pneumococcal polysaccharide was achieved by 60% (95% CI: 46.4, 73.6) of patients receiving tocilizumab and MTX versus 70.8% (95% CI: 52.6, 89.0) of patients receiving MTX only.

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 treatment with Tyenne. The interval between live vaccinations and initiation of Tyenne therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Macrophage Activation Syndrome (MAS)

MAS is a serious life-threatening disorder that may develop in patients with sJIA. In clinical trials, tocilizumab has not been studied in patients during an episode of active MAS. Cases of MAS, including a case with a fatal outcome [15 days following the 4th tocilizumab dose (8 mg/kg)], have been reported in clinical trials. MAS has also been reported in the post-marketing setting.

Serious Infections

Concurrent therapy with Tyenne and another biologic agent is not recommended. When transitioning from another biologic therapy to Tyenne, patients should be monitored for signs of infection. In the clinical trials in adults, a higher incidence of infections was observed in patients previously exposed to a TNF inhibitor.

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic infections have been observed in patients receiving immunosuppressive agents including tocilizumab for rheumatoid arthritis. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Opportunistic infections including tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with tocilizumab. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidiomycosis, listeriosis). Patients have presented with disseminated rather than localized disease. Rheumatoid arthritis itself as well as concomitant immunosuppressant treatment such as methotrexate or corticosteroids are additional risk factors for serious infections. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tocilizumab.

Patients with sJIA also reported the following serious infections: varicella and mycoplasmal pneumonia.

Treatment with Tyenne should not be initiated in patients with active infections including chronic or localized infections. Administration of Tyenne should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis, until the infection is controlled (see 4.1 Dosing Considerations).

The risks and benefits of treatment should be considered prior to initiating Tyenne 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.

In patients with COVID-19, Tyenne should not be administered if patients also have any other concurrent active infection.

Vigilance for the timely detection of serious infection is recommended for patients receiving treatment with immunosuppressive agents, such as Tyenne, as signs and symptoms of acute inflammation may be lessened, due to suppression of the acute phase reactants. A patient who develops a new infection during treatment with Tyenne should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

Patients (which include younger children who may be less able to communicate their symptoms) and parents/guardians of minors should be instructed to contact a physician immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.

Tuberculosis

Patients should be evaluated for tuberculosis risk factors and tested for latent and active infection prior to initiating Tyenne.

Patients with latent or active tuberculosis should complete treatment with standard anti-mycobacterial therapy before initiating Tyenne. Anti-tuberculosis therapy should also be considered prior to initiation of Tyenne 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 and/or Tyenne is appropriate for an individual patient.

Patients should be closely monitored for the development of signs and symptoms of tuberculosis including patients who tested negative for tuberculosis infection prior to initiating therapy.

Viral Reactivation

Treatment with TNF inhibitors has been associated with reactivation of hepatitis B and C and cases of herpes zoster exacerbation were observed in clinical studies with tocilizumab. Therefore, screening for viral hepatitis should be performed in accordance with published guidelines before starting therapy with tocilizumab. In clinical studies with tocilizumab, patients who screened positive for hepatitis were excluded from the study.

Monitoring and Laboratory Tests

Liver Function Tests

Treatment with tocilizumab particularly when administered concomitantly with MTX, was associated with a higher incidence of mild to severe elevations in hepatic enzymes (see 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data, Liver Enzyme Elevations).

In clinical trials, one patient who had received tocilizumab 8 mg/kg monotherapy without elevations in transaminases experienced elevation in AST to above 10x ULN and elevation in ALT to above 16x ULN when MTX was initiated in combination with tocilizumab. Transaminases normalized when both treatments were held, but elevations recurred when MTX and tocilizumab were restarted at lower doses. Elevations resolved when MTX and tocilizumab were discontinued.

Mild to severe elevations of hepatic transaminases have been observed with tocilizumab treatment. In the intravenous all-exposure RA population, of the 463 patients who reported an elevation above 3x ULN post baseline, 21 patients (4.5%) also reported a moderate or severe hepatic AEs at any time, of which 11 patients (2.4%) reported hepatic AEs after the elevation (see 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data).

In patients who entered the studies with liver enzymes within the normal range and experienced a liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of tocilizumab, or reduction in tocilizumab dose, resulted in normalization of liver enzymes in 199 of 285 patients (see 4.2 Recommended Dose and Dosage Adjustment).

Increased frequency of these elevations was observed when potential hepatotoxic drugs (e.g. methotrexate) were used in combination with tocilizumab.

It is not recommended to initiate Tyenne treatment in patients with elevated transaminases ALT or AST above 1.5x ULN. Discontinue Tyenne in patients who develop persistent elevated ALT or AST above 3x ULN or who develop ALT or AST above 5x ULN (see 4.2 Recommended Dose and Dosage Adjustment).

For RA and GCA patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating Tyenne, every 4 to 8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter.

In pJIA and sJIA, ALT and AST should be monitored prior to the initiation of treatment, at the time of the second Tyenne treatment and thereafter every 2 to 4 weeks according to good clinical practice (see 4.2 Recommended Dose and Dosage Adjustment, Dose Adjustments for pJIA and sJIA).

Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or AST due to the underlying malignancy, preceding lymphodepleting chemotherapy or the CRS. The decision to administer Tyenne should take into account the potential benefit of treating the CRS versus the risks of short-term treatment with Tyenne. For recommended monitoring frequency refer to 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic.

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 Tyenne should balance the potential benefit against the risks of acute treatment with Tyenne. In COVID-19 patients with elevated ALT or AST above 10x ULN, administration of Tyenne treatment is not recommended (see 4.2 Recommended Dose and Dosage Adjustment, COVID-19 [Intravenous formulation only]).

In COVID-19 patients, ALT/AST should be monitored according to current standard clinical practices (see 4.2 Recommended Dose and Dosage Adjustment, COVID-19 [Intravenous formulation only]).

Lipids

Lipid levels in untreated RA patients tend to be lower compared to the general population as it relates to the increase in systemic inflammation in patients with RA. Treatment with tocilizumab was associated with increases in lipid parameters such as total cholesterol, triglycerides, and/or low density lipoprotein (LDL) cholesterol, (see 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data, Elevations in lipid parameters).

In patients treated with Tyenne, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of Tyenne therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidemia.

Neutrophils

Treatment with tocilizumab was associated with a higher incidence of neutropenia (see 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data, Hematology Abnormalities). A serious infection has been reported in 1/223 patients with grade 3 treatment-related neutropenia in the intravenous all-exposure RA population.

Caution should be exercised when considering initiation of treatment with Tyenne in patients with a low neutrophil count i.e. absolute neutrophil count (ANC) below 2x10⁹/L. In RA, GCA, pJIA and sJIA patients with an absolute neutrophil count below 0.5x10⁹/L treatment is not recommended (see also 4.2 Recommended Dose and Dosage Adjustment). In COVID-19 patients with an ANC below 1x10⁹/L, administration of treatment is not recommended (see 4.2 Recommended Dose and Dosage Adjustment, COVID-19 [Intravenous formulation only]).

In RA and GCA patients, neutrophils should be monitored 4 to 8 weeks after start of therapy and thereafter according to good clinical practice (see 10.2 Pharmacodynamics). For recommended modifications based on ANC results, see 4 Dosage and Administration.

In pJIA and sJIA patients, neutrophils should be monitored prior to the initiation of treatment, at the time of the second Tyenne treatment and thereafter every 2 to 4 weeks according to good clinical practice (see 4.2 Recommended Dose and Dosage Adjustment, Dose Adjustments for pJIA and sJIA).

In COVID-19 patients, the neutrophil count should be monitored according to current standard clinical practices.

Platelets (Thrombocytopenia)

Treatment with tocilizumab was associated with a reduction in platelet counts.

Caution should be exercised when considering initiation of Tyenne treatment in patients with a platelet count below 100x10³/mcL. In all patients, including COVID-19, with a platelet count below 50x10³/mcL treatment is not recommended (see also 4.2 Recommended Dose and Dosage Adjustment).

In RA and GCA patients, platelets should be monitored 4 to 8 weeks after start of therapy and thereafter according to good clinical practice. For recommended modifications based on platelet counts, see 4 Dosage and Administration.

In pJIA and sJIA patients, platelets should be monitored prior to the initiation of treatment, at the time of the second Tyenne treatment and thereafter every 2 to 4 weeks according to good clinical practice (see 4.2 Recommended Dose and Dosage Adjustment, Dose Adjustments for pJIA and sJIA).

In COVID-19 patients, platelets should be monitored according to current standard clinical practices.

Neurologic

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

7.1 Special Populations

7.1.1 Pregnancy

Women of Childbearing Potential: Women of childbearing potential must use effective contraception during and up to 3 months after treatment.

Pregnant Women: There are no adequate data from the use of tocilizumab in pregnant women. A study in monkeys did not indicate any dysmorphogenic potential but has showed a higher number of spontaneous abortions /embryo-fetal deaths at a high dose (see 16 Non-Clinical Toxicology). The relevance of these data for humans is unknown.

In the intravenous all-exposure RA population, a total of 48 pregnancies were reported in 43 patients. The outcome is known for 44 of the cases: 18 had therapeutic terminations, 10 resulted in spontaneous miscarriage, one pregnancy was later reported as suspected gestational trophoblastic tumor, 14 delivered to term and one baby was born prematurely. In the 14 pregnancies that delivered to term 12 resulted in normal and healthy newborns. Of the remaining two there was one neonatal death due to acute respiratory distress syndrome (ARDS), and one baby was born with a left kidney pelviectasis.

Tyenne should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

7.1.2 Breastfeeding

Excretion of a murine analogue of tocilizumab into the milk of lactating mice has been observed, however, it is unknown whether tocilizumab is excreted in human breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with tocilizumab should be made taking into account the benefit of breast-feeding to the child and the benefit of tocilizumab therapy to the woman.

8 Adverse Reactions

The adverse drug reaction profiles reported in clinical studies that compared Tyenne to the reference biologic drug were comparable. The description of adverse reactions in this section is based on clinical experience with the reference biologic drug.

