RoActemra

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ANNEX I 

 
SUMMARY OF PRODUCT CHARACTERISTICS 

 



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1. NAME OF THE MEDICINAL PRODUCT 
 
RoActemra 20 mg/mL concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL concentrate contains 20 mg tocilizumab*. 
 
Each vial contains 80 mg of tocilizumab* in 4 mL (20 mg/mL). 
Each vial contains 200 mg of tocilizumab* in 10 mL (20 mg/mL).  
Each vial contains 400 mg of tocilizumab* in 20 mL (20 mg/mL).  
 
*humanised IgG1 monoclonal antibody against the human interleukin-6 (IL-6) receptor produced in 
Chinese hamster ovary (CHO) cells by recombinant DNA technology. 
 
Excipients with known effects 
Each 80 mg vial contains 0.10 mmol (2.21 mg) sodium. 
Each 200 mg vial contains 0.20 mmol (4.43 mg) sodium.  
Each 400 mg vial contains 0.39 mmol (8.85 mg) sodium.  
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate). 
 
Clear to opalescent, colourless to pale yellow solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
RoActemra, in combination with methotrexate (MTX), is indicated for: 
 

• the treatment of severe, active and progressive rheumatoid arthritis (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. 
 
RoActemra is indicated for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in 
patients 2 years of age and older, who have responded inadequately to previous therapy with 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. 
 
RoActemra in combination with methotrexate (MTX) is indicated for the treatment of juvenile 
idiopathic polyarthritis (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. 



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RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment 
with MTX is inappropriate. 
 
RoActemra is indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or 
life-threatening cytokine release syndrome (CRS) in adults and paediatric patients 2 years of age and 
older.  
 
4.2 Posology and method of administration 
 
Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment 
of RA, sJIA, pJIA or CRS.  
All patients treated with RoActemra should be given the Patient Alert 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 studies (see section 5.1). 
 
Dose adjustments due to laboratory abnormalities (see section 4.4). 
 
• Liver enzyme abnormalities 
 
Laboratory Value Action 

> 1 to 3 x Upper 
Limit of Normal 
(ULN) 

Modify the dose of the concomitant MTX if appropriate 

For persistent increases in this range, reduce RoActemra dose to 4 mg/kg or 
interrupt RoActemra 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 x ULN 

(confirmed by 
repeat testing, see 
section 4.4). 

Interrupt RoActemra dosing until < 3 x ULN and follow recommendations 
above for > 1 to 3 x ULN 

For persistent increases > 3 x ULN, discontinue RoActemra 

> 5 x ULN Discontinue RoActemra 

 
• Low absolute neutrophil count (ANC) 
 
In patients not previously treated with RoActemra, initiation is not recommended in patients with an 
absolute neutrophil count (ANC) below 2 x 109/l. 
 



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Laboratory Value 
(cells x 109/ l ) 

Action 

ANC > 1  Maintain dose 

ANC 0.5 to 1 Interrupt RoActemra dosing 

When ANC increases > 1 x 109/ l resume RoActemra at 4 mg/kg and increase to 
8 mg/kg as clinically appropriate 

ANC < 0.5 Discontinue RoActemra 

 
• Low platelet count 
 
Laboratory Value 
(cells x 103/ μL) 

Action 

50 to 100 Interrupt RoActemra dosing 

When platelet count > 100 x 103/ μ resume RoActemra at 4 mg/kg and increase 
to 8 mg/kg as clinically appropriate 

< 50 Discontinue RoActemra 

 
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. RoActemra 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 RoActemra may be administered. The interval between consecutive doses should 
be at least 8 hours. Doses exceeding 800 mg per infusion are not recommended in CRS patients.  
 
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 
 
Paediatric patients   
 
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 should 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 RoActemra in children below 2 years of age has not been 
established.  
 
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 medications 
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, 



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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 x ULN Modify the dose of the concomitant MTX if appropriate 

For persistent increases in this range, interrupt RoActemra until 
ALT/AST have normalized.  

