tocilizumab: prescribing information – dosing, contraindications, interactions, side effects

Rheumatoid arthritis (RA)
RoActemra, in combination with methotrexate (MTX), is indicated for:
 the treatment of severe, active and progressive RA in adults not previously treated with MTX.
 the treatment of moderate to severe active RA in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease- modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists.
In these patients, RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.
RoActemra has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function when given in combination with MTX.
Coronavirus disease 2019 (COVID-19)
RoActemra is indicated for the treatment of COVID-19 in adults who are receiving systemic corticosteroids and require supplemental oxygen or mechanical ventilation.
Systemic juvenile idiopathic arthritis (sJIA)
RoActemra is indicated for the treatment of active sJIA in patients 2 years of age and older, who have responded inadequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and

systemic corticosteroids. RoActemra can be given as monotherapy (in case of intolerance to MTX or where treatment with MTX is inappropriate) or in combination with MTX.
Polyarticular juvenile idiopathic arthritis (pJIA)
RoActemra in combination with MTX is indicated for the treatment of pJIA (rheumatoid factor positive or negative and extended oligoarthritis) in patients 2 years of age and older, who have responded inadequately to previous therapy with MTX. RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.
Cytokine release syndrome (CRS)
RoActemra is indicated for the treatment of chimeric antigen receptor (CAR) T cell induced severe or life-threatening CRS in adults and paediatric patients 2 years of age and older.

Rheumatoid arthritis (RA)
RoActemra, in combination with methotrexate (MTX), is indicated for
 the treatment of severe, active and progressive RA in adults not previously treated with MTX.
 the treatment of moderate to severe active RA in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease- modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists.
In these patients, RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.
RoActemra has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function when given in combination with methotrexate.
Systemic juvenile idiopathic arthritis (sJIA)
RoActemra is indicated for the treatment of active sJIA in patients 1 year of age and older, who have responded inadequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and systemic corticosteroids. RoActemra can be given as monotherapy (in case of intolerance to MTX or where treatment with MTX is inappropriate) or in combination with MTX.
Polyarticular juvenile idiopathic arthritis (pJIA)
RoActemra in combination with MTX is indicated for the treatment of pJIA (rheumatoid factor positive or negative and extended oligoarthritis) in patients 2 years of age and older, who have responded inadequately to previous therapy with MTX. RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.

Giant cell arteritis (GCA)
RoActemra is indicated for the treatment of GCA in adult patients.

Rheumatoid arthritis (RA)
RoActemra, in combination with methotrexate (MTX), is indicated for
 the treatment of severe, active and progressive RA in adults not previously treated with MTX.
 the treatment of moderate to severe active RA in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease- modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists.
In these patients, RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.
RoActemra has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function when given in combination with methotrexate.
Systemic juvenile idiopathic arthritis (sJIA)
RoActemra is indicated for the treatment of active sJIA in patients 12 years of age and older, who have responded inadequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and systemic corticosteroids.
RoActemra can be given as monotherapy (in case of intolerance to MTX or where treatment with MTX is inappropriate) or in combination with MTX.
Polyarticular juvenile idiopathic arthritis (pJIA)
RoActemra in combination with MTX is indicated for the treatment of pJIA (rheumatoid factor positive or negative and extended oligoarthritis) in patients 12 years of age and older, who have responded inadequately to previous therapy with MTX.

RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.
Giant cell arteritis (GCA)
RoActemra is indicated for the treatment of GCA in adult patients.

Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of RA, COVID-19, sJIA, pJIA or CRS.
All patients treated with RoActemra must be given the Patient Card.
Posology
RA patients
The recommended posology is 8 mg/kg body weight, given once every four weeks.
For individuals whose body weight is more than 100 kg, doses exceeding 800 mg per infusion are not recommended (see section 5.2).
Doses above 1.2 g have not been evaluated in clinical trials (see section 5.1).
Dose adjustments due to laboratory abnormalities (see section 4.4)

Liver enzyme abnormalities
Laboratory value
Action
> 1 to 3 × Upper
Limit of Normal
(ULN)
Modify the dose of the concomitant MTX if appropriate.
For persistent increases in this range, reduce tocilizumab dose to 4 mg/kg or interrupt treatment until alanine aminotransferase (ALT) or aspartate aminotransferase (AST) have normalised.
Restart with 4 mg/kg or 8 mg/kg, as clinically appropriate.
> 3 to 5 × ULN
(confirmed by repeat testing, see section 4.4).
Interrupt tocilizumab dosing until < 3 × ULN and follow recommendations above for > 1 to 3 × ULN.
For persistent increases > 3 × ULN, discontinue treatment.
> 5 × ULN
Discontinue treatment.

Low absolute neutrophil count (ANC)
In patients not previously treated with tocilizumab, initiation is not recommended in patients with an absolute neutrophil count (ANC) below 2 × 109/L.

Laboratory Value
(cells × 109/L)
Action
ANC > 1
Maintain dose.
ANC 0.5 to 1
Interrupt tocilizumab dosing.
When ANC increases > 1 × 109/ L resume treatment at 4 mg/kg and increase to
8 mg/kg as clinically appropriate.
ANC < 0.5
Discontinue treatment.

Low platelet count
Laboratory Value
(cells × 103/µL)
Action
50 to 100
Interrupt tocilizumab dosing.
When platelet count > 100 × 103/µL resume treatment at 4 mg/kg and increase to 8 mg/kg as clinically appropriate.
< 50
Discontinue treatment.
COVID-19 patients
The recommended posology for treatment of COVID-19 is a single 60-minute intravenous infusion of 8 mg/kg body weight in patients who are receiving systemic corticosteroids and require supplemental oxygen or mechanical ventilation, see section 5.1. If clinical signs or symptoms worsen or do not improve after the first dose, one additional infusion of tocilizumab 8 mg/kg may be administered. The interval between the two infusions must be at least 8 hours.
For individuals whose body weight is more than 100 kg, doses exceeding 800 mg per infusion are not recommended (see section 5.2).
Administration of tocilizumab is not recommended in patients with COVID-19 who have any of the following laboratory abnormalities:
Laboratory test type
Laboratory value
Action
Liver enzyme
> 10 × ULN
Administration of tocilizumab is not recommended
Absolute neutrophil count
< 1 × 109/L
Platelet count
< 50 × 103/µL
Cytokine Release Syndrome (CRS) (adults and paediatrics)
The recommended posology 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. Tocilizumab 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 tocilizumab may be administered. The interval between consecutive doses must be at least 8 hours. Doses exceeding 800 mg per infusion are not recommended in CRS patients.
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.

Special populations
Elderly
No dose adjustment is required in elderly patients > 65 years of age.
Renal impairment
No dose adjustment is required in patients with mild renal impairment. Tocilizumab has not been studied in patients with moderate to severe renal impairment (see section 5.2). Renal function must be monitored closely in these patients.
Hepatic impairment
Tocilizumab has not been studied in patients with hepatic impairment. Therefore, no dose recommendations can be made.
Paediatric population sJIA patients
The recommended posology in patients above 2 years of age is 8 mg/kg once every 2 weeks in patients weighing greater than or equal to 30 kg or 12 mg/kg once every 2 weeks in patients weighing less than 30 kg. The dose must be calculated based on the patient’s body weight at each administration. A change in dose should only be based on a consistent change in the patient’s body weight over time.
The safety and efficacy of intravenous tocilizumab in children below 2 years of age has not been established. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.
Dose interruptions of tocilizumab for the following laboratory abnormalities are recommended in sJIA patients in the tables below. If appropriate, the dose of concomitant MTX and/or other medicinal products should be modified or dosing stopped and tocilizumab dosing interrupted until the clinical situation has been evaluated. As there are many co-morbid conditions that may affect laboratory values in sJIA, the decision to discontinue tocilizumab for a laboratory abnormality should be based upon the medical assessment of the individual patient.

Liver enzyme abnormalities
Laboratory Value
Action
> 1 to 3 × ULN
Modify the dose of the concomitant MTX if appropriate.
For persistent increases in this range, interrupt tocilizumab until ALT/AST have normalised.
> 3 × ULN to

Tocilizumab subcutaneous formulation is administered with a single-use PFS+NSD (pre-filled syringe and needle safety device). Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of RA, sJIA, pJIA and / or GCA. The first injection must be performed under the supervision of a qualified health care professional. A patient or parent/guardian can inject this medicinal product only if the physician determines that it is appropriate and the patient or parent/guardian agrees to medical follow-up as necessary and has been trained in proper injection technique.
Patients who transition from tocilizumab 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 health care professional.
All patients treated with RoActemra must be given the Patient Card.
Suitability of the patient or their parent/guardian for subcutaneous home use should be assessed and patients or their parent/guardian should be instructed to inform a healthcare professional before administering the next dose if they experience symptoms of an allergic reaction. Patients should seek immediate medical attention if developing symptoms of serious allergic reactions (see section 4.4).
Posology
RA patients
The recommended posology is subcutaneous 162 mg once every week.
Limited information is available regarding switching patients from tocilizumab intravenous formulation to tocilizumab subcutaneous fixed dose formulation. The once every week dosing interval should be followed.
Patients transitioning from intravenous to subcutaneous formulation should administer their first subcutaneous dose instead of the next scheduled intravenous dose under the supervision of a qualified healthcare professional.
GCA patients
The recommended posology is subcutaneous 162 mg once every week in combination with a tapering course of glucocorticoids. This medicinal product can be used alone following discontinuation of glucocorticoids.
Tocilizumab monotherapy should not be used for the treatment of acute relapses (see section 4.4).
Based upon the chronic nature of GCA, treatment beyond 52 weeks should be guided by disease activity, physician discretion, and patient choice.

RA and GCA patients
Dose adjustments due to laboratory abnormalities (see section 4.4).

Liver enzyme abnormalities
Laboratory Value
Action
> 1 to 3 × Upper
Limit of
Normal
(ULN)
Dose modify concomitant DMARDs (RA) or immunomodulatory agents
(GCA) if appropriate.
For persistent increases in this range, reduce tocilizumab dose frequency to every other week injection or interrupt treatment until alanine aminotransferase (ALT) or aspartate aminotransferase (AST) have normalised.
Restart with weekly or every other week injection, as clinically appropriate.
> 3 to 5 × ULN
Interrupt treatment dosing until < 3 × ULN and follow recommendations above for > 1 to 3 × ULN.
For persistent increases > 3 × ULN (confirmed by repeat testing, see section 4.4.), discontinue treatment.
> 5 × ULN
Discontinue treatment.

Low absolute neutrophil count (ANC)
In patients not previously treated with tocilizumab, initiation is not recommended in patients with an ANC below 2 × 109/L.
Laboratory Value
(cells × 109/L)
Action
ANC > 1
Maintain dose.
ANC 0.5 to 1
Interrupt tocilizumab dosing.
When ANC increases > 1 × 109/L resume treatment dosing every other week and increase to every week injection, as clinically appropriate.
ANC < 0.5
Discontinue treatment.

Low platelet count
Laboratory Value
(cells × 103/µL)
Action
50 to 100
Interrupt tocilizumab dosing.
When platelet count > 100 × 103/µL resume treatment dosing every other week and increase to every week injection as clinically appropriate.
< 50
Discontinue treatment.

RA and GCA patients
Missed dose
If a patient misses a subcutaneous weekly injection of tocilizumab within 7 days of the scheduled dose, he/she should be instructed to take the missed dose on the next scheduled day. If a patient misses a subcutaneous once every other week injection of tocilizumab within 7 days of the scheduled dose, he/she should be instructed to take the missed dose immediately and the next dose on the next scheduled day.
Special populations
Elderly
No dose adjustment is required in elderly patients > 65 years of age.
Renal impairment
No dose adjustment is required in patients with mild or moderate renal impairment. Tocilizumab has not been studied in patients with severe renal impairment (see section 5.2). Renal function must be monitored closely in these patients.
Hepatic impairment
Tocilizumab has not been studied in patients with hepatic impairment. Therefore, no dose recommendations can be made.
Paediatric population
The safety and efficacy of tocilizumab subcutaneous formulation in children from birth to less than 1 year have not been established. No data are available.
A change in dose should only be based on a consistent change in the patient’s body weight over time.
Tocilizumab can be used alone or in combination with MTX.
sJIA patients
The recommended posology in patients above 1 year of age is subcutaneous 162 mg once every week in patients weighing greater than or equal to 30 kg or subcutaneous 162 mg once every 2 weeks in patients weighing less than 30 kg.
Patients must have a minimum body weight of 10 kg when receiving tocilizumab subcutaneously.
pJIA patients
The recommended posology in patients above 2 years of age is subcutaneous 162 mg once every 2 weeks in patients weighing greater than or equal to 30 kg or subcutaneous 162 mg once every 3 weeks in patients weighing less than 30 kg.
sJIA and pJIA patients
Dose adjustments due to laboratory abnormalities
If appropriate, the dose of concomitant MTX and/or other medicinal products should be modified or dosing stopped and tocilizumab dosing interrupted until the clinical situation has been evaluated. As there are many co-morbid conditions that may effect laboratory values in sJIA or pJIA, the decision to discontinue tocilizumab for a laboratory abnormality should be based upon the medical assessment of the individual patient.