8.1 Adverse Reaction Overview

RHEUMATOID ARTHRITIS

Patients Treated with Intravenous Tyenne:

The tocilizumab data described below includes 5 Phase III, double-blind, controlled, multicenter studies and their extension periods. In the double-blind controlled studies, patients received doses of tocilizumab 8 mg/kg monotherapy (288 patients), tocilizumab 8 mg/kg in combination with DMARDs (including methotrexate) (1582 patients), or tocilizumab 4 mg/kg in combination with methotrexate (774 patients).

Safety data is also presented from study II, LITHE, (see 14 Clinical Trials) from the initial randomized treatment period up to 24 months. This data also contributed to the 6-month controlled study data presented below and in Table 1 and intravenous all-exposure RA population data described below.

Long-term safety data was also evaluated in two open-label extension trials (see 14 Clinical Trials) in adult patients with moderate to severe RA. Overall, treatment with tocilizumab was well tolerated during studies VII (LTE Study I) and VIII (LTE Study II). The safety profile was not apparently different from that of the core studies (the studies that contributed patients into the LTE studies) and it did not worsen as tocilizumab exposure increased during the studies [the median study durations (exposure), including the core studies, was 5.37 years (2461.94 PYs) and 5.22 years (9179.83 PYs), respectively]. No new safety signals emerged during the long-term treatment. The majority of all reported AEs in these studies were of mild or moderate intensity, and there was no evidence of an increase in the rate of AEs per 100 PYs over time.

The intravenous all-exposure RA population includes all patients who received at least one dose of tocilizumab either in the double-blind control period or open-label extension phase on studies. This includes adult patients with moderate to severe RA in Studies I-V, VII and VIII (see Table 15) as well as patients in ADACTA (see 14 Clinical Trials, Monotherapy) and a small drug-drug interaction study with simvastatin (see 9 Drug Interactions). Of the 4171 patients in this intravenous all-exposure RA population, 3809 received treatment for at least 6 months, 3410 for approximately one year, 3082 for approximately 2 years, 2870 for approximately 3 years, 2686 for approximately 4 years and 1982 patients for approximately 5 years (May 2, 2012 cut-off).

Due to the design of the phase III studies, 836 (86%) of the 974 patients who received 4 mg/kg as their first dose of tocilizumab also received at least one dose of 8 mg/kg before or at entry into the long term extension studies. Therefore, the majority of the safety data is for patients receiving 8 mg/kg dose. Of the total tocilizumab exposure in the clinical studies 5% was in patients receiving 4 mg/kg and 95% was in patients receiving 8 mg/kg.

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

The most frequent serious adverse events (SAE) were serious infections, including pneumonia and cellulitis (see 7 Warnings and Precautions). The second most frequently reported type of SAE was injury, poisoning, and procedural complications, specifically fractures. The most frequently reported adverse events in 6-month controlled studies (occurring in ≥3% of patients treated with monotherapy or in combination with traditional DMARDs) were upper respiratory tract infections, headache, nasopharyngitis, urinary tract infections, nausea, hypertension, increased alanine amino transferase (ALT), diarrhea, abdominal pain, dyspepsia, sinusitis, bronchitis, rash, back pain, rheumatoid arthritis, and dizziness.

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

Infections

In the 6-month controlled studies, the rate of all infections reported in the 4 mg/kg and 8 mg/kg tocilizumab plus traditional DMARD treatment was 133 and 127 events per 100 patient years, respectively, compared to 112 events per 100 patient years in the placebo plus traditional DMARD group.

In Study II (LITHE), during the initial randomized treatment up to 12 months, the proportion of patients with an infection was higher in the tocilizumab + MTX groups compared with the placebo + MTX group (tocilizumab 4 mg/kg + MTX 46.9%, tocilizumab 8 mg/kg + MTX 49.9% vs placebo 39.5%) as was the overall rate of infections per 100 patient-years (110.1 and 97.1 vs 92.9 events respectively). In the cumulative data up to 24 months, the profile of infections was comparable with that reported up to 12 months with no changes in either the type of infections reported or the rates per 100 patient-years. The rates of infections across all treatment groups were highest during the first 6 months of treatment and did not increase over time up to month 24.

The overall rate of infections with tocilizumab in the intravenous all-exposure RA population was 93 events per 100 patient years exposure.

Serious Infections

In the 6-month controlled clinical studies, the rate of serious infections (bacterial, viral and invasive fungal) in the 4 mg/kg and 8 mg/kg tocilizumab plus traditional DMARDs was 4.4 and 5.3 events per 100 patient years, respectively, compared to 3.9 events per 100 patient years exposure in the placebo plus traditional DMARD group. In the monotherapy study the rate of serious infections was 3.6 events per 100 patient years of exposure in the tocilizumab group and 1.5 events per 100 patient years of exposure in the MTX group.

In Study II (LITHE), during initial randomized treatment up to 12 months, the proportion of patients with serious infections was infrequent in all three treatment groups (2.5% in the tocilizumab 4 mg/kg + MTX group, 3.0% in the tocilizumab 8 mg/kg + MTX group and 1.5% in the placebo + MTX group) as were the rates per 100 patient-years (3.7, 4.0 and 2.3, respectively). Pneumonia was the most commonly reported serious infection in all three groups. Cumulative data up to month 24 demonstrate that the rates of serious infections across all treatment groups were highest during the first 12 months of treatment and did not increase over time.