> 3 x ULN to 5x 
ULN 

 

Modify the dose of the concomitant MTX if appropriate 

Interrupt RoActemra dosing until < 3x ULN and follow 
recommendations above for >1 to 3x ULN 

 

> 5x ULN Discontinue RoActemra.  

The decision to discontinue RoActemra in sJIA for a laboratory 
abnormality should be based on the medical assessment of the 
individual patient. 

 
• Low absolute neutrophil count (ANC) 
 

Laboratory 
Value 
(cells x 
109/ l ) 

Action 

ANC > 1  Maintain dose 

ANC 0.5 to 
1 

Interrupt RoActemra dosing 

When ANC increases to > 1 x 109/ l resume RoActemra  

ANC < 0.5 Discontinue RoActemra 

The decision to discontinue RoActemra in sJIA for a laboratory 
abnormality should be based on the medical assessment of the individual 
patient. 

 



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• Low platelet count  
 

Laboratory 
Value 

(cells x 103/µl) 

Action 

50 to 100 Modify the dose of the concomitant MTX if appropriate 

Interrupt RoActemra dosing 

When platelet count is > 100 x 103/µl resume RoActemra  

 

< 50  Discontinue RoActemra.  

The decision to discontinue RoActemra in sJIA for a laboratory 
abnormality should be based on the medical assessment of the 
individual patient. 

 
Reduction of tocilizumab dose due to laboratory abnormalities has not been studied in sJIA patients. 
 
Available data suggest that clinical improvement is observed within 6 weeks of initiation of treatment 
with RoActemra. Continued therapy should be carefully reconsidered in a patient exhibiting no 
improvement within this timeframe. 
 
pJIA Patients 
 
The recommended posology in patients above 2 years of age is 8 mg/kg once every 4 weeks in 
patients weighing greater than or equal to 30 kg or 10 mg/kg once every 4 weeks in patients weighing 
less than 30 kg. The dose should 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 RoActemra in children below 2 years of age has not been 
established.  
 
Dose interruptions of tocilizumab for the following laboratory abnormalities are recommended in pJIA 
patients in the tables below. If appropriate, the dose of concomitant MTX and/or other medications 
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 pJIA, 
the decision to discontinue tocilizumab for a laboratory abnormality should be based upon the medical 
assessment of the individual patient. 
 



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• Liver enzyme abnormalities 
 

Laboratory 
Value 

Action 

> 1 to 3 x ULN Modify the dose of the concomitant MTX if appropriate 

For persistent increases in this range, interrupt RoActemra until 
ALT/AST have normalized.  

> 3 x ULN to 5x 
ULN 

 

Modify the dose of the concomitant MTX if appropriate 

Interrupt RoActemra dosing until < 3x ULN and follow 
recommendations above for >1 to 3x ULN 

 

> 5x ULN Discontinue RoActemra.  

The decision to discontinue RoActemra in pJIA for a laboratory 
abnormality should be based on the medical assessment of the 
individual patient. 

 
• Low absolute neutrophil count (ANC) 
 

Laboratory 
Value 
(cells x 
109/ l ) 

Action 

ANC > 1  Maintain dose 

ANC 0.5 to 
1 

Interrupt RoActemra dosing 

When ANC increases to > 1 x 109/ l resume RoActemra  

ANC < 0.5 Discontinue RoActemra 

The decision to discontinue RoActemra in pJIA for a laboratory 
abnormality should be based on the medical assessment of the individual 
patient. 

 



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• Low platelet count  
 

Laboratory 
Value 

(cells x 103/µl) 

Action 

50 to 100 Modify the dose of the concomitant MTX if appropriate 

Interrupt RoActemra dosing 

When platelet count is > 100 x 103/µl resume RoActemra  

 

< 50  Discontinue RoActemra.  

The decision to discontinue RoActemra in pJIA for a laboratory 
abnormality should be based on the medical assessment of the 
individual patient. 