Liver enzyme abnormalities
Laboratory Value
Action
> 1 to 3 × ULN
Modify the dose of the concomitant MTX if appropriate.
For persistent increases in this range, interrupt tocilizumab until ALT/AST have normalised.
> 3 × ULN to

Tocilizumab subcutaneous formulation is administered with a single-use pre-filled pen. Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of RA, sJIA, pJIA and/or GCA.
The pre-filled pen must not be used to treat paediatric patients < 12 years of age since there is a potential risk of intramuscular injection due to thinner subcutaneous tissue layer.
The first injection must be performed under the supervision of a qualified health care professional. A patient or parent/guardian can inject this medicinal product only if the physician determines that it is appropriate and the patient or parent/guardian agrees to medical follow-up as necessary and has been trained in proper injection technique.
Patients who transition from tocilizumab 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 health care professional.
All patients treated with RoActemra must be given the Patient Card.
Suitability of the patient or their parent/guardian for subcutaneous home use should be assessed and patients or their parent/guardian should be instructed to inform a healthcare professional before administering the next dose if they experience symptoms of an allergic reaction. Patients should seek immediate medical attention if developing symptoms of serious allergic reactions (see section 4.4).
Posology
RA patients
The recommended posology is subcutaneous 162 mg once every week.
Limited information is available regarding switching patients from tocilizumab intravenous formulation to tocilizumab subcutaneous fixed dose formulation. The once every week dosing interval should be followed.
Patients transitioning from intravenous to subcutaneous formulation should administer their first subcutaneous dose instead of the next scheduled intravenous dose under the supervision of a qualified healthcare professional.
GCA patients
The recommended posology is subcutaneous 162 mg once every week in combination with a tapering course of glucocorticoids. This medicinal product can be used alone following discontinuation of glucocorticoids.
Tocilizumab monotherapy should not be used for the treatment of acute relapses (see section 4.4).
Based upon the chronic nature of GCA, treatment beyond 52 weeks should be guided by disease activity, physician discretion, and patient choice.

RA and GCA patients
Dose adjustments due to laboratory abnormalities (see section 4.4).

Liver enzyme abnormalities
Laboratory Value
Action
> 1 to 3 × Upper
Limit of Normal
(ULN)
Dose modify concomitant DMARDs (RA) or immunomodulatory agents
(GCA) if appropriate.
For persistent increases in this range, reduce tocilizumab dose frequency to every other week injection or interrupt treatment until alanine aminotransferase (ALT) or aspartate aminotransferase (AST) have normalised.
Restart with weekly or every other week injection, as clinically appropriate.
> 3 to 5 × ULN
Interrupt treatment dosing until < 3 × ULN and follow recommendations above for > 1 to 3 × ULN.
For persistent increases > 3 × ULN (confirmed by repeat testing, see section 4.4.), discontinue treatment.
> 5 × ULN
Discontinue treatment.

Low absolute neutrophil count (ANC)
In patients not previously treated with tocilizumab, initiation is not recommended in patients with an ANC below 2 × 109/L.
Laboratory Value
(cells × 109/L)
Action
ANC > 1
Maintain dose.
ANC 0.5 to 1
Interrupt tocilizumab dosing.
When ANC increases > 1 × 109/L resume treatment dosing every other week and increase to every week injection, as clinically appropriate.
ANC < 0.5
Discontinue treatment.

Low platelet count
Laboratory Value
(cells × 103/µL)
Action
50 to 100
Interrupt tocilizumab dosing.
When platelet count > 100 × 103/μL resume treatment dosing every other week and increase to every week injection as clinically appropriate.
< 50
Discontinue treatment.

RA and GCA patients
Missed dose
If a patient misses a subcutaneous weekly injection of tocilizumab within 7 days of the scheduled dose, he/she should be instructed to take the missed dose on the next scheduled day. If a patient misses a subcutaneous once every other week injection of tocilizumab within 7 days of the scheduled dose, he/she should be instructed to take the missed dose immediately and the next dose on the next scheduled day.
Special populations
Elderly
No dose adjustment is required in elderly patients > 65 years of age.
Renal impairment
No dose adjustment is required in patients with mild or moderate renal impairment. Tocilizumab has not been studied in patients with severe renal impairment (see section 5.2). Renal function must be monitored closely in these patients.
Hepatic impairment
Tocilizumab has not been studied in patients with hepatic impairment. Therefore, no dose recommendations can be made.
Paediatric population
The safety and efficacy of tocilizumab subcutaneous formulation in children from birth to less than 1 year have not been established. No data are available.
A change in dose should only be based on a consistent change in the patient’s body weight over time.
Tocilizumab can be used alone or in combination with MTX.
sJIA patients
The recommended posology in patients above 12 years of age is subcutaneous 162 mg once every week in patients weighing greater than or equal to 30 kg or subcutaneous 162 mg once every 2 weeks in patients weighing less than 30 kg.
The pre-filled pen should not be used to treat paediatric patients < 12 years of age.
Patients must have a minimum body weight of 10 kg when receiving tocilizumab subcutaneously.
pJIA patients
The recommended posology in patients above 12 years of age is subcutaneous 162 mg once every 2 weeks in patients weighing greater than or equal to 30 kg or subcutaneous 162 mg once every 3 weeks in patients weighing less than 30 kg.
The pre-filled pen should not be used to treat paediatric patients < 12 years of age.
sJIA and pJIA patients
Dose adjustments due to laboratory abnormalities
If appropriate, the dose of concomitant MTX and/or other medicinal products should be modified or dosing stopped and tocilizumab dosing interrupted until the clinical situation has been evaluated. As there are many co-morbid conditions that may effect laboratory values in sJIA or pJIA, the decision to discontinue tocilizumab for a laboratory abnormality should be based upon the medical assessment of the individual patient.


Liver enzyme abnormalities
Laboratory Value
Action
> 1 to 3 × ULN
Modify the dose of the concomitant MTX if appropriate.
For persistent increases in this range, interrupt tocilizumab until ALT/AST have normalised.
> 3 × ULN to

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active, severe infections with the exception of COVID-19 (see section 4.4).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active, severe infections (see section 4.4).

Summary of the safety profile
RA, sJIA, pJIA and CRS
The most commonly reported adverse reactions are upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.

The most serious adverse reactions are serious infections, complications of diverticulitis, and hypersensitivity reactions.
COVID-19
The most commonly reported adverse reactions are hepatic transaminases increased, constipation, and urinary tract infection.
Tabulated list of adverse reactions
Adverse reactions from clinical trials and/or post-marketing experience with tocilizumab based on spontaneous case reports, literature cases and cases from non-interventional trial programs are listed in Table 1 and in Table 2 by MedDRA system organ class (SOC). The corresponding frequency category for each adverse reaction is based on the following convention: very common ( ≥ 1/10); common ( ≥ 1/100 to < 1/10), uncommon ( ≥ 1/1 000 to < 1/100), rare ( ≥ 1/10 000 to < 1/1 000), very rare ( < 1/10 000), and frequency not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
RA patients
Table 1. List of adverse reactions occurring in patients with RA receiving tocilizumab as monotherapy or in combination with MTX or other DMARDs in the double-blind controlled period or during post-marketing experience MedDRA SOC Frequency categories with preferred terms Very common Common Uncommon Rare Very rare Infections and infestations Upper respiratory tract infections Cellulitis, Pneumonia, Oral herpes simplex, Herpes zoster Diverticulitis Blood and lymphatic system disorders Leukopenia, Neutropenia, Hypofibrino- genaemia Immune system disorders Anaphylaxis (fatal)1, 2 ,3 Endocrine disorders Hypothy- roidism Metabolism and nutrition disorders Hypercholeste rolaemia* Hypertri- glyceridaemia Nervous system disorders Headache, Dizziness Eye disorders Conjunctivitis Vascular disorders Hypertension Respiratory , thoracic and mediastinal disorders Cough, Dyspnoea

MedDRA
SOC
Frequency categories with preferred terms
Very common
Common
Uncommon
Rare
Very rare
Gastroin- testinal disorders
Abdominal pain, Mouth ulceration,
Gastritis
Stomatitis,
Gastric ulcer
Hepatobi- liary disorders
Drug-induced liver injury,
Hepatitis,
Jaundice,
:
Hepatic failure
Skin and subcutane- ous tissue disorders
Rash,
Pruritus,
Urticaria
Stevens-
Johnson-
Syndrome3
Renal and urinary disorders
Nephroli- thiasis
General disorders and administra- tion site conditions
Peripheral oedema,
Hypersensitiv ity reactions
Investiga- tions
Hepatic transaminases increased,
Weight increased,
Total bilirubin increased*
* Includes elevations collected as part of routine laboratory monitoring (see text below) 1 See section 4.3 2 See section 4.4 3 This adverse reaction was identified through post-marketing surveillance but not observed in controlled clinical trials. The frequency category was estimated as the upper limit of the 95 % confidence interval calculated on the basis of the total number of patients exposed to tocilizumab in clinical trials.
Patients with COVID-19
The safety evaluation of this medicinal product in COVID-19 was based on 3 randomised, double-blind, placebo-controlled trials (Trials ML42528, WA42380, and WA42511). A total of 974 patients were exposed to tocilizumab in these trials. Collection of safety data from the RECOVERY trial was limited and is not presented here.
The following adverse reactions, listed by MedDRA SOC in Table 2, have been adjudicated from events which occurred in at least 3 % of tocilizumab treated patients and more commonly than that in patients on placebo in the pooled safety-evaluable population from clinical Trials ML42528, WA42380, and WA42511.

Table 2. List of adverse reactions1 identified from the pooled safety-evaluable population from tocilizumab clinical trials in COVID-19 patients2 MedDRA SOC Class Preferred Terms and frequency Common Infections and infestations Urinary tract infection Metabolism and nutrition disorders Hypokalaemia Psychiatric disorders Anxiety, Insomnia Vascular disorders Hypertension Gastrointestinal disorders Constipation, Diarrhoea, Nausea Hepatobiliary disorders Hepatic transaminases increased 1 Patients are counted once for each category regardless of the number of reactions 2 Includes adjudicated reactions reported in Trials WA42511, WA42380 and ML42528 Patients with sJIA or pJIA Adverse reactions in the sJIA and pJIA patients treated with tocilizumab are listed in the Table 3 and presented by MedDRA SOC. The corresponding frequency category for each adverse reaction is based on the following convention: very common ( ≥ 1/10); common ( ≥ 1/100 to < 1/10) or uncommon ( ≥ 1/1 000 to < 1/100).
Table 3. List of adverse reactions occurring in clinical trial patients with sJIA or pJIA receiving tocilizumab as monotherapy or in combination with MTX.
MedDRA SOC
Preferrred term (PT)
Frequency
Infections and Infestations
Very Common
Common
Uncommon
Upper Respiratory
Tract Infections pJIA, sJIA
Nasopharyngitis pJIA, sJIA
Nervous system disorders
Headache pJIA sJIA
Gastrointestinal Disorders
Nausea pJIA
Diarrhoea pJIA, sJIA
General disorders and administration site conditions
Infusion related reactions pJIA1, sJIA2
Investigations
Hepatic transaminases increased pJIA
Decrease in neutrophil count sJIA pJIA
Platelet count decreased sJIA pJIA
Cholesterol increased sJIA pJIA
1. Infusion-related reaction events in pJIA patients included but were not limited to headache, nausea and hypotension 2. Infusion-related reaction events in sJIA patients included but were not limited to rash, urticaria, diarrhoea, epigastric discomfort, arthralgia and headache

Description of selected adverse reactions
RA patients
Infections
In the 6-month controlled trials the rate of all infections reported with tocilizumab 8 mg/kg plus DMARD treatment was 127 events per 100 patient years compared to 112 events per 100 patient years in the placebo plus DMARD group. In the long-term exposure population, the overall rate of infections with tocilizumab was 108 events per 100 patient years exposure.
In 6-month controlled clinical trials, the rate of serious infections with tocilizumab 8 mg/kg plus DMARDs was 5.3 events per 100 patient years exposure compared to 3.9 events per 100 patient years exposure in the placebo plus DMARD group. In the monotherapy trial, 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 the long-term exposure population, the overall rate of serious infections (bacterial, viral and fungal) was 4.7 events per 100 patient years. Reported serious infections, some with fatal outcome, included active tuberculosis, which may present with intrapulmonary or extrapulmonary disease, invasive pulmonary infections, including candidiasis, aspergillosis, coccidioidomycosis and pneumocystis jirovecii, pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported.
Interstitial lung disease
Impaired lung function may increase the risk for developing infections. There have been post-marketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.
Gastrointestinal perforation
During the 6-month controlled clinical trials, the overall rate of gastrointestinal perforation, was 0.26 events per 100 patient years with tocilizumab therapy. In the long-term exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 patient years. Reports of gastrointestinal perforation on treatment were primarily reported as complications of diverticulitis including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess.
Infusion related reactions
In the 6-month controlled trials adverse events associated with infusion (selected events occurring during or within 24 hours of infusion) were reported by 6.9 % of patients in the tocilizumab 8 mg/kg plus DMARD group and 5.1 % of patients in the placebo plus DMARD group. Events reported during the infusion were primarily episodes of hypertension; events reported within 24 hours of finishing an infusion were headache and skin reactions (rash, urticaria). These events were not treatment limiting.
The rate of anaphylactic reactions (occurring in a total of 8/4 009 patients, 0.2 %) was several fold higher with the 4 mg/kg dose, compared to the 8 mg/kg dose. Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported in a total of 56 out of 4 009 patients (1.4 %) treated during the controlled and open label clinical trials. These reactions were generally observed during the second to fifth infusions of tocilizumab (see section 4.4).
Fatal anaphylaxis has been reported after marketing authorisation during treatment with tocilizumab (see section 4.4).
Immunogenicity
A total of 2 876 patients have been tested for anti-tocilizumab antibodies in the 6-month controlled clinical trials. Of the 46 patients (1.6 %) who developed anti-tocilizumab antibodies, 6 had an associated medically significant hypersensitivity reaction, of which 5 led to permanent discontinuation of treatment. Thirty patients (1.1 %) developed neutralising antibodies.
Neutrophils
In the 6-month controlled trials decreases in neutrophil counts below 1 × 109/L occurred in 3.4 % of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 0.1 % of patients on placebo plus