In the intravenous all-exposure RA population, the overall rate of serious infections observed was 4.4 events per 100 patient years exposure. Reported serious infections, some with fatal outcome, included pneumonia, cellulitis, urinary tract infection, herpes zoster, gastroenteritis, diverticulitis, sepsis, bacterial arthritis, bronchitis and erysipelas. Twenty-six fatal infections/4171 patients (0.6%) were reported with the most common infections resulting in death being pneumonia and sepsis/septic shock. Infectious agents included: streptococcus, staphylococcus, enterococcus, pseudomonas, blastomycosis and E.coli.

Opportunistic Infections

In the intravenous all-exposure RA population, a total of 38 opportunistic infections (excluding tuberculosis) were reported in 35 patients. Eleven of the 38 opportunistic infections were serious. Of the 38 opportunistic infections, 2 events of systemic candida contributed to the patient’s death, and 6 (16%) led to tocilizumab dose modification. One patient with systemic candida also had concomitant staphylococcal sepsis, which was the cause of death.

In addition, 17 AEs of tuberculosis, 13 of which were SAEs, were reported in 15/4171 patients (14 de novo and 1 reactivation). Fifteen (15) cases of tuberculosis occurred after 24 months of treatment with tocilizumab [0.16 per 100 patient years exposure, 95% CI (0.09, 0.28)] compared to 2 cases during the first 24 months [0.03 per 100 patient years exposure, 95% CI (0.00, 0.11)] although due to the low numbers of events the increase in the rate of TB events over time cannot be confirmed. The 17 tuberculosis cases (0.11 per 100 patient years) occurred in patients receiving the higher dose of tocilizumab, i.e. 8 mg/kg (see 8.1 Adverse Reaction Overview).

In Study II (LITHE), five opportunistic infections were reported: Candida osteomyelitis, GI candidiasis, Cryptococcal pneumonia, Pseudomonas and Serratia bursitis, and tuberculous pleurisy. All occurred in patients on tocilizumab 8 mg/kg, the former two events during the initial 52 weeks of the study.

Gastrointestinal Perforation

During the 6-month controlled clinical trials, the incidence overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with tocilizumab therapy.

In Study II (LITHE), for the cumulative data up to 24 months, four patients reported GI perforations: one patient receiving tocilizumab 4 mg/kg + MTX and three patients receiving tocilizumab 8 mg/kg + MTX. The rate of GI perforation in the tocilizumab 4 mg/kg and 8 mg/kg groups (0.19 and 0.23 events per 100 patient-years, respectively) is consistent with the overall rates reported below in the intravenous all-exposure RA population. Two additional cases of diverticulitis (one serious) were reported in patients receiving tocilizumab 8 mg/kg.

In the intravenous all-exposure RA population, the overall rate of medically confirmed gastrointestinal perforation was 0.20 events per 100 patient years (33/4171 patients, 0.79%). Reports of gastrointestinal perforation on tocilizumab were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant non-steroidal anti-inflammatory medications (NSAIDs), corticosteroids, or methotrexate (see 7 Warnings and Precautions, Gastrointestinal Perforation).

The relative contribution of these concomitant medications versus tocilizumab to the development of GI perforations is not known.

Infusion Reactions

In the 6-month controlled clinical studies, adverse events associated with infusion (occurring during or within 24 hours of infusion) were reported in 8% and 7% of patients in the 4 mg/kg and 8 mg/kg tocilizumab plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg/kg and 8 mg/kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria. These events were not treatment limiting. No premedication was administered in the clinical trials.

Anaphylaxis

Clinically significant hypersensitivity reactions (e.g., anaphylactoid and anaphylactic reactions) associated with tocilizumab and requiring treatment discontinuation were reported in 0.1% (3/2644) in the 6-month, controlled trials and in 0.2% (8/4171) in the intravenous all-exposure RA population. These reactions were generally observed during the second to fourth infusion of tocilizumab (see 7 Warnings and Precautions, Hypersensitivity Reactions).

In Study II (LITHE), up to 24 months, four serious anaphylactic reaction or shock events that required treatment discontinuation were reported, all with tocilizumab 4 mg/kg + MTX treatment. These reactions were all observed in the first 12 months of the study, during the second or third infusion of tocilizumab. There were in addition, two cases of infusion-associated hypersensitivity reactions (both on tocilizumab 4 mg/kg + MTX) that led to premature withdrawal from treatment.

Immunogenicity

In 6-month controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (1.6%) developed positive anti-tocilizumab antibodies of whom 5 had an associated medically significant hypersensitivity reaction leading to withdrawal. Thirty patients (1.1%) developed neutralizing antibodies.

Malignancies

During the 6-month controlled period of the studies, 15 malignancies were diagnosed in patients receiving tocilizumab, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the tocilizumab groups (1.32 events per 100 patient years) and in the placebo plus DMARD group (1.37 events per 100 patient years).

In Study II (LITHE), during the first 52 weeks, one solid tumour was reported in the placebo-MTX group (1/392 patients ≤1%). Twelve malignancies were reported in the tocilizumab groups: (12/798 patients=1.5%): eight solid tumours (two prostate cancers, two cervical carcinomas and one each of breast cancer, kidney clear cell carcinoma, uterine endometrial cancer, and stage III squamous cell lung carcinoma); and four skin carcinomas.