 
Reduction of tocilizumab dose due to laboratory abnormalities has not been studied in pJIA patients. 
 
Available data suggest that clinical improvement is observed within 12 weeks of initiation of treatment 
with RoActemra. Continued therapy should be carefully reconsidered in a patient exhibiting no 
improvement within this timeframe. 
 
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. RoActemra has not been 
studied in patients with moderate to severe renal impairment (see section 5.2). Renal function should 
be monitored closely in these patients. 
 
Hepatic impairment 
RoActemra has not been studied in patients with hepatic impairment. Therefore, no dose 
recommendations can be made. 
 
Method of administration 
 
After dilution, RoActemra for RA, sJIA, pJIA, and CRS patients should be administered as an 
intravenous infusion over 1 hour. 
 
RA, sJIA, pJIA and CRS Patients ≥ 30 kg 
RoActemra should be diluted to a final volume of 100 mL with sterile, non-pyrogenic sodium chloride 
9 mg/mL (0.9%) solution for injection using aseptic technique.  
 
For instructions on dilution of the medicinal product before administration, see section 6.6.  
 
sJIA,pJIA and CRS Patients < 30 kg 
RoActemra should be diluted to a final volume of 50 mL with sterile, non-pyrogenic sodium chloride 
9 mg/mL (0.9%) solution for injection using aseptic technique. 
 
For instructions on dilution of the medicinal product before administration, see section 6.6. 
 



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4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Active, severe infections (see section 4.4). 
 
4.4 Special warnings and precautions for use 
 
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. 
 
Infections  
Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive 
agents including RoActemra (see section 4.8, undesirable effects). RoActemra treatment must not be 
initiated in patients with active infections (see section 4.3). Administration of RoActemra should 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 RoActemra 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 for moderate to severe RA, sJIA or pJIA 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 should 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, RA, sJIA and pJIA patients should be screened for 
latent tuberculosis (TB) infection prior to starting RoActemra therapy. Patients with latent TB should 
be treated with standard anti-mycobacterial therapy before initiating RoActemra. 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 RoActemra.   
 
Viral reactivation 
Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinical 
studies 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 RoActemra in RA patients (see section 4.8). RoActemra 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 should be evaluated promptly for early identification of 
diverticulitis which can be associated with gastrointestinal perforation. 
 



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Hypersensitivity reactions 
Serious hypersensitivity reactions have been reported in association with infusion of RoActemra (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 with RoActemra. If an 
anaphylactic reaction or other serious hypersensitivity / serious infusion related reaction occurs, 
administration of RoActemra should be stopped immediately and RoActemra should be permanently 
discontinued. 
 
Active hepatic disease and hepatic impairment 
Treatment with RoActemra, 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 RoActemra treatment (see section 4.8). An increased frequency of these elevations 
was observed when potentially hepatotoxic drugs (e.g. MTX) were used in combination with 
RoActemra. 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 RoActemra (see section 4.8). Serious hepatic injury occurred between 2 weeks to more 
than 5 years after initiation of RoActemra. Cases of liver failure resulting in liver transplantation have 
been reported. Patients should be advised to immediately seek medical help if they experience signs 
and symptoms of hepatic injury.  
 
Caution should be exercised when considering initiation of RoActemra treatment in patients with 
elevated ALT or AST > 1.5 x ULN. In patients with baseline ALT or AST > 5 x 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 RoActemra discontinuation, based on transaminases levels see section 4.2. For ALT or AST 
elevations > 3–5 x ULN, confirmed by repeat testing, RoActemra 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 RoActemra, initiation is not recommended in patients with an 
absolute neutrophil count (ANC) below 2 x 109/l. Caution should be exercised when considering 
initiation of RoActemra treatment in patients with a low platelet count (i.e. platelet count below 
100 x 103/ μL). In patients who develop an ANC < 0.5 x 109/ l or a platelet count < 50 x 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 RoActemra 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. 
 