DMARDs. Approximately half of the patients who developed an ANC < 1 × 109/ L did so within 8 weeks after starting therapy. Decreases below 0.5 × 109/L were reported in 0.3 % patients receiving tocilizumab 8 mg/kg plus DMARDs. Infections with neutropenia have been reported.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 6-month controlled clinical trials.
Platelets
In the 6-month controlled trials decreases in platelet counts below 100 × 103/µL occurred in 1.7 % of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 1 % on placebo plus DMARDs. These decreases occurred without associated bleeding events.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 6-month controlled clinical trials.
Very rare reports of pancytopenia have occurred in the post-marketing setting.
Hepatic transaminase elevations
During the 6-month controlled trials transient elevations in ALT/AST > 3 × ULN were observed in 2.1 % of patients on tocilizumab 8 mg/kg compared to 4.9 % of patients on MTX and in 6.5 % of patients who received 8 mg/kg tocilizumab plus DMARDs compared to 1.5 % of patients on placebo plus DMARDs.
The addition of potentially hepatotoxic medicinal products (e.g. MTX) to tocilizumab monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST > 5 × ULN were observed in 0.7 % of tocilizumab monotherapy patients and 1.4 % of tocilizumab plus DMARD patients, the majority of whom were discontinued permanently from tocilizumab treatment. During the double-blind controlled period, the incidence of indirect bilirubin greater than the upper limit of normal, collected as a routine laboratory parameter, is 6.2 % in patients treated with 8 mg/kg tocilizumab + DMARD. A total of 5.8 % of patients experienced an elevation of indirect bilirubin of > 1 to 2 × ULN and 0.4 % had an elevation of > 2 × ULN.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevation in ALT/AST remained consistent with what was seen in the 6-month controlled clinical trials.
Lipid parameters
During the 6-month controlled trials, increases of lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol have been reported commonly. With routine laboratory monitoring it was seen that approximately 24 % of patients receiving tocilizumab in clinical trials experienced sustained elevations in total cholesterol ≥ 6.2 mmol/L with 15 % experiencing a sustained increase in LDL to ≥ 4.1 mmol/L. Elevations in lipid parameters responded to treatment with lipid-lowering agents.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevations in lipid parameters remained consistent with what was seen in the 6-month controlled trials.
Skin reactions
Rare reports of Stevens-Johnson Syndrome have occurred in the post-marketing setting.

COVID-19 patients
Infections
In the pooled safety-evaluable population from Trials ML42528, WA42380, and WA42511, the rates of infection/serious infection events were balanced between COVID-19 patients receiving tocilizumab (30.3 %/18.6 %, n = 974) versus placebo (32.1 %/22.8 %, n = 483).
The safety profile observed in the baseline systemic corticosteroids treatment group was consistent with the safety profile of tocilizumab from the overall population presented in Table 2. In this subgroup, infections and serious infections occurred in 27.8 % and 18.1 % of patients treated with intravenous tocilizumab and in 30.5 % and 22.9 % of patients treated with placebo, respectively.
Laboratory abnormalities
The incidence of laboratory abnormalities was generally similar between patients with COVID-19 who received one or two doses of tocilizumab-intravenous compared with those who received placebo in the randomised, double-blind, placebo-controlled trials with few exceptions. Decreases in platelets and neutrophils and elevations of ALT and AST were more frequent among patients receiving tocilizumab-intravenous versus placebo (see section 4.2 and 4.4).
Paediatric population
In general, the adverse reactions in pJIA and sJIA patients were similar in type to those seen in RA patients, see section 4.8.
Description of selected adverse reactions in pJIA patients
The safety profile of intravenous tocilizumab in pJIA has been studied in 188 patients from 2 to 17 years of age. The total patient exposure was 184.4 patient years. The frequency of adverse reactions in pJIA patients can be found in Table 3. The types of adverse reactions in pJIA patients were similar to those seen in RA and sJIA patients. When compared to the adult RA population, events of nasopharyngitis, headache, nausea, and decreased neutrophil count were more frequently reported in the pJIA population. Events of cholesterol increased were less frequently reported in the pJIA population than in the adult RA population.
Infections
The rate of infections in the tocilizumab all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing < 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing ≥ 30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing < 30 kg treated with 10 mg/kg tocilizumab (21.4 %) compared to patients weighing ≥ 30 kg, treated with 8 mg/kg tocilizumab (7.6 %).
Infusion-related reactions
In pJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the tocilizumab all exposure population, 11 patients (5.9 %) experienced infusion-related reactions during the infusion and 38 patients (20.2 %) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension and within 24 hours of infusion were dizziness and hypotension. In general, the adverse reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and sJIA patients, see section 4.8.
No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported.
Immunogenicity
One patient in the 10 mg/kg < 30 kg group developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the trial.

Neutrophils
During routine laboratory monitoring in the tocilizumab all exposure population, a decrease in neutrophil count below 1 × 109/L occurred in 3.7 % of patients.
Platelets
During routine laboratory monitoring in the tocilizumab all exposure population, 1 % of patients had a decrease in platelet count to ≤ 50 × 103/µL without associated bleeding events.
Hepatic transaminase elevations
During routine laboratory monitoring in the tocilizumab all exposure population, elevation in ALT or AST ≥ 3 × ULN occurred in 3.7 % and < 1 % of patients, respectively.
Lipid parameters
During routine laboratory monitoring in the intravenous tocilizumab Trial WA19977 3.4 % and 10.4 % of patients experienced a post-baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time during the trial treatment, respectively.
Description of selected adverse reactions in sJIA patients
The safety profile of intravenous tocilizumab in sJIA has been studied in 112 patients from 2 to 17 years of age. In the 12 week double-blind, controlled phase, 75 patients received treatment with tocilizumab (8 mg/kg or 12 mg/kg based upon body weight). After 12 weeks or at the time of switching from placebo to tocilizumab, due to disease worsening, patients were treated in the open label extension phase.
In general, the adverse reactions in sJIA patients were similar in type to those seen in RA patients. The frequency of adverse reactions in sJIA patients can be found in Table 3. When compared to the adult RA population, patients with sJIA experienced a higher frequency of nasopharyngitis, decrease in neutrophil counts, hepatic transaminases increased, and diarrhoea. Events of cholesterol increased were less frequently reported in the sJIA population than in the adult RA population.
Infections
In the 12 week controlled phase, the rate of all infections in the intravenous tocilizumab group was 344.7 per 100 patient years and 287.0 per 100 patient years in the placebo group. In the open label extension phase (Part II), the overall rate of infections remained similar at 306.6 per 100 patient years.
In the 12 week controlled phase, the rate of serious infections in the intravenous tocilizumab group was 11.5 per 100 patient years. At one year in the open label extension phase the overall rate of serious infections remained stable at 11.3 per 100 patient years. Reported serious infections were similar to those seen in RA patients with the addition of varicella and otitis media.
Infusion-related reactions
Infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion.
In the 12 week controlled phase, 4 % of patients from the tocilizumab group experienced events occurring during infusion. One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from trial treatment.
In the 12 week controlled phase, 16 % of patients in the tocilizumab group and 5.4 % of patients in the placebo group experienced an event within 24 hours of infusion. In the tocilizumab group, the events included, but were not limited to rash, urticaria, diarrhoea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious.
Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation, were reported in 1 out of 112 patients ( < 1 %) treated with tocilizumab during the controlled and up to and including the open label clinical trial.

Immunogenicity
All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti-tocilizumab antibodies with one of these patients having a hypersensitivity reaction leading to withdrawal. The incidence of anti-tocilizumab antibody formation might be underestimated because of interference of tocilizumab with the assay and higher tocilizumab concentration observed in children compared to adults.
Neutrophils
During routine laboratory monitoring in the 12 week controlled phase, a decrease in neutrophil counts below 1 × 109/L occurred in 7 % of patients in the tocilizumab group, and no decreases in the placebo group.
In the open label extension phase, decreases in neutrophil counts below 1 × 109/L, occurred in 15 % of the tocilizumab group.
Platelets
During routine laboratory monitoring in the 12 week controlled phase, 3 % of patients in the placebo group and 1 % in the tocilizumab group had a decrease in platelet count to ≤ 100 × 103/µL.
In the open label extension phase, decreases in platelet counts below 100 × 103/µL, occurred in 3 % of patients in the tocilizumab group, without associated bleeding events.
Hepatic transaminase elevations
During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST ≥ 3 × ULN occurred in 5 % and 3 % of patients, respectively, in the tocilizumab group, and 0 % in the placebo group.
In the open label extension phase, elevation in ALT or AST ≥ 3 × ULN occurred in 12 % and 4 % of patients, respectively, in the tocilizumab group.
Immunoglobulin G
IgG levels decrease during therapy. A decrease to the lower limit of normal occurred in 15 patients at some point in the trial.
Lipid parameters
During routine laboratory monitoring in the 12 week controlled phase (Trial WA18221), 13.4 % and 33.3 % of patients experienced a post-baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time during trial treatment, respectively.
In the open label extension phase (Trial WA18221), 13.2 % and 27.7 % of patients experienced a post- baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time during trial treatment, respectively.
CRS patients
The safety of tocilizumab in CRS has been evaluated in a retrospective analysis of data from clinical trials, where 51 patients were treated with intravenous tocilizumab 8 mg/kg (12 mg/kg for patients less than 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening CAR T cell-induced CRS. A median of 1 dose of tocilizumab (range, 1-4 doses) was administered.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Summary of the safety profile
The safety profile comes from 4 510 patients exposed to tocilizumab in clinical trials; the majority of these patients were participating in adult RA trials (n = 4 009), while the remaining experience comes from GCA (n = 149), pJIA (n = 240) and sJIA (n = 112) trials. The safety profile of tocilizumab across these indications remains similar and undifferentiated.
The most commonly reported adverse reactions were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.
The most serious adverse reactions were serious infections, complications of diverticulitis, and hypersensitivity reactions.
Tabulated list of adverse reactions
Adverse reactions from clinical trials and/or post-marketing experience with tocilizumab based on spontaneous case reports, literature cases and cases from non-interventional trial programs are listed in Table 1 and are presented by MedDRA system organ class. The corresponding frequency category is based on the following convention: very common ( ≥ 1/10); common ( ≥ 1/100 to < 1/10), uncommon ( ≥ 1/1 000 to < 1/100) rare ( ≥ 1/10 000 to < 1/1 000), very rare ( < 1/10 000), and frequency not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. List of adverse reactions occurring in patients treated with tocilizumab MedDRA SOC Frequency category with preferred term Very common Common Uncommon Rare Very rare Infections and infestations Upper respiratory tract infections Cellulitis, Pneumonia, Oral herpes simplex, Herpes zoster Diverticulitis Blood and lymphatic system disorders Leukopenia, Neutropenia, Hypofibrinogenaemia Immune system disorders Anaphylaxis (fatal)1, 2 ,3 Endocrine disorders Hypothyroidi sm Metabolism and nutrition disorders Hypercholestero laemia* Hypertriglyc eridaemia Nervous system disorders Headache, Dizziness Eye disorders Conjunctivitis Vascular disorders Hypertension Respiratory, thoracic and mediastinal disorders Cough, Dyspnoea Gastrointestin al disorders Abdominal pain, Mouth ulceration, Gastritis Stomatitis, Gastric ulcer Hepatobiliary disorders Drug-induced liver injury, Hepatitis, Jaundice Hepatic failure Skin and subcutaneous tissue disorders Rash, Pruritus, Urticaria Stevens- Johnson- Syndrome3 Renal and urinary disorders Nephrolithias is General disorders and administration site conditions Injection site reaction Peripheral oedema Hypersensitivity reaction,