During the second year (open-label phase), nine solid tumours were reported in the tocilizumab groups: three lung cancers (lung cancer, metastatic lung adenocarcinoma, and metastatic non-small cell cancer) and one each of anal cancer, metastatic endometrial cancer, gastro-oesophageal cancer, malignant melanoma metastatic to liver, thyroid cancer, metastatic tongue cancer, and squamous cell carcinoma of the skin.

An overall total of 204 malignancies were reported in the intravenous all-exposure RA population. Malignancies represent all histologically-confirmed cases of invasive cancer and are divided in to solid tumours (stage and type unspecified; only solid tumours occurring in 2 or more patients included) (including 28 cases of lung cancer, 21 cases of breast cancer, 12 cases of prostate cancer, 7 cases of colon cancer, 5 cases of cervical cancer, 4 cases each of endometrial cancer, ovarian, and thyroid cancer and 3 cases each of gastric cancer, gastrointestinal tract cancer, melanoma, pancreatic cancer and sarcomas. Additionally, 2 cases each of anal, bladder, tongue, carcinoid, hepatic cancer, rectal, renal cell, and transitional cell cancers have been reported and 1 case each of astrocytoma, glioblastoma, laryngeal, nasal cavity, neuroendocrine, pharyngeal, respiratory tract, and uterine cancer); non-melanoma skin cancers (41 cases of basal cell carcinoma and 25 cases of squamous cell carcinoma and 1 case of basosquamous carcinoma); and hematologic cancers (2 cases of diffuse large B-cell lymphoma, 1 case each of acute myeloid leukemia, chronic lymphocytic leukemia, and diffuse large B-cell lymphoma stage III, and gammopathy, myelodysplastic syndrome, non-Hodgkin’s lymphoma and extranodal marginal zone B cell lymphoma).

The rate of medically confirmed malignancies (including non-melanoma skin cancer) remained consistent (1.26 events per 100 patient years) with the rate observed in the 6-month, controlled period. The rate of medically confirmed malignancy excluding non-melanoma skin cancer was 0.84 events per 100 patient years.

Cardiovascular/Hypertension

In the intravenous all-exposure RA population, 910 hypertension events (5.62 per 100 patient years) were reported.

In study II (LITHE) through 24 months of treatment, hypertension was more common in patients receiving tocilizumab: 13 events (4.56 per 100 patient years) in patients receiving placebo, 42 events (8.05 per 100 patient years) in patients receiving 4 mg/kg tocilizumab and 91 events (6.89 per 100 patient years) in patients receiving 8 mg/kg tocilizumab; event rates for hypertension occurring during or within 24 hours of infusion reactions were: 3 events (1.05 per 100 patient years) in patients receiving placebo, 7 events (1.34 per 100 patient years) in patients receiving 4 mg/kg tocilizumab and 22 events (1.67 per 100 patient years) in patients receiving 8 mg/kg tocilizumab respectively.

Deaths

During the placebo-controlled Phase III trials in RA, there were 5 (<1%) deaths among 1454 patients in the placebo group and 5 deaths (<1%) among 2644 patients in the combined tocilizumab group. There was no predominant cause of death among patients treated with tocilizumab (cardio-respiratory arrest, gastrointestinal haemorrhage, haemorrhagic stroke, myocardial ischemia, post procedural complication). In the intravenous all-exposure RA population, there were 94 deaths among 4171 patients treated with at least one dose of tocilizumab over an exposure period of 16205 patient years (0.58 per 100 patient years), and 6 deaths among 1555 placebo patients over an exposure period of 824.56 patient years (0.73 per 100 patient years). The most common causes of death among patients treated with tocilizumab were bronchopneumonia and myocardial infarction (5 deaths each), pulmonary embolism and pneumonia (4 deaths each), cardio-respiratory arrest, haemorrhagic stroke, sepsis & septic shock (3 deaths each), and acute myocardial infarction, cerebrovascular accident, metastatic pancreatic cancer, metastatic small cell lung cancer, multi-organ failure, subarachnoid haemorrhage & suicide (2 deaths each).

In study II (LITHE), a total of 10 deaths were reported, 6 during the initial 52-week study period (1 of which occurred on placebo, 4 in 8 mg/kg and 1 in placebo with escape to 4 mg/kg) and 4 during the second 52 weeks of the study (all on tocilizumab 8 mg/kg, due respectively to gastroesophageal cancer, metastatic malignant melanoma, metastatic lung adenocarcinoma and cardiomyopathy).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Table 1 below lists the adverse events (regardless of causality) occurring in >1% of patients treated with tocilizumab during placebo-controlled double-blind rheumatoid arthritis studies.

Table 1 Adverse Events Reported by >1% of Patients Treated with tocilizumab Dosed Every 4 weeks during Phase III Rheumatoid Arthritis Placebo Controlled Studies (6 month control portion)

Table 2 below lists the adverse events (regardless of causality) occurring in ≥1% of patients treated with tocilizumab through 12-months treatment in Study II (LITHE). As patients were allowed to have escape therapy and the data in this table includes adverse events during original treatment group and escape therapy, patients may be represented in more than one treatment group.