MedDRA
SOC
Frequency category with preferred term
Very common
Common
Uncommon
Rare
Very rare
Investigations
Hepatic transaminases increased, Weight increased, Total bilirubin increased*
* Includes elevations collected as part of routine laboratory monitoring (see text below) 1 See section 4.3 2 See section 4.4 3 This adverse reaction was identified through post-marketing surveillance but not observed in controlled clinical trials. The frequency category was estimated as the upper limit of the 95 % confidence interval calculated on the basis of the total number of patients exposed to tocilizumab in clinical trials.
Description of selected adverse reactions (subcutaneous use)
RA patients
The safety of subcutaneous tocilizumab in RA includes a double-blind, controlled, multi-centre trial, SC-I. SC-I was a non-inferiority trial that compared the efficacy and safety of 162 mg administered every week versus 8 mg/kg intravenous in 1 262 patients with RA. All patients received background non-biologic DMARD(s). 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 reactions were observed (see Table 1). A higher frequency of injection site reactions was observed in the subcutaneous arms compared with placebo subcutaneous injections in the intravenous arms.
Injection site reactions
During the 6-month controlled period, in SC-I, the frequency of injection site reactions was 10.1 % (64/631) and 2.4 % (15/631) for the subcutaneous tocilizumab and the subcutaneous placebo (intravenous group) weekly injections, 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 treatment discontinuation.
Immunogenicity
In SC-I, 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 neutralising anti-tocilizumab antibodies. One patient was tested positive for IgE isotype (0.2 %).
In SC-II, a total of 434 patients treated with tocilizumab 162 mg every other week were tested for anti- tocilizumab antibodies in the 6 month controlled period. Seven patients (1.6 %) developed positive anti-tocilizumab antibodies; of these, six (1.4 %) developed neutralising anti-tocilizumab antibodies.
Four patients were tested positive for IgE isotype (0.9 %).
No correlation of antibody development to clinical response or adverse events was observed.
Neutrophils
During routine laboratory monitoring in the tocilizumab 6 month controlled clinical Trial SC-I, a decrease in neutrophil count below 1 × 109/L occurred in 2.9 % of patients on the subcutaneous weekly dose.
There was no clear relationship between decreases in neutrophils below 1 × 109/L and the occurrence of serious infections.
Platelets
During routine laboratory monitoring in the tocilizumab 6 month clinical Trial SC-I, none of the patients on the subcutaneous weekly dose had a decrease in platelet count to ≤ 50 × 103/µL.

Hepatic transaminase elevations
During routine laboratory monitoring in the tocilizumab 6-month controlled clinical Trial SC-I, elevation in ALT or AST ≥ 3 × ULN occurred in 6.5 % and 1.4 % of patients, respectively on the subcutaneous weekly dose.
Lipid parameters
During routine laboratory monitoring in the tocilizumab 6 month controlled clinical Trial SC-I, 19 % of patients experienced sustained elevations in total cholesterol > 6.2 mmol/L (240 mg/dL), with 9 % experiencing a sustained increase in LDL to ≥ 4.1 mmol/L (160 mg/dL) on the subcutaneous weekly dose.
sJIA patients
The safety profile of subcutaneous tocilizumab was evaluated in 51 paediatric patients (1 to 17 years of age) with sJIA. In general, the adverse reactions in patients with sJIA were similar in type to those seen in RA patients (see section 4.8).
Infections
The rate of infection in sJIA patients treated with subcutaneous tocilizumab was comparable to sJIA patients treated with intravenous tocilizumab.
Injection Site Reactions (ISRs)
In the subcutaneous trial (WA28118), a total of 41.2 % (21/51) sJIA patients experienced ISRs to tocilizumab subcutaneous. The most common ISRs were erythema, pruritus, pain, and swelling at the injection site. The majority of ISRs reported were Grade 1 events and all ISRs reported were non- serious and none required patient withdrawal from treatment or dose interruption.
Immunogenicity
In the subcutaneous trial (WA28118), 46 of the 51 (90.2 %) patients tested for anti-tocilizumab antibodies at baseline had at least one post-baseline screening assay result. No patient developed positive anti-tocilizumab antibodies post baseline.
Laboratory Abnormalities
In the 52-week open-label subcutaneous trial (WA28118), neutrophil count decrease to below 1 × 109/L occurred in 23.5 % of patients treated with tocilizumab subcutaneous. Decreases in platelet counts to below 100 × 103/µL occurred in 2 % of the patients treated with tocilizumab subcutaneous.
An elevation in ALT or AST to ≥ 3 × ULN occurred in 9.8 % and 4.0 % patients treated with tocilizumab subcutaneous, respectively.
Lipid parameters
In the 52-week open-label subcutaneous trial (WA28118), 23.4 % and 35.4 % of patients experienced a post-baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time during trial treatment, respectively.
pJIA patients
The safety profile of subcutaneous tocilizumab was also evaluated in 52 paediatric patients with pJIA.
The total patient exposure to tocilizumab in the pJIA all exposure population was 184.4 patient years for intravenous and 50.4 patient years for subcutaneous tocilizumab. In general, the safety profile observed in patients with pJIA was consistent with the known safety profile of tocilizumab with the exception of ISRs (see Table 1). A higher frequency of pJIA patients experienced ISRs following subcutaneous injections compared to adult RA.
Infections
In the subcutaneous tocilizumab trial, the rate of infection in pJIA patients treated with subcutaneous tocilizumab was comparable with pJIA patients treated with intravenous tocilizumab.

Injection Site Reactions
A total of 28.8 % (15/52) pJIA patients experienced ISRs to tocilizumab subcutaneous. These ISRs occurred in a 44 % of patients ≥ 30 kg compared to 14.8 % of patients below 30 kg. The most common ISRs were injection site erythema, swelling, haematoma, pain and pruritis. All ISRs reported were non-serious Grade 1 events, and none of the ISRs required patient withdrawal from treatment or dose interruption.
Immunogenicity
In the subcutaneous trial 5.8 % [3/52] developed positive neutralising anti-tocilizumab antibodies without developing a serious or clinically significant hypersensitivity reaction. Of these 3 patients, 1 subsequently withdrew from the trial. No correlation between antibody development and clinical response or adverse events was observed Laboratory abnormalities During routine laboratory monitoring in the tocilizumab all exposure population, a decrease in neutrophil count below 1 × 109/L occurred in 15.4 % of patients treated with subcutaneous tocilizumab. An elevation in ALT or AST ≥ 3 × ULN occurred in 9.6 % and 3.8 % patients treated with tocilizumab subcutaneous, respectively. No patients treated with subcutaneous tocilizumab experienced a decrease in platelet count to ≤ 50 × 103/µL.
Lipid parameters
In the subcutaneous trial, 14.3 % and 12.8 % of patients experienced a post-baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time during trial treatment, respectively.
GCA patients
The safety of subcutaneous tocilizumab has been studied in one Phase III trial (WA28119) with 251 GCA patients. The total patient years duration in the tocilizumab all exposure population was 138.5 patient years during the 12 month double-blind, placebo-controlled phase of the trial. The overall safety profile observed in the treatment groups was consistent with the known safety profile of tocilizumab (see Table 1).
Infections
The rate of infection/serious infection events was balanced between the tocilizumab weekly group (200.2/9.7 events per 100 patient years) vs. placebo plus 26 weeks prednisone taper (156.0/4.2 events per 100 patient years) and placebo plus 52 weeks taper (210.2/12.5 events per 100 patient years) groups.
Injection site reactions
In the tocilizumab subcutaneous weekly group, a total of 6 % (6/100) patients reported an adverse reaction occurring at the site of a subcutaneous injection. No injection site reaction was reported as a serious adverse event or required treatment discontinuation.
Immunogenicity
In the tocilizumab subcutaneous weekly group, one patient (1.1 %, 1/95) developed positive neutralising anti-tocilizumab antibodies, though not of the IgE isotype. This patient did not develop a hypersensitivity reaction or injection site reaction.
Neutrophils
During routine laboratory monitoring in the tocilizumab 12 month controlled clinical trial, a decrease in neutrophil count below 1 × 109/L occurred in 4 % of patients in the tocilizumab subcutaneous weekly group. This was not observed in either of the placebo plus prednisone taper groups.
Platelets
During routine laboratory monitoring in the tocilizumab 12 month controlled clinical trial, one patient (1 %, 1/100) in the tocilizumab subcutaneous weekly group had a single transient occurence of

decrease in platelet count to < 100 × 103/µL without associated bleeding events. A decrease in platelet count below 100 × 103/µL was not observed in either of the placebo plus prednisone taper groups.
Hepatic transaminase elevations
During routine laboratory monitoring in the tocilizumab 12 month controlled clinical trial, elevation in ALT ≥ 3 × ULN occurred in 3 % of patients in the tocilizumab subcutaneous weekly group compared to 2 % in the placebo plus 52 week prednisone taper group and none in the placebo plus 26 week prednisone taper group. An elevation in AST > 3 ULN occurred in 1 % of patients in the tocilizumab subcutaneous weekly group, compared to no patients in either of the placebo plus prednisone taper groups.
Lipid parameters
During routine laboratory monitoring in the tocilizumab 12 month controlled clinical trial, 34 % of patients experienced sustained elevations in total cholesterol > 6.2 mmol/L (240 mg/dL), with 15 % experiencing a sustained increase in LDL to ≥ 4.1 mmol/L (160 mg/dL) in the tocilizumab subcutaneous weekly group.
Description of selected adverse reactions (intravenous use)
RA patients
The safety of tocilizumab has been studied in 5 Phase III, double-blind controlled trials and their extension periods (see section 5.1).
The all control population includes all patients from the double-blind phases of each core trial from randomisation until either the first change in the treatment regimen, or two years is reached. The control period in 4 of the trials was 6 months and in 1 trial was up to 2 years. In the double-blind controlled trials 774 patients received tocilizumab 4 mg/kg in combination with MTX, 1870 patients received tocilizumab 8 mg/kg in combination with MTX/other DMARDs and 288 patients received tocilizumab 8 mg/kg monotherapy.
The all exposure population includes all patients who received at least one dose of tocilizumab either in the double-blind control period or open label extension phase in the trials. Of the 4 009 patients in this population, 3 577 received treatment for at least 6 months, 3 296 for at least one year, 2 806 received treatment for at least 2 years and 1 222 for 3 years.
Infections
In the 6-month controlled trials the rate of all infections reported with tocilizumab 8 mg/kg plus DMARD treatment was 127 events per 100 patient years compared to 112 events per 100 patient years in the placebo plus DMARD group. In the long-term exposure population, the overall rate of infections with tocilizumab was 108 events per 100 patient years exposure.
In 6-month controlled clinical trials, the rate of serious infections with tocilizumab 8 mg/kg plus DMARDs was 5.3 events per 100 patient years exposure compared to 3.9 events per 100 patient years exposure in the placebo plus DMARD group. In the monotherapy trial 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 the long-term exposure population, the overall rate of serious infections (bacterial, viral and fungal) was 4.7 events per 100 patient years. Reported serious infections, some with fatal outcome, included active tuberculosis, which may present with intrapulmonary or extrapulmonary disease, invasive pulmonary infections, including candidiasis, aspergillosis, coccidioidomycosis and pneumocystis jirovecii, pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have also been reported.

Interstitial lung disease
Impaired lung function may increase the risk for developing infections. There have been post-marketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.
Gastrointestinal perforation
During the 6-month controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient years with tocilizumab therapy. In the long-term exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 patient years. Reports of gastrointestinal perforation on treatment were primarily reported as complications of diverticulitis including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess.
Infusion related reactions
In the 6-month controlled trials adverse events associated with infusion (selected events occurring during or within 24 hours of infusion) were reported by 6.9 % of patients in the tocilizumab 8 mg/kg plus DMARD group and 5.1 % of patients in the placebo plus DMARD group. Events reported during the infusion were primarily episodes of hypertension; events reported within 24 hours of finishing an infusion were headache and skin reactions (rash, urticaria). These events were not treatment limiting.
The rate of anaphylactic reactions (occurring in a total of 8/4 009 patients, 0.2 %) was several fold higher with the 4 mg/kg dose, compared to the 8 mg/kg dose. Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported in a total of 56 out of 4 009 patients (1.4 %) treated during the controlled and open label clinical trials. These reactions were generally observed during the second to fifth infusions of tocilizumab (see section 4.4).
Fatal anaphylaxis has been reported after marketing authorisation during treatment with intravenous tocilizumab (see section 4.4).
Immunogenicity
A total of 2876 patients have been tested for anti-tocilizumab antibodies in the 6-month controlled clinical trials. Of the 46 patients (1.6 %) who developed anti-tocilizumab antibodies, 6 had an associated medically significant hypersensitivity reaction, of which 5 led to permanent discontinuation of treatment. Thirty patients (1.1 %) developed neutralising antibodies.
Neutrophils
In the 6-month controlled trials decreases in neutrophil counts below 1 × 109/L occurred in 3.4 % of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 0.1 % of patients on placebo plus DMARDs. Approximately half of the patients who developed an ANC < 1 × 109/L did so within 8 weeks after starting therapy. Decreases below 0.5 × 109/L were reported in 0.3 % of patients receiving tocilizumab 8 mg/kg plus DMARDs. Infections with neutropenia have been reported.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 6-month controlled clinical trials.
Platelets
In the 6-month controlled trials decreases in platelet counts below 100 × 103/µL occurred in 1.7 % of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 1 % on placebo plus DMARDs. These decreases occurred without associated bleeding events.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 6-month controlled clinical trials.
Very rare reports of pancytopenia have occurred in the post-marketing setting.

Hepatic transaminase elevations
During the 6-month controlled trials transient elevations in ALT/AST > 3 × ULN were observed in 2.1 % of patients on tocilizumab 8 mg/kg compared to 4.9 % of patients on MTX and in 6.5 % of patients who received 8 mg/kg tocilizumab plus DMARDs compared to 1.5 % of patients on placebo plus DMARDs.
The addition of potentially hepatotoxic medicinal products (e.g. MTX) to tocilizumab monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST > 5 × ULN were observed in 0.7 % of tocilizumab monotherapy patients and 1.4 % of tocilizumab plus DMARD patients, the majority of whom were discontinued permanently from tocilizumab treatment. During the double-blind controlled period, the incidence of indirect bilirubin greater than the upper limit of normal, collected as a routine laboratory parameter, is 6.2 % in patients treated with 8 mg/kg tocilizumab + DMARD. A total of 5.8 % of patients experienced an elevation of indirect bilirubin of > 1 to 2 × ULN and 0.4 % had an elevation of > 2 × ULN.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevation in ALT/AST remained consistent with what was seen in the 6-month controlled clinical trials.
Lipid parameters
During the 6-month controlled trials, increases of lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol have been reported commonly. With routine laboratory monitoring it was seen that approximately 24 % of patients receiving tocilizumab in clinical trials experienced sustained elevations in total cholesterol ≥ 6.2 mmol/L, with 15 % experiencing a sustained increase in LDL to ≥ 4.1 mmol/L. Elevations in lipid parameters responded to treatment with lipid-lowering agents.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevations in lipid parameters remained consistent with what was seen in the 6-month controlled trials.
Skin reactions
Rare reports of Stevens-Johnson Syndrome have occurred in the post-marketing setting.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Summary of the safety profile
The safety profile comes from 4 510 patients exposed to tocilizumab in clinical trials; the majority of these patients were participating in adult RA trials (n = 4 009), while the remaining experience comes from GCA (n = 149), pJIA (n = 240) and sJIA (n = 112) trials. The safety profile of tocilizumab across these indications remains similar and undifferentiated.
The most commonly reported adverse reactions were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.
The most serious adverse reactions were serious infections, complications of diverticulitis, and hypersensitivity reactions.
Tabulated list of adverse reactions
Adverse reactions from clinical trials and/or post-marketing experience with tocilizumab based on spontaneous case reports, literature cases and cases from non-interventional trial programs are listed in Table 1 and are presented by MedDRA system organ class. The corresponding frequency category is based on the following convention: very common ( ≥ 1/10); common ( ≥ 1/100 to < 1/10), uncommon ( ≥ 1/1 000 to < 1/100) rare ( ≥ 1/10 000 to < 1/1 000), very rare ( < 1/10 000), and frequency not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. List of adverse reactions occurring in patients treated with tocilizumab MedDRA SOC Frequency category with preferred term Very common Common Uncommon Rare Very rare Infections and infestations Upper respiratory tract infections Cellulitis, Pneumonia, Oral herpes simplex, Herpes zoster Diverticulitis Blood and lymphatic system disorders Leukopenia, Neutropenia, Hypofibrinogenae mia Immune system disorders Anaphylaxis (fatal)1, 2 ,3 Endocrine disorders Hypothyroidism Metabolism and nutrition disorders Hypercholester olaemia* Hypertriglycerida emia Nervous system disorders Headache, Dizziness Eye disorders Conjunctivitis Vascular disorders Hypertension Respiratory, thoracic and mediastinal disorders Cough, Dyspnoea Gastrointestin al disorders Abdominal pain, Mouth ulceration, Gastritis Stomatitis, Gastric ulcer

MedDRA
SOC
Frequency category with preferred term
Very common
Common
Uncommon
Rare
Very rare
Hepatobiliary disorders
Drug-induced liver injury,
Hepatitis,
Jaundice
Hepatic failure
Skin and subcutaneous tissue disorders
Rash, Pruritus,
Urticaria
Stevens-
Johnson-
Syndrome3
Renal and urinary disorders
Nephrolithiasis
General disorders and administration site conditions
Injection site reaction
Peripheral oedema
Hypersensitivity reaction,
Investigations
Hepatic transaminases increased, Weight increased, Total bilirubin increased*
* Includes elevations collected as part of routine laboratory monitoring (see text below) 1 See section 4.3 2 See section 4.4 3 This adverse reaction was identified through post-marketing surveillance but not observed in controlled clinical trials. The frequency category was estimated as the upper limit of the 95 % confidence interval calculated on the basis of the total number of patients exposed to tocilizumab in clinical trials.
Description of selected adverse reactions (subcutaneous use)
RA patients
The safety of subcutaneous tocilizumab in RA includes a double-blind, controlled, multi-centre trial, SC-I. SC-I was a non-inferiority trial that compared the efficacy and safety of 162 mg administered every week versus 8 mg/kg intravenous in 1 262 patients with RA. All patients received background non-biologic DMARD(s). 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 reactions were observed (see Table 1). A higher frequency of injection site reactions was observed in the subcutaneous arms compared with placebo subcutaneous injections in the intravenous arms.
Injection site reactions
During the 6-month controlled period, in SC-I, the frequency of injection site reactions was 10.1 % (64/631) and 2.4 % (15/631) for the subcutaneous tocilizumab and the subcutaneous placebo (intravenous group) weekly injections, 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 treatment discontinuation.
Immunogenicity
In SC-I, 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 neutralising anti-tocilizumab antibodies. One patient was tested positive for IgE isotype (0.2 %).
In SC-II, a total of 434 patients treated with tocilizumab 162 mg every other week were tested for anti- tocilizumab antibodies in the 6 month controlled period. Seven patients (1.6 %) developed positive

anti-tocilizumab antibodies; of these, six (1.4 %) developed neutralising anti-tocilizumab antibodies.
Four patients were tested positive for IgE isotype (0.9 %).
No correlation of antibody development to clinical response or adverse events was observed.
Neutrophils
During routine laboratory monitoring in the tocilizumab 6-month controlled clinical Trial SC-I, a decrease in neutrophil count below 1 × 109/L occurred in 2.9 % of patients on the subcutaneous weekly dose.
There was no clear relationship between decreases in neutrophils below 1 × 109/L and the occurrence of serious infections.
Platelets
During routine laboratory monitoring in the tocilizumab 6-month clinical Trial SC-I, none of the patients on the subcutaneous weekly dose had a decrease in platelet count to ≤ 50 × 103/µL.
Hepatic transaminase elevations
During routine laboratory monitoring in the tocilizumab 6-month controlled clinical Trial SC-I, elevation in ALT or AST ≥ 3 × ULN occurred in 6.5 % and 1.4 % of patients, respectively on the subcutaneous weekly dose.
Lipid parameters
During routine laboratory monitoring in the tocilizumab 6-month controlled clinical Trial SC-I, 19 % of patients experienced sustained elevations in total cholesterol > 6.2 mmol/L (240 mg/dL), with 9 % experiencing a sustained increase in LDL to ≥ 4.1 mmol/L (160 mg/dL) on the subcutaneous weekly dose.
sJIA patients
The safety profile of subcutaneous tocilizumab was evaluated in 51 paediatric patients (1 to 17 years of age) with sJIA. In general, the adverse reactions in patients with sJIA were similar in type to those seen in RA patients (see section 4.8).
Infections
The rate of infection in sJIA patients treated with subcutaneous tocilizumab was comparable to sJIA patients treated with intravenous tocilizumab.
Injection Site Reactions (ISRs)
In the subcutaneous trial (WA28118), a total of 41.2 % (21/51) sJIA patients experienced ISRs to tocilizumab subcutaneous. The most common ISRs were erythema, pruritus, pain, and swelling at the injection site. The majority of ISRs reported were Grade 1 events and all ISRs reported were non- serious and none required patient withdrawal from treatment or dose interruption.
Immunogenicity
In the subcutaneous trial (WA28118), 46 of the 51 (90.2 %) patients tested for anti-tocilizumab antibodies at baseline had at least one post-baseline screening assay result. No patient developed positive anti-tocilizumab antibodies post baseline.
Laboratory Abnormalities
In the 52-week open-label subcutaneous trial (WA28118), neutrophil count decrease to below 1 × 109/L occurred in 23.5 % of patients treated with tocilizumab subcutaneous. Decreases in platelet counts to below 100 × 103/μL occurred in 2 % of the patients treated with tocilizumab subcutaneous.
An elevation in ALT or AST to ≥ 3 × ULN occurred in 9.8 % and 4.0 % patients treated with tocilizumab subcutaneous, respectively.

Lipid parameters
In the 52-week open-label subcutaneous trial (WA28118), 23.4 % and 35.4 % of patients experienced a post-baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time during trial treatment, respectively.
pJIA patients
The safety profile of subcutaneous tocilizumab was also evaluated in 52 paediatric patients with pJIA.
The total patient exposure to tocilizumab in the pJIA all exposure population was 184.4 patient years for intravenous and 50.4 patient years for subcutaneous tocilizumab. In general, the safety profile observed in patients with pJIA was consistent with the known safety profile of tocilizumab with the exception of ISRs (see Table 1). A higher frequency of pJIA patients experienced ISRs following subcutaneous injections compared to adult RA.
Infections
In the subcutaneous tocilizumab trial, the rate of infection in pJIA patients treated with subcutaneous tocilizumab was comparable with pJIA patients treated with intravenous tocilizumab.
Injection site reactions
A total of 28.8 % (15/52) pJIA patients experienced ISRs to tocilizumab subcutaneous. These ISRs occurred in a 44 % of patients ≥ 30 kg compared to 14.8 % of patients below 30 kg. The most common ISRs were injection site erythema, swelling, haematoma, pain and pruritis. All ISRs reported were non-serious Grade 1 events, and none of the ISRs required patient withdrawal from treatment or dose interruption.
Immunogenicity
In the subcutaneous trial 5.8 % [3/52] developed positive neutralising anti-tocilizumab antibodies without developing a serious or clinically significant hypersensitivity reaction. Of these 3 patients, 1 subsequently withdrew from the trial. No correlation between antibody development and clinical response or adverse events was observed Laboratory abnormalities During routine laboratory monitoring in the tocilizumab all exposure population, a decrease in neutrophil count below 1 × 109/L occurred in 15.4 % of patients treated with subcutaneous tocilizumab. An elevation in ALT or AST ≥ 3 × ULN occurred in 9.6 % and 3.8 % patients treated with tocilizumab subcutaneous, respectively. No patients treated with subcutaneous tocilizumab experienced a decrease in platelet count to ≤ 50 × 103/µL.
Lipid parameters
In the subcutaneous trial, 14.3 % and 12.8 % of patients experienced a post-baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time during trial treatment, respectively.
GCA patients
The safety of subcutaneous tocilizumab has been studied in one Phase III trial (WA28119) with 251 GCA patients. The total patient years duration in the tocilizumab all exposure population was 138.5 patient years during the 12 month double-blind, placebo-controlled phase of the trial. The overall safety profile observed in the treatment groups was consistent with the known safety profile of tocilizumab (see Table 1).
Infections
The rate of infection/serious infection events was balanced between the tocilizumab weekly group (200.2/9.7 events per 100 patient years) vs. placebo plus 26 weeks prednisone taper (156.0/4.2 events per 100 patient years) and placebo plus 52 weeks taper (210.2/12.5 events per 100 patient years) groups.