Table 2 Adverse Events Reported by ≥1% of Patients Treated with tocilizumab Dosed Every 4 weeks during Study II, (LITHE) through 12 Months of Treatment (events on escape therapy are included)

Serious Adverse Events

Within Study II, (LITHE) (see 14 Clinical Trials) during the initial randomized treatment up to month 12, a higher proportion of patients in the tocilizumab + MTX groups (4 mg/kg dose: 35 (9%); 8 mg/kg dose: 34 (9%)) experienced SAEs compared with the placebo + MTX group (22 (6%)). Regardless of causality, SAEs occurred most frequently in the following body systems: infections (mainly pneumonia), injury and poisoning (primarily fractures of various types), neoplasms, GI disorders, nervous system disorders and cardiac disorders.

Infections and infestations, the most frequently reported SAEs, were observed in 2.5% of patients in the tocilizumab 4 mg/kg + MTX group, 3.0% of patients in the tocilizumab 8 mg/kg + MTX group and 1.5% of patients in the placebo + MTX group. Among the tocilizumab + MTX, groups, neoplasms were more frequent in the tocilizumab 4 mg/kg + MTX group (2.5%) than in the tocilizumab 8 mg/kg + MTX group (0.3%).

In the intravenous all-exposure RA population, the rate of SAEs was 14.4 per 100 patient-years. This is consistent with rates seen in the 12-month period of Study II (LITHE) (placebo patients: 10.15 per 100 patient years; 4 mg/kg dose: 12.78 per 100 patient years 8 mg/kg dose: 11.46 per 100 patient years). There was no evidence of an increased risk of SAEs with prolonged exposure to tocilizumab.

Dose Interruptions

In study II (LITHE), dose interruptions were permitted for safety reasons (in particular, for active infections and for ALT/AST elevations).

During initial randomized treatment up to week 52, 19% and 22% of patients in the tocilizumab + MTX groups (4 mg/kg and 8 mg/kg, respectively) compared with 11% of patients in the placebo + MTX group had dose interruptions for AEs. The most common AEs that led to dose interruptions were infections and infestations, which were reported in 12% and 15% of patients in the tocilizumab + MTX 4 mg/kg and 8 mg/kg groups, respectively, compared with 6.4% in the placebo + MTX group, elevated liver transaminases (3.3% and 5.3% in the tocilizumab + MTX 4 mg/kg and 8 mg/kg groups, respectively) and GI disorders including mouth ulcers and abdominal pain (1.3% and 1.8% in the tocilizumab + MTX 4 mg/kg and 8 mg/kg groups, respectively) compared with patients in the placebo + MTX group (1.0% elevated liver transaminases; 0.5% GI disorders).

Early Rheumatoid Arthritis

Tocilizumab was also studied in 1162 patients with early, moderate to severe RA who were naïve to treatment with both MTX and a biologic agent (see 14 Clinical Trials, Rheumatoid Arthritis). The overall safety profile observed in the tocilizumab treatment groups was consistent with the known safety profile of tocilizumab as outlined in Table 1 and Table 2 above.

Table 3 below lists the adverse events (regardless of causality) occurring in ≥1% of patients treated with tocilizumab during the 52-week double-blind portion of the study.

Most AEs in Study VI (FUNCTION) were of mild or moderate intensity, and the rates of each intensity category were similar between placebo + MTX and the tocilizumab treatment groups. The pattern of AEs observed in Study VI (FUNCTION) was overall similar to that reported in the intravenous all-exposure RA population described above. The most frequently affected system organ class (SOC) in Study VI (FUNCTION) was Infections and Infestations, followed by Gastrointestinal Disorders, and Investigations (chiefly liver transaminase increases). The most frequent individual AEs were nausea, upper respiratory tract infection (URTI), increased alanine aminotransferase (ALT), nasopharyngitis and increased transaminases.

Table 3 Adverse Events (regardless of causality) Reported by ≥1% of Patients treated with tocilizumab dosed every 4 weeks up to Week 52 in Patients with Early RA

Serious Adverse Events

The number and proportions of patients who experienced at least one SAE was similar between the treatment groups (tocilizumab 8 mg/kg + MTX: 31 [10.7%]; tocilizumab 8 mg/kg + placebo: 25 [8.6%]; tocilizumab 4 mg/kg + MTX: 29 [10.0%]; and placebo + MTX: 24[8.5%]).

Infections and infestations were the most frequently reported SAEs followed by neoplasms, benign, malignant, and unspecified (including cysts and polyps), and respiratory, thoracic and mediastinal disorders.

Deaths

There were nine deaths reported in the study up to week 52: 2 in the tocilizumab 8 mg/kg + MTX group (1 each due to tension pneumothorax and hypoglycemic coma); 1 in the tocilizumab 8 mg/kg + placebo group (due to lung neoplasm); 4 in the tocilizumab 4 mg/kg + MTX group (1 each due to cerebral haemorrhage, lung infection, pneumonia and arteriosclerosis; and 2 in the placebo + MTX group (1 each due to sepsis and pneumonia).

Dose Interruptions

Dose modifications and interruptions for an AE were more common in the tocilizumab + MTX combination therapy groups (tocilizumab 8 mg/kg + MTX: 171 [59%]; tocilizumab 4 mg/kg + MTX: 153 [52.9%]) compared with placebo + MTX (134 [47.5%] and tocilizumab 8 mg/kg + placebo 128 [43.8%]) groups. This includes modifications in either tocilizumab or MTX as both drugs were considered study drugs.