Injection site reactions
In the tocilizumab subcutaneous weekly group, a total of 6 % (6/100) patients reported an adverse reaction occurring at the site of a subcutaneous injection. No injection site reaction was reported as a serious adverse event or required treatment discontinuation.
Immunogenicity
In the tocilizumab subcutaneous weekly group, one patient (1.1 %, 1/95) developed positive neutralising anti-tocilizumab antibodies, though not of the IgE isotype. This patient did not develop a hypersensitivity reaction or injection site reaction.
Neutrophils
During routine laboratory monitoring in the tocilizumab 12 month controlled clinical trial, a decrease in neutrophil count below 1 × 109/L occurred in 4 % of patients in the tocilizumab subcutaneous weekly group. This was not observed in either of the placebo plus prednisone taper groups.
Platelets
During routine laboratory monitoring in the tocilizumab 12 month controlled clinical trial, one patient (1 %, 1/100) in the tocilizumab subcutaneous weekly group had a single transient occurence of decrease in platelet count to < 100 × 103/µL without associated bleeding events. A decrease in platelet count below 100 × 103/µL was not observed in either of the placebo plus prednisone taper groups.
Hepatic transaminase elevations
During routine laboratory monitoring in the tocilizumab 12 month controlled clinical trial, elevation in ALT ≥ 3 × ULN occurred in 3 % of patients in the tocilizumab subcutaneous weekly group compared to 2 % in the placebo plus 52 week prednisone taper group and none in the placebo plus 26 week prednisone taper group. An elevation in AST > 3 ULN occurred in 1 % of patients in the tocilizumab subcutaneous weekly group, compared to no patients in either of the placebo plus prednisone taper groups.
Lipid parameters
During routine laboratory monitoring in the tocilizumab 12 month controlled clinical trial, 34 % of patients experienced sustained elevations in total cholesterol > 6.2 mmol/L (240 mg/dL), with 15 % experiencing a sustained increase in LDL to ≥ 4.1 mmol/L (160 mg/dL) in the tocilizumab subcutaneous weekly group.
Description of selected adverse reactions (intravenous use)
RA patients
The safety of tocilizumab has been studied in 5 Phase III, double-blind controlled trials and their extension periods (see section 5.1).
The all control population includes all patients from the double-blind phases of each core trial from randomisation until either the first change in the treatment regimen, or two years is reached. The control period in 4 of the trials was 6 months and in 1 trial was up to 2 years. In the double-blind controlled trials, 774 patients received tocilizumab 4 mg/kg in combination with MTX, 1 870 patients received tocilizumab 8 mg/kg in combination with MTX / other DMARDs and 288 patients received tocilizumab 8 mg/kg monotherapy.
The all exposure population includes all patients who received at least one dose of tocilizumab either in the double-blind control period or open label extension phase in the trials. Of the 4 009 patients in this population, 3 577 received treatment for at least 6 months, 3296 for at least one year, 2 806 received treatment for at least 2 years and 1 222 for 3 years.
Infections
In the 6-month controlled trials the rate of all infections reported with tocilizumab 8 mg/kg plus DMARD treatment was 127 events per 100 patient years compared to 112 events per 100 patient years in the placebo plus DMARD group. In the long-term exposure population, the overall rate of infections with tocilizumab was 108 events per 100 patient years exposure.

In 6-month controlled clinical trials, the rate of serious infections with tocilizumab 8 mg/kg plus DMARDs was 5.3 events per 100 patient years exposure compared to 3.9 events per 100 patient years exposure in the placebo plus DMARD group. In the monotherapy trial 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 the long-term exposure population, the overall rate of serious infections (bacterial, viral and fungal) was 4.7 events per 100 patient years. Reported serious infections, some with fatal outcome, included active tuberculosis, which may present with intrapulmonary or extrapulmonary disease, invasive pulmonary infections, including candidiasis, aspergillosis, coccidioidomycosis and pneumocystis jirovecii, pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have also been reported.
Interstitial lung disease
Impaired lung function may increase the risk for developing infections. There have been post-marketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.
Gastrointestinal perforation
During the 6-month controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient years with tocilizumab therapy. In the long-term exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 patient years. Reports of gastrointestinal perforation on treatment were primarily reported as complications of diverticulitis including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess.
Infusion related reactions
In the 6-month controlled trials adverse events associated with infusion (selected events occurring during or within 24 hours of infusion) were reported by 6.9 % of patients in the tocilizumab 8 mg/kg plus DMARD group and 5.1 % of patients in the placebo plus DMARD group. Events reported during the infusion were primarily episodes of hypertension; events reported within 24 hours of finishing an infusion were headache and skin reactions (rash, urticaria). These events were not treatment limiting.
The rate of anaphylactic reactions (occurring in a total of 8/4 009 patients, 0.2 %) was several fold higher with the 4 mg/kg dose, compared to the 8 mg/kg dose. Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported in a total of 56 out of 4 009 patients (1.4 %) treated during the controlled and open label clinical trials. These reactions were generally observed during the second to fifth infusions of tocilizumab (see section 4.4).
Fatal anaphylaxis has been reported after marketing authorisation during treatment with intravenous tocilizumab (see section 4.4).
Immunogenicity
A total of 2 876 patients have been tested for anti-tocilizumab antibodies in the 6-month controlled clinical trials. Of the 46 patients (1.6 %) who developed anti-tocilizumab antibodies, 6 had an associated medically significant hypersensitivity reaction, of which 5 led to permanent discontinuation of treatment. Thirty patients (1.1 %) developed neutralising antibodies.
Neutrophils
In the 6-month controlled trials decreases in neutrophil counts below 1 × 109/L occurred in 3.4 % of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 0.1 % of patients on placebo plus DMARDs. Approximately half of the patients who developed an ANC < 1 × 109/L did so within 8 weeks after starting therapy. Decreases below 0.5 × 109/L were reported in 0.3 % of patients receiving tocilizumab 8 mg/kg plus DMARDs. Infections with neutropenia have been reported.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 6-month controlled clinical trials.

Platelets
In the 6-month controlled trials decreases in platelet counts below 100 × 103/µL occurred in 1.7 % of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 1 % on placebo plus DMARDs. These decreases occurred without associated bleeding events.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 6-month controlled clinical trials.
Very rare reports of pancytopenia have occurred in the post-marketing setting.
Hepatic transaminase elevations
During the 6-month controlled trials transient elevations in ALT/AST > 3 × ULN were observed in 2.1 % of patients on tocilizumab 8 mg/kg compared to 4.9 % of patients on MTX and in 6.5 % of patients who received 8 mg/kg tocilizumab plus DMARDs compared to 1.5 % of patients on placebo plus DMARDs.
The addition of potentially hepatotoxic medicinal products (e.g. MTX) to tocilizumab monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST > 5 × ULN were observed in 0.7 % of tocilizumab monotherapy patients and 1.4 % of tocilizumab plus DMARD patients, the majority of whom were discontinued permanently from tocilizumab treatment. During the double-blind controlled period, the incidence of indirect bilirubin greater than the upper limit of normal, collected as a routine laboratory parameter, is 6.2 % in patients treated with 8 mg/kg tocilizumab + DMARD. A total of 5.8 % of patients experienced an elevation of indirect bilirubin of > 1 to 2 × ULN and 0.4 % had an elevation of > 2 × ULN.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevation in ALT/AST remained consistent with what was seen in the 6-month controlled clinical trials.
Lipid parameters
During the 6-month controlled trials, increases of lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol have been reported commonly. With routine laboratory monitoring it was seen that approximately 24 % of patients receiving tocilizumab in clinical trials experienced sustained elevations in total cholesterol ≥ 6.2 mmol/L, with 15 % experiencing a sustained increase in LDL to ≥ 4.1 mmol/L. Elevations in lipid parameters responded to treatment with lipid-lowering agents.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevations in lipid parameters remained consistent with what was seen in the 6-month controlled trials.
Skin reactions
Rare reports of Stevens-Johnson Syndrome have occurred in the post-marketing setting.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
RA, pJIA and sJIA patients
Infections
Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including tocilizumab (see section 4.8). Treatment must not be initiated in patients with active infections (see section 4.3). Administration of tocilizumab must be interrupted if a patient develops a serious infection until the infection is controlled (see section 4.8). Healthcare professionals should exercise caution when considering the use of this medicinal product in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes and interstitial lung disease) which may predispose patients to infections.
Vigilance for the timely detection of serious infection is recommended for patients receiving biological treatments as signs and symptoms of acute inflammation may be lessened, associated with suppression of the acute phase reaction. The effects of tocilizumab on C-reactive protein (CRP), neutrophils and signs and symptoms of infection must be considered when evaluating a patient for a potential infection. Patients (which includes younger children with sJIA or pJIA who may be less able to communicate their symptoms) and parents/guardians of sJIA or pJIA patients should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.

Tuberculosis (TB)
As recommended for other biological treatments, RA, pJIA and sJIA patients should be screened for latent TB infection prior to starting tocilizumab therapy. Patients with latent TB must be treated with standard anti-mycobacterial therapy before initiating treatment. Prescribers are reminded of the risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in patients who are severely ill or immunocompromised.
Patients should be instructed to seek medical advice if signs/symptoms (e.g., persistent cough, wasting/weight loss, low grade fever) suggestive of a tuberculosis infection occur during or after therapy with this medicinal product.
Viral reactivation
Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinical trials with tocilizumab, patients who screened positive for hepatitis were excluded.
Complications of diverticulitis
Events of diverticular perforations as complications of diverticulitis have been reported uncommonly with tocilizumab in RA patients (see section 4.8). This medicinal product should be used with caution in patients with previous history of intestinal ulceration or diverticulitis. Patients presenting with symptoms potentially indicative of complicated diverticulitis, such as abdominal pain, haemorrhage and/or unexplained change in bowel habits with fever must be evaluated promptly for early identification of diverticulitis, which can be associated with gastrointestinal perforation.
Hypersensitivity reactions
Serious hypersensitivity reactions have been reported in association with infusion of tocilizumab (see section 4.8). Such reactions may be more severe, and potentially fatal in patients who have experienced hypersensitivity reactions during previous infusions even if they have received premedication with steroids and antihistamines. Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during treatment. If an anaphylactic reaction or other serious hypersensitivity / serious infusion-related reaction occurs, administration of tocilizumab must be stopped immediately and treatment should be permanently discontinued.
Active hepatic disease and hepatic impairment
Treatment with tocilizumab, particularly when administered concomitantly with MTX, may be associated with elevations in hepatic transaminases, therefore, caution should be exercised when considering treatment of patients with active hepatic disease or hepatic impairment (see sections 4.2 and 4.8).
Hepatotoxicity
Transient or intermittent mild and moderate elevations of hepatic transaminases have been reported commonly with tocilizumab treatment (see section 4.8). An increased frequency of these elevations was observed when potentially hepatotoxic medicinal products (e.g. MTX) were used in combination with tocilizumab. When clinically indicated, other liver function tests including bilirubin should be considered.
Serious drug-induced liver injury, including acute liver failure, hepatitis and jaundice, have been observed with tocilizumab (see section 4.8). Serious hepatic injury occurred between 2 weeks to more than 5 years after initiation of treatment. Cases of liver failure resulting in liver transplantation have been reported. Patients must be advised to immediately seek medical help if they experience signs and symptoms of hepatic injury.
Caution should be exercised when considering initiation of treatment in patients with elevated ALT or AST > 1.5 × ULN. In RA, pJIA and sJIA patients with baseline ALT or AST > 5 × ULN, treatment is not recommended.
In RA, pJIA and sJIA patients, ALT/AST should be monitored every 4 to 8 weeks for the first 6 months of treatment followed by every 12 weeks thereafter. For recommended modifications,

including tocilizumab discontinuation, based on transaminases levels see section 4.2. For ALT or AST elevations > 3-5 × ULN, confirmed by repeat testing, treatment must be interrupted.
Haematological abnormalities
Decreases in neutrophil and platelet counts have occurred following treatment with tocilizumab 8 mg/kg in combination with MTX (see section 4.8). There may be an increased risk of neutropenia in patients who have previously been treated with a TNF antagonist.
In patients not previously treated with tocilizumab, initiation is not recommended in patients with an (ANC) below 2 × 109/L. Caution should be exercised when considering initiation of treatment in patients with a low platelet count (i.e. platelet count below 100 × 103/µL). In RA, pJIA and sJIA patients who develop an ANC < 0.5 × 109/L or a platelet count < 50 × 103/µL, continued treatment is not recommended.
Severe neutropenia may be associated with an increased risk of serious infections, although there has been no clear association between decreases in neutrophils and the occurrence of serious infections in clinical trials with tocilizumab to date.
In RA patients, neutrophils and platelets should be monitored 4 to 8 weeks after start of therapy and thereafter according to standard clinical practice. For recommended dose modifications based on ANC and platelet counts, see section 4.2.
In pJIA and sJIA patients, neutrophils and platelets should be monitored at the time of second infusion and thereafter according to good clinical practice, see section 4.2.
Lipid parameters
Elevations in lipid parameters including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides were observed in patients treated with tocilizumab (see section 4.8). In the majority of patients, there was no increase in atherogenic indices, and elevations in total cholesterol responded to treatment with lipid lowering agents.
In RA, pJIA andsJIA patients, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidaemia.
Neurological disorders
Physicians should be vigilant for symptoms potentially indicative of new-onset central demyelinating disorders. The potential for central demyelination with tocilizumab is currently unknown.
Malignancy
The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products may increase the risk of malignancy. The clinical data are insufficient to assess the potential incidence of malignancy following exposure to tocilizumab. Long-term safety evaluations are ongoing.
Vaccinations
Live and live attenuated vaccines should not be given concurrently with this medicinal product as clinical safety has not been established. In a randomised open-label trial, adult RA patients treated with tocilizumab and MTX were able to mount an effective response to both the 23-valent pneumococcal polysaccharide and tetanus toxoid vaccines which was comparable to the response seen in patients on MTX only. It is recommended that all patients, particularly pJIA and sJIA patients, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating therapy. The interval between live vaccinations and initiation of therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Cardiovascular risk
RA patients have an increased risk for cardiovascular disorders and must have risk factors (e.g. hypertension, hyperlipidaemia) managed as part of usual standard of care.

Combination with TNF antagonists
There is no experience with the use of tocilizumab with TNF antagonists or other biological treatments for RA, pJIA or sJIA patients. This medicinal product is not recommended for use with other biological agents.
COVID-19 patients

The efficacy of this medicinal product has not been established in the treatment of COVID-19 patients who do not have elevated CRP levels, see section 5.1.