In total, 149 patients withdrew prematurely from study treatment due to an AE (including SAEs). A greater percentage of patients in the tocilizumab treatment groups prematurely discontinued study treatment because of an AE compared with patients in the placebo group, with the highest number of withdrawals observed in the tocilizumab 8 mg/kg + MTX group.

In all three tocilizumab treatment groups, the most common reasons for treatment discontinuation were attributed to the Investigations SOC, in particular events related to liver enzyme elevations. In contrast, in the placebo + MTX group, AEs under the SOC of Infections and Infestations; and Musculoskeletal and connective Tissue Disorders were the leading cause of treatment discontinuation.

Patients Treated with Subcutaneous tocilizumab:

The safety of subcutaneous tocilizumab in RA was studied in two trials (see 14 Clinical Trials). SC-I (SUMMACTA) compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneous versus 8 mg/kg intravenous in 1262 subjects with adult RA. SC-II (BREVACTA) compared the safety and efficacy of tocilizumab 162 mg administered every other week subcutaneous versus placebo in 656 subjects with adult RA. All patients in both studies received background non-biologic DMARD(s). During the 6-month controlled treatment period, the safety and immunogenicity observed for tocilizumab administered subcutaneous was consistent with the known safety profile of intravenous tocilizumab and no new or unexpected adverse drug reactions were observed. A higher frequency of injection site reactions was observed in the subcutaneous arms compared with placebo subcutaneous injections in the intravenous/placebo arms.

In studies SC-I (SUMMACTA) and SC-II (BREVACTA), patients who completed the 6-month double-blind treatment period were re-randomized into a 72-week open-label, long-term extension for each study.

In both Studies SC-I (SUMMACTA) and SC-II (BREVACTA), the safety profile of tocilizumab subcutaneous in the open-label, long-term extension was generally consistent with the safety observed during the first 6-month double-blinded period, and no new safety issues emerged with the longer duration of tocilizumab subcutaneous treatment. In the weekly administration regimen (162 mg subcutaneous) more adverse events leading to withdrawals were noted relative to once every two-week administration (162 mg subcutaneous).

Injection Site Reactions

During the 6-month controlled period, in SC-I (SUMMACTA), the frequency of injection site reactions (ISRs) was 10.1% (64/631) and 2.4% (15/631) for the subcutaneous tocilizumab and the subcutaneous placebo (Intravenous group) weekly injections, respectively. In SC-II (BREVACTA), the frequency of injection site reactions was 7.1% (31/437) and 4.1% (9/218) for every other week subcutaneous tocilizumab and placebo groups, respectively. These injection site reactions (including erythema, pruritus, pain and haematoma) were mild to moderate in severity. The majority was resolved without any treatment and none necessitated drug discontinuation.

Immunogenicity

In SC-I (SUMMACTA), a total of 625 patients treated with tocilizumab 162 mg weekly were tested for anti-tocilizumab antibodies in the 6-month controlled period. Five patients (0.8%) developed positive anti-tocilizumab antibodies; of these, all developed neutralizing anti-tocilizumab antibodies. In SC-II (BREVACTA), a total of 434 patients treated with tocilizumab 162 mg every two weeks and 217 placebo treated patients were tested for anti-tocilizumab antibodies in the 6 month controlled period. Seven patients (1.6%) in the tocilizumab-subcutaneous arm compared with 3 patients (1.4 %) in the placebo arm developed anti-tocilizumab antibodies; of these, 6 (1.4%) in the tocilizumab-subcutaneous arm and 1(0.5% ) in the placebo arm also developed neutralizing antibodies.

A total of 1463 patients in the tocilizumab subcutaneous all-exposure RA population have been tested for anti-tocilizumab antibodies, 27 patients (1.8%) developed anti-tocilizumab antibodies, and of these 25 patients (1.7%) developed neutralizing anti-tocilizumab antibodies.

No correlation of antibody development to clinical response or adverse events was observed.

Table 4 below lists the adverse events (regardless of causality) occurring in >1% of patients treated with tocilizumab, either subcutaneous or intravenous or Placebo, during the 6-month double-blind controlled period of the studies.

Table 4 Adverse Events Reported by >1% of Patients Treated with tocilizumab subcutaneous or intravenous or Placebo through 6 Months of Treatment

Monotherapy: tocilizumab versus HUMIRA®

In study WA19924, a 24-week randomized, double-blinded, parallel study monotherapy with tocilizumab 8 mg/kg intravenous q4w (N=162) was compared to HUMIRA 40 mg subcutaneous q2w (N=162).

Serious Adverse Events

The proportion of patients with serious adverse events was tocilizumab 11.7% vs. HUMIRA 9.9% with the most common event being infections [3.1% (5) each]. In the cases where an organism was identified and reported, the infectious agents were: Escherichia coli (urinary tract infection), gram negative cocci (urosepsis) and staphylococcus aureus (cellulitis).

Immunogenicity testing was event driven and was not done routinely in either arm of the trial. Patients were identified for anti-TCZ antibody testing if they had an event of anaphylaxis or a serious hypersensitivity reaction that the investigator considered potentially related to tocilizumab.