This medicinal product must not be administered to COVID-19 patients who are not receiving systemic corticosteroids as an increase in mortality cannot be excluded in this subgroup, see section 5.1.
Infections
In COVID-19 patients, this medicinal product should not be administered if they have any other concurrent severe active infection. Healthcare professionals should exercise caution when considering the use of tocilizumab in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes, and interstitial lung disease) which may predispose patients to infections.
Hepatotoxicity
Patients hospitalised with COVID-19 may have elevated ALT or AST levels. Multi-organ failure with involvement of the liver is recognised as a complication of severe COVID-19. The decision to administer tocilizumab should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with tocilizumab. In COVID-19 patients with elevated ALT or AST above 10 × ULN, administration of tocilizumab treatment is not recommended. In COVID-19 patients, ALT /AST should be monitored according to current standard clinical practices.
Haematological abnormalities
In COVID-19 patients who develop an ANC < 1 × 109/L or a platelet count < 50 × 103/µL, administration of treatment is not recommended. Neutrophil and platelet counts should be monitored according to current standard clinical practices, see section 4.2.
Paediatric population sJIA Patients
Macrophage activation syndrome (MAS) is a serious life-threatening disorder that may develop in sJIA patients. In clinical trials, tocilizumab has not been studied in patients during an episode of active MAS.
Sodium
After dilution with 0.9 % sodium chloride solution, this medicinal product contains 230.6 mg sodium per maximum dose of 800 mg, equivalent to 11.5 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Polysorbate 80 (E 433)
This medicinal product contains 2 mg of polysorbate 80 in each 80 mg vial, 5 mg of polysorbate 80 in each 200 mg vial and 10 mg polysorbate 80 in each 400 mg vial, which is equivalent to 0.5 mg/mL.
Polysorbates may cause allergic reactions. Patients' known allergies shall be taken into consideration.

RoActemra subcutaneous formulation is not intended for intravenous administration.
RoActemra subcutaneous formulation is not intended to be given to children with sJIA weighing less than 10 kg.
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
All indications
Infections
Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including tocilizumab (see section 4.8). Treatment must not be initiated in patients with active infections (see section 4.3). Administration of tocilizumab must be interrupted if a patient develops a serious infection until the infection is controlled (see section 4.8). Healthcare professionals should exercise caution when considering the use of this medicinal product in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes and interstitial lung disease) which may predispose patients to infections.
Vigilance for the timely detection of serious infection is recommended for patients receiving immunosuppressive agents such as tocilizumab as signs and symptoms of acute inflammation may be

lessened, due to suppression of the acute phase reactants. The effects of tocilizumab on C-reactive protein (CRP), neutrophils and signs and symptoms of infection must be considered when evaluating a patient for a potential infection. Patients, (which includes younger children with sJIA or pJIA who may be less able to communicate their symptoms) and parents/guardians of sJIA or pJIA patients, should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.
Tuberculosis
As recommended for other biological treatments, all patients should be screened for latent tuberculosis (TB) infection prior to starting tocilizumab therapy. Patients with latent TB must be treated with standard anti-mycobacterial therapy before initiating treatment. Prescribers are reminded of the risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in patients who are severely ill or immunocompromised.
Patients, and parents/guardians of sJIA or pJIA patients should be advised to seek medical advice if signs/symptoms (e.g., persistent cough, wasting/weight loss, low grade fever) suggestive of a tuberculosis infection occur during or after therapy with this medicinal product.
Viral reactivation
Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinical trials with tocilizumab, patients who screened positive for hepatitis were excluded.
Complications of diverticulitis
Events of diverticular perforations as complications of diverticulitis have been reported uncommonly in patients treated with tocilizumab (see section 4.8). This medicinal product should be used with caution in patients with previous history of intestinal ulceration or diverticulitis. Patients presenting with symptoms potentially indicative of complicated diverticulitis, such as abdominal pain, haemorrhage and/or unexplained change in bowel habits with fever must be evaluated promptly for early identification of diverticulitis which can be associated with gastrointestinal perforation.
Hypersensitivity reactions
Serious hypersensitivity reactions, including anaphylaxis have been reported in association with tocilizumab (see section 4.8). Such reactions may be more severe, and potentially fatal in patients who have experienced hypersensitivity reactions during previous treatment with tocilizumab even if they have received premedication with steroids and antihistamines. If an anaphylactic reaction or other serious hypersensitivity reaction occurs, administration of tocilizumab must be stopped immediately, appropriate therapy initiated and treatment should be permanently discontinued.
Active hepatic disease and hepatic impairment
Treatment with tocilizumab, particularly when administered concomitantly with MTX, may be associated with elevations in hepatic transaminases, therefore, caution should be exercised when considering treatment of patients with active hepatic disease or hepatic impairment (see sections 4.2 and 4.8).
Hepatotoxicity
Transient or intermittent mild and moderate elevations of hepatic transaminases have been reported commonly with tocilizumab treatment (see section 4.8). An increased frequency of these elevations was observed when potentially hepatotoxic medicinal products (e.g. MTX) were used in combination with tocilizumab. When clinically indicated, other liver function tests including bilirubin should be considered.
Serious drug-induced liver injury, including acute liver failure, hepatitis and jaundice, have been observed with tocilizumab (see section 4.8). Serious hepatic injury occurred between 2 weeks to more than 5 years after initiation of treatment. Cases of liver failure resulting in liver transplantation have been reported. Patients must be advised to immediately seek medical help if they experience signs and symptoms of hepatic injury.

Caution should be exercised when considering initiation of treatment in patients with elevated ALT or AST > 1.5 × ULN. In patients with baseline ALT or AST > 5 × ULN, treatment is not recommended.
In RA, GCA, pJIA and sJIA patients, ALT/AST should be monitored every 4 to 8 weeks for the first 6 months of treatment followed by every 12 weeks thereafter. For recommended modifications, including tocilizumab discontinuation, based on transaminases levels see section 4.2. For ALT or AST elevations > 3–5 × ULN, treatment should be interrupted.
Haematological abnormalities
Decreases in neutrophil and platelet counts have occurred following treatment with tocilizumab 8 mg/kg in combination with MTX (see section 4.8). There may be an increased risk of neutropenia in patients who have previously been treated with a TNF antagonist.
In patients not previously treated with tocilizumab, initiation is not recommended in patients with an ANC below 2 × 109/L. Caution should be exercised when considering initiation of treatment in patients with a low platelet count (i.e. platelet count below 100 × 103/µL). In patients who develop an ANC < 0.5 × 109/L or a platelet count < 50 × 103/µL, continued treatment is not recommended.
Severe neutropenia may be associated with an increased risk of serious infections, although there has been no clear association between decreases in neutrophils and the occurrence of serious infections in clinical trials with tocilizumab to date.
In RA and GCA patients, neutrophils and platelets should be monitored 4 to 8 weeks after start of therapy and thereafter according to standard clinical practice. For recommended dose modifications based on ANC and platelet counts, see section 4.2.
In sJIA and pJIA patients, neutrophils and platelets should be monitored at the time of the second administration and thereafter according to good clinical practice (see section 4.2).
Lipid parameters
Elevations in lipid parameters including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides were observed in patients treated with tocilizumab (see section 4.8). In the majority of patients, there was no increase in atherogenic indices, and elevations in total cholesterol responded to treatment with lipid lowering agents.
In all patients, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidaemia.
Neurological disorders
Physicians should be vigilant for symptoms potentially indicative of new-onset central demyelinating disorders. The potential for central demyelination with tocilizumab is currently unknown.
Malignancy
The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products may increase the risk of malignancy. The clinical data are insufficient to assess the potential incidence of malignancy following exposure to tocilizumab. Long-term safety evaluations are ongoing.
Vaccinations
Live and live attenuated vaccines should not be given concurrently with this medicinal product as clinical safety has not been established. In a randomised open-label trial, adult RA patients treated with tocilizumab and MTX were able to mount an effective response to both the 23-valent pneumococcal polysaccharide and tetanus toxoid vaccines which was comparable to the response seen in patients on MTX only. It is recommended that all patients particularly paediatric or elderly patients, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating therapy. The interval between live vaccinations and initiation of therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Cardiovascular risk
RA patients have an increased risk for cardiovascular disorders and must have risk factors (e.g.
hypertension, hyperlipidaemia) managed as part of usual standard of care.
Combination with TNF antagonists
There is no experience with the use of tocilizumab with TNF antagonists or other biological treatments for RA patients. This medicinal product is not recommended for use with other biological agents.
GCA patients
Tocilizumab monotherapy should not be used for the treatment of acute relapses as efficacy in this setting has not been established. Glucocorticoids should be given according to medical judgement and practice guidelines.
sJIA patients
Macrophage activation syndrome (MAS) is a serious life-threatening disorder that may develop in sJIA patients. In clinical trials, tocilizumab has not been studied in patients during an episode of active MAS.
Polysorbate 80 (E 433)
This medicinal product contains 0.18 mg of polysorbate 80 in each 162 mg/0.9 mL syringe which is equivalent to 0.2 mg/mL. Polysorbates may cause allergic reactions. Patients' known allergies shall be taken into consideration.

RoActemra subcutaneous formulation is not intended for intravenous administration.
RoActemra subcutaneous formulation is not intended to be given to children with sJIA weighing less than 10 kg.
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
All indications
Infections
Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including tocilizumab (see section 4.8). Treatment must not be initiated in patients with active infections (see section 4.3). Administration of tocilizumab must be interrupted if a patient develops a serious infection until the infection is controlled (see section 4.8). Healthcare professionals should exercise caution when considering the use of this medicinal product in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes and interstitial lung disease) which may predispose patients to infections.
Vigilance for the timely detection of serious infection is recommended for patients receiving immunosuppressive agents such as tocilizumab as signs and symptoms of acute inflammation may be lessened, due to suppression of the acute phase reactants. The effects of tocilizumab on C-reactive protein (CRP), neutrophils and signs and symptoms of infection must be considered when evaluating a patient for a potential infection. Patients, (which includes younger children with sJIA or pJIA who may be less able to communicate their symptoms) and parents/guardians of sJIA or pJIA patients,

should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.
Tuberculosis
As recommended for other biological treatments, all patients should be screened for latent tuberculosis (TB) infection prior to starting tocilizumab therapy. Patients with latent TB must be treated with standard anti-mycobacterial therapy before initiating treatment. Prescribers are reminded of the risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in patients who are severely ill or immunocompromised.
Patients, and parents/guardians of sJIA or pJIA patients should be advised to seek medical advice if signs/symptoms (e.g., persistent cough, wasting/weight loss, low grade fever) suggestive of a tuberculosis infection occur during or after therapy with this medicinal product.
Viral reactivation
Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinical trials with tocilizumab, patients who screened positive for hepatitis were excluded.
Complications of diverticulitis
Events of diverticular perforations as complications of diverticulitis have been reported uncommonly in patients treated with tocilizumab (see section 4.8). This medicinal product should be used with caution in patients with previous history of intestinal ulceration or diverticulitis. Patients presenting with symptoms potentially indicative of complicated diverticulitis, such as abdominal pain, haemorrhage and/or unexplained change in bowel habits with fever must be evaluated promptly for early identification of diverticulitis which can be associated with gastrointestinal perforation.
Hypersensitivity reactions
Serious hypersensitivity reactions, including anaphylaxis have been reported in association with tocilizumab (see section 4.8). Such reactions may be more severe, and potentially fatal in patients who have experienced hypersensitivity reactions during previous treatment with tocilizumab even if they have received premedication with steroids and antihistamines. If an anaphylactic reaction or other serious hypersensitivity reaction occurs, administration of tocilizumab must be stopped immediately, appropriate therapy initiated and treatment should be permanently discontinued.
Active hepatic disease and hepatic impairment
Treatment with tocilizumab, particularly when administered concomitantly with MTX, may be associated with elevations in hepatic transaminases, therefore, caution should be exercised when considering treatment of patients with active hepatic disease or hepatic impairment (see sections 4.2 and 4.8).
Hepatotoxicity
Transient or intermittent mild and moderate elevations of hepatic transaminases have been reported commonly with tocilizumab treatment (see section 4.8). An increased frequency of these elevations was observed when potentially hepatotoxic medicinal products (e.g. MTX) were used in combination with tocilizumab. When clinically indicated, other liver function tests including bilirubin should be considered.
Serious drug-induced liver injury, including acute liver failure, hepatitis and jaundice, have been observed with tocilizumab (see section 4.8). Serious hepatic injury occurred between 2 weeks to more than 5 years after initiation of treatment. Cases of liver failure resulting in liver transplantation have been reported. Patients must be advised to immediately seek medical help if they experience signs and symptoms of hepatic injury.
Caution should be exercised when considering initiation of treatment in patients with elevated ALT or AST > 1.5 × ULN. In patients with baseline ALT or AST > 5 × ULN, treatment is not recommended.