There were no events of anaphylaxis and one SAE of drug hypersensitivity in a patient in the HUMIRA arm whose reaction occurred while receiving commercial tocilizumab (following withdrawal from the trial). One patient in the tocilizumab arm was withdrawn for an infusion-related reaction (IRR). Only the patient with the IRR had pre-and post-event samples available for immunogenicity testing and tested positive for anti-TCZ antibodies.

Two deaths were reported during the study. Both patients were in the tocilizumab treatment group. The first patient died suddenly and the cause of death is unknown. The investigator attributed the cause of death in the second patient to an illicit drug overdose.

Dose Interruptions

More patients in the tocilizumab arm [25% (40 patients)] compared with the HUMIRA arm [19% (30 patients)] had a dose modification or interruption due to AEs. This included 15% of tocilizumab vs. 12% of HUMIRA patients with an AE of infection, 3% of tocilizumab vs. 1.2% of HUMIRA patients with an AE of transaminase elevation, and 1.2% of tocilizumab vs. 0% of HUMIRA patients with an AE of neutropenia.

The proportion of patients who prematurely discontinued treatment was 18% (30 patients) in the HUMIRA arm and 15% (24 patients) in the tocilizumab arm.

Abnormal Laboratory Findings

The magnitude of change and the frequency of marked laboratory abnormalities was higher with tocilizumab compared with HUMIRA and occurred more commonly during the first month of treatment. Low neutrophil counts (<1.5x10⁹/L) were more common in the tocilizumab arm (14% tocilizumab vs. 5% HUMIRA). Four (2.5%) patients in the tocilizumab arm and two (1.2%) patients in the HUMIRA arm experienced Common Toxicity Criteria (CTC) grade 3 or 4 neutrophil count decreases. Eleven (6.8%) patients in the tocilizumab arm and five (3.1%) patients in the HUMIRA arm experienced ALT increases of CTC grade 2 or higher) including 2 patients in each treatment group with grade 3 or higher. Four (2.5%) patients in the tocilizumab arm and two (1.2%) patients in the HUMIRA arm experienced AST increases of CTC grade 2 and 1 patient in the HUMIRA arm experienced AST increases of CTC grade 3.

In patients not receiving lipid lowering agents during the study, the mean LDL increase from baseline was 0.64 mmol/L for patients in the tocilizumab arm and 0.19 mmol/L for patients in the HUMIRA arm. Twenty-three (19.5%) patients in the tocilizumab arm and ten (8%) patients in the HUMIRA arm had a week 24 LDL >4.2mmol/l.

The safety observed in the tocilizumab arm was consistent with the known safety profile of tocilizumab (see Table 1) (see 14 Clinical Trials). Table 5 below lists the adverse events (regardless of causality) occurring in ≥1% of patients in either treatment arm through 24 weeks of treatment.

Table 5 Adverse Events (regardless of causality) Occurring in ≥1% of Patients in Either Treatment Arm through 24 weeks of Treatment in Study WA19924

GIANT CELL ARTERITIS

The safety of tocilizumab subcutaneous has been studied in one Phase III (GiACTA) study with 251 GCA patients. The total patient years duration in the tocilizumab all exposure population was 138.5 patient years during the 52-week double blind, placebo-controlled phase of the study. The overall safety profile observed in the tocilizumab treatment groups was, in general, consistent with the known safety profile of tocilizumab.

Infections

There was an overall higher incidence of infections/serious infections in GCA patients relative to RA patients. The incidence rate of infection/serious infection events was comparable between tocilizumab and placebo treated groups in GiACTA study. The rate of infections/serious infections was 200.2/9.7 events per 100 patient years (PY) in the tocilizumab weekly group and 160.2/4.4 events per 100 PY in the tocilizumab every other week group as compared to 156.0/4.2 events per 100 PY in the placebo + 26-week prednisone taper and 210.2/12.5 events per 100 PY in the placebo + 52 week taper groups. In the intravenous all-exposure RA population, the incidence of infection/serious infection was 92.7/4.4 events per 100 PY.

Hypersensitivity and anaphylaxis

The rates of hypersensitivity reactions were higher in GCA patients as compared to RA patients. The rate of hypersensitivity reactions was 26.9 events per 100 PY in the weekly group and 17.6 events per 100 PY in every other week group in the GiACTA study. In the intravenous all-exposure RA population, the rate of hypersensitivity reactions was 10.4 events per 100 PY. Hypersensitivity reactions leading to withdrawal from study treatment were reported in 1.3% (2 out of 149) of patients, in the tocilizumab every other week group, in the GiACTA study.

Immunogenicity

In GCA patients, 1 patient (1.1%) in the tocilizumab weekly group and 3 patients (6.5%) in the tocilizumab every other week group developed treatment-induced anti-drug antibodies (ADAs) after exposure to tocilizumab for up to 12 months. All 4 cases of ADAs were neutralizing antibodies. Among these 4 patients, none experienced any anaphylaxis, serious/clinically significant hypersensitivity, or injection site reactions.

Table 6 Summary of Adverse Events (Regardless of Causality) Occurring in ≥1% of Patients in Study GiACTA

COVID-19