In RA, GCA, pJIA and sJIA patients, ALT/AST should be monitored every 4 to 8 weeks for the first 6 months of treatment followed by every 12 weeks thereafter. For recommended modifications, including tocilizumab discontinuation, based on transaminases levels see section 4.2. For ALT or AST elevations > 3-5 × ULN, treatment should be interrupted.
Haematological abnormalities
Decreases in neutrophil and platelet counts have occurred following treatment with tocilizumab 8 mg/kg in combination with MTX (see section 4.8). There may be an increased risk of neutropenia in patients who have previously been treated with a TNF antagonist.
In patients not previously treated with tocilizumab, initiation is not recommended in patients with an ANC below 2 × 109/L. Caution should be exercised when considering initiation of treatment in patients with a low platelet count (i.e. platelet count below 100 × 103/µL). In patients who develop an ANC < 0.5 × 109/L or a platelet count < 50 × 103/µL, continued treatment is not recommended.
Severe neutropenia may be associated with an increased risk of serious infections, although there has been no clear association between decreases in neutrophils and the occurrence of serious infections in clinical trials with tocilizumab to date.
In RA and GCA patients, neutrophils and platelets should be monitored 4 to 8 weeks after start of therapy and thereafter according to standard clinical practice. For recommended dose modifications based on ANC and platelet counts, see section 4.2.
In sJIA and pJIA patients, neutrophils and platelets should be monitored at the time of the second administration and thereafter according to good clinical practice (see section 4.2).
Lipid parameters
Elevations in lipid parameters including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides were observed in patients treated with tocilizumab (see section 4.8). In the majority of patients, there was no increase in atherogenic indices, and elevations in total cholesterol responded to treatment with lipid lowering agents.
In all patients, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidaemia.
Neurological disorders
Physicians should be vigilant for symptoms potentially indicative of new-onset central demyelinating disorders. The potential for central demyelination with tocilizumab is currently unknown.
Malignancy
The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products may increase the risk of malignancy. The clinical data are insufficient to assess the potential incidence of malignancy following exposure to tocilizumab. Long-term safety evaluations are ongoing.
Vaccinations
Live and live attenuated vaccines should not be given concurrently with this medicinal product as clinical safety has not been established. In a randomised open-label trial, adult RA patients treated with tocilizumab and MTX were able to mount an effective response to both the 23-valent pneumococcal polysaccharide and tetanus toxoid vaccines which was comparable to the response seen in patients on MTX only. It is recommended that all patients particularly paediatric or elderly patients, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating therapy. The interval between live vaccinations and initiation of therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Cardiovascular risk
RA patients have an increased risk for cardiovascular disorders and must have risk factors (e.g.
hypertension, hyperlipidaemia) managed as part of usual standard of care.
Combination with TNF antagonists
There is no experience with the use of tocilizumab with TNF antagonists or other biological treatments for RA patients. This medicinal product is not recommended for use with other biological agents.
GCA patients
Tocilizumab monotherapy should not be used for the treatment of acute relapses as efficacy in this setting has not been established. Glucocorticoids should be given according to medical judgement and practice guidelines.
sJIA patients
Macrophage activation syndrome (MAS) is a serious life-threatening disorder that may develop in sJIA patients. In clinical trials, tocilizumab has not been studied in patients during an episode of active MAS.
Polysorbate 80(E 433)
This medicinal product contains 0.18 mg of polysorbate 80 in each 162 mg/0.9 mL PFP which is equivalent to 0.2 mg/mL. Polysorbates may cause allergic reactions. Patients' known allergies shall be taken into consideration.

Interaction trials have only been performed in adults.
Concomitant administration of a single dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure.

Population pharmacokinetic analyses did not detect any effect of MTX, NSAIDs or corticosteroids on tocilizumab clearance.
The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL-6, that stimulate chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as tocilizumab, is introduced.
In vitro trials with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19 and CYP3A4 enzyme expression. Tocilizumab normalises expression of these enzymes.
In a trial in RA patients, levels of simvastatin (CYP3A4) were decreased by 57 % one week following a single dose of tocilizumab, to the level similar to, or slightly higher than, those observed in healthy subjects.
When starting or stopping therapy with tocilizumab, patients taking medicinal products which are individually adjusted and are metabolised via CYP450 3A4, 1A2 or 2C9 (e.g. methylprednisolone, dexamethasone, (with the possibility for oral glucocorticoid withdrawal syndrome), atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, ciclosporin, or benzodiazepines) must be monitored as doses may need to be increased to maintain therapeutic effect.
Given its long elimination half-life (t1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.

Interaction trials have only been performed in adults.
Concomitant administration of a single dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure.
Population pharmacokinetic analyses did not detect any effect of MTX, NSAIDs or corticosteroids on tocilizumab clearance in RA patients. In GCA patients, no effect of cumulative corticosteroid dose on tocilizumab exposure was observed.
The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL-6, that stimulate chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as tocilizumab, is introduced.
In vitro trials with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. Tocilizumab normalises expression of these enzymes.
In a trial in RA patients, levels of simvastatin (CYP3A4) were decreased by 57 % one week following a single dose of tocilizumab, to the level similar to, or slightly higher than, those observed in healthy subjects.
When starting or stopping therapy with tocilizumab, patients taking medicinal products which are individually adjusted and are metabolised via CYP450 3A4, 1A2 or 2C9 (e.g. methylprednisolone, dexamethasone, (with the possibility for oral glucocorticoid withdrawal syndrome), atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, ciclosporin, or benzodiazepines) must be monitored as doses may need to be increased to maintain therapeutic effect.
Given its long elimination half-life (t1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.

Women of childbearing potential
Women of childbearing potential have to use effective contraception during and up to 3 months after treatment.
Pregnancy
There are no adequate data from the use of tocilizumab in pregnant women. A trial in animals has shown an increased risk of spontaneous abortion/embryo-foetal death at a high dose (see section 5.3).
The potential risk for humans is unknown.
RoActemra should not be used during pregnancy unless clearly necessary.
Breast-feeding
It is unknown whether tocilizumab is excreted in human milk. The excretion of tocilizumab in milk has not been studied in animals. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from RoActemra therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
Available non-clinical data do not suggest an effect on fertility under tocilizumab treatment.

RoActemra has minor influence on the ability to drive and use machines, e.g. dizziness (see section 4.8).

RoActemra has a minor influence on the ability to drive and use machines, e.g. dizziness (see section 4.8).

There are limited data available on overdose with tocilizumab. One case of accidental overdose was reported in which a patient with multiple myeloma received a single dose of 40 mg/kg. No adverse reactions were observed.
No serious adverse reactions were observed in healthy volunteers who received a single dose up to 28 mg/kg, although dose limiting neutropenia was observed.
5.
PHARMACOLOGICAL PROPERTIES

There are limited data available on overdose with tocilizumab. One case of accidental overdose was reported in which a patient with multiple myeloma received a single dose of 40 mg/kg administered intravenously. No adverse reactions were observed.
No serious adverse reactions were observed in healthy volunteers who received a single dose up to 28 mg/kg, although dose limiting neutropenia was observed.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Immunosuppressants, Interleukin inhibitors; ATC code: L04AC07.
Mechanism of action
Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R). Tocilizumab has been shown to inhibit sIL-6R and mIL-6R-mediated signalling. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, monocytes and fibroblasts. IL-6 is involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, induction of hepatic acute phase protein synthesis and stimulation of haemopoiesis. IL-6 has been implicated in the pathogenesis of diseases including inflammatory diseases, osteoporosis and neoplasia.
Pharmacodynamic effects
In clinical trials with RA patients treated with tocilizumab, rapid decreases in CRP, erythrocyte sedimentation rate (ESR), serum amyloid A (SAA) and fibrinogen were observed. Consistent with the effect on acute phase reactants, treatment with tocilizumab was associated with reduction in platelet count within the normal range. Increases in haemoglobin levels were observed, through tocilizumab decreasing the IL-6 driven effects on hepcidin production to increase iron availability. In treated patients, decreases in the levels of CRP to within normal ranges were seen as early as week 2, with decreases maintained while on treatment.
In healthy subjects administered tocilizumab in doses from 2 to 28 mg/kg, absolute neutrophil counts decreased to their lowest 3 to 5 days following administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis patients demonstrated a similar pattern of absolute neutrophil counts following tocilizumab administration (see section 4.8).
In COVID-19 patients with one dose of tocilizumab 8 mg/kg administered intravenously, decreases in the levels of CRP to within normal ranges were seen as early as day 7.
RA patients
Clinical efficacy and safety
The efficacy of tocilizumab in alleviating the signs and symptoms of RA was assessed in five randomised, double-blind, multi-centre trials. Trials I-V enrolled patients ≥ 18 years of age with active RA diagnosed according to the American College of Rheumatology (ACR) criteria and who had at least eight tender and six swollen joints at baseline.
In Trial I, tocilizumab was administered intravenously every four weeks as monotherapy. In Trials II, III and V, tocilizumab was administered intravenously every four weeks in combination with MTX vs.
placebo and MTX. In Trial IV, tocilizumab was administered intravenously every 4 weeks in combination with other DMARDs vs. placebo and other DMARDs. The primary endpoint for each of the five trials was the proportion of patients who achieved an ACR 20 response at week 24.

Pharmacotherapeutic group: Immunosuppressants, Interleukin inhibitors; ATC code: L04AC07.

Mechanism of action
Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R). Tocilizumab has been shown to inhibit sIL-6R and mIL-6R-mediated signalling. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, monocytes and fibroblasts. IL-6 is involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, induction of hepatic acute phase protein synthesis and stimulation of haemopoiesis. IL-6 has been implicated in the pathogenesis of diseases including inflammatory diseases, osteoporosis and neoplasia.
Pharmacodynamic effects
In RA clinical trials with tocilizumab, rapid decreases in CRP, erythrocyte sedimentation rate (ESR), serum amyloid A (SAA) and fibrinogen were observed. Consistent with the effect on acute phase reactants, treatment with tocilizumab was associated with reduction in platelet count within the normal range. Increases in haemoglobin levels were observed, through tocilizumab decreasing the IL-6 driven effects on hepcidin production to increase iron availability. In treated patients, decreases in the levels of CRP to within normal ranges were seen as early as week 2, with decreases maintained while on treatment.
In GCA clinical Trial WA28119, similar rapid decreases in CRP and ESR were observed along with slight increases in mean corpuscular haemoglobin concentration. In healthy subjects administered tocilizumab in doses from 2 to 28 mg/kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to their lowest 2 to 5 days following administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner.
RA and GCA patients demonstrate a comparable (to healthy subjects) decrease of absolute neutrophil counts following tocilizumab administration (see section 4.8).
Subcutaneous use
RA patients
Clinical efficacy
The efficacy of subcutaneous administered tocilizumab in alleviating the signs and symptoms of RA and radiographic response, was assessed in two randomised, double-blind, controlled, multi-centre trials. For Trial I (SC-I), patients were required to be > 18 years of age with moderate to severe active RA diagnosed according to ACR criteria who had at least 4 tender and 4 swollen joints at baseline. All patients received background non-biologic DMARD(s). For Trial II (SC-II), patients were required to be > 18 years of age with moderate to severe active RA diagnosed according to ACR criteria who had at least 8 tender and 6 swollen joints at baseline.

RA patients
The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 3 552 RA patients treated with a one-hour infusion of 4 or 8 mg/kg tocilizumab every 4 weeks for 24 weeks or with 162 mg tocilizumab given subcutaneously either once a week or every other week for 24 weeks.
The following parameters (predicted mean ± SD) were estimated for a dose of 8 mg/kg tocilizumab given every 4 weeks: steady-state area under curve (AUC) = 38 000 ± 13 000 h µg/mL, trough concentration (Cmin) = 15.9 ± 13.1 µg/mL and maximum concentration (Cmax) = 182 ± 50.4 µg/mL, and the accumulation ratios for AUC and Cmax were small, 1.32 and 1.09, respectively. The accumulation ratio was higher for Cmin (2.49), which was expected based on the non-linear clearance contribution at lower concentrations. Steady-state was reached following the first administration for Cmax and after 8 and 20 weeks for AUC and Cmin, respectively. Tocilizumab AUC, Cmin and Cmax increased with increase of body weight. At body weight ≥ 100 kg, the predicted mean (± SD)

steady-state AUC, Cmin and Cmax of tocilizumab were 50 000 ± 16 800 μg × h/mL, 24.4 ± 17.5 μg/mL, and 226 ± 50.3 μg/mL, respectively, which are higher than mean exposure values for the patient population (i.e. all body weights) reported above. The dose-response curve for tocilizumab flattens at higher exposure, resulting in smaller efficacy gains for each incremental increase in tocilizumab concentration such that clinically meaningful increases in efficacy were not demonstrated in patients treated with > 800 mg of tocilizumab. Therefore, tocilizumab doses exceeding 800 mg per infusion are not recommended (see section 4.2).
COVID-19 patients

The pharmacokinetics of tocilizumab is characterised by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination. The nonlinear part of elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time. Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.
Intravenous use
RA patients
The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 3 552 RA patients treated with a one-hour infusion of 4 or 8 mg/kg

tocilizumab every 4 weeks for 24 weeks or with 162 mg tocilizumab given subcutaneously either once a week or every other week for 24 weeks.