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In sJIA and pJIA 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 sJIA, pJIA and RA patients, assessment of lipid parameters should be performed 4 to 8 weeks 
following initiation of RoActemra 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 RoActemra is currently unknown. 
 
Malignancy 
The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products may 
increase the risk of malignancy. 
 
Vaccinations 
Live and live attenuated vaccines should not be given concurrently with RoActemra as clinical safety 
has not been established. In a randomized open-label study, adult RA patients treated with RoActemra 
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 sJIA and pJIA patients, be brought up to 
date with all immunisations in agreement with current immunisation guidelines prior to initiating 
RoActemra therapy. The interval between live vaccinations and initiation of RoActemra therapy 
should be in accordance with current vaccination guidelines regarding immunosuppressive agents. 
 
Cardiovascular risk 
RA patients have an increased risk for cardiovascular disorders and should have risk factors 
(e.g. hypertension, hyperlipidaemia) managed as part of usual standard of care. 
 
Combination with TNF antagonists 
There is no experience with the use of RoActemra with TNF antagonists or other biological treatments 
for RA, sJIA or pJIA patients. RoActemra is not recommended for use with other biological agents.  
 
Sodium 
This medicinal product contains 1.17 mmol (or 26.55 mg) sodium per maximum dose of 1200 mg. To 
be taken into consideration by patients on a controlled sodium diet. Doses below 1025 mg of this 
medicinal product contain less than 1 mmol sodium (23 mg), i.e. essentially ‘sodium free’. 
 
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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction studies 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. 



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Population pharmacokinetic analyses did not detect any effect of MTX, non-steroidal anti-
inflammatory drugs (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 studies 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 study 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) should 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.  
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential  
Women of childbearing potential must 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 study 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 breast milk. The excretion of tocilizumab in 
milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or 
to continue/discontinue therapy with RoActemra should be made taking into account the benefit of 
breast-feeding to the child and the benefit of RoActemra therapy to the woman. 
 
Fertility 
Available non-clinical data do not suggest an effect on fertility under tocilizumab treatment.  
 
4.7 Effects on ability to drive and use machines 
 
RoActemra has minor influence on the ability to drive and use machines (see section 4.8, dizziness). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The most commonly reported ADRs (occurring in ≥ 5% of patients treated with tocilizumab 
monotherapy or in combination with DMARDs) were upper respiratory tract infections, 
nasopharyngitis, headache, hypertension and increased ALT. 
 



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The most serious ADRs were serious infections, complications of diverticulitis, and hypersensitivity 
reactions. 
 
RA Patients 
The safety profile of tocilizumab has been studied in 4 placebo-controlled studies (studies II, III, IV 
and V), 1 MTX-controlled study (study I) and their extension periods (see section 5.1).  
 
The double-blind controlled period was 6 months in four studies (studies I, III, IV and V) and was up 
to 2 years in one study (study II). In the double-blind controlled studies, 774 patients received 
tocilizumab 4 mg/kg in combination with MTX, 1870 patients received tocilizumab 8 mg/kg in 
combination with MTX or other DMARDs and 288 patients received tocilizumab 8 mg/kg 
monotherapy.  
 
The long-term 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 studies. Of the 4009 
patients in this population, 3577 received treatment for at least 6 months, 3296 for at least one year, 
2806 received treatment for at least 2 years and 1222 for 3 years. 
 
ADRs from clinical trials and/or post marketing experience with RoActemra based on spontaneous 
case reports, literature cases and cases from non-interventional study programs are listed in Table 1 
and are presented by MedDRA system organ class. The corresponding frequency category for each 
ADR 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) or very rare (<1/10,000). Within each 
frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
 



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Table 1. List of ADRs 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 
postmarketing experience  

 
MedDRA 

System Organ 
Class 

Frequency categories with preferred terms 
Very Common 

 
Common 

 
Uncommon 

 
Rare 

 
Infections and 
infestations 

Upper respiratory 
tract infections 

Cellulitis, 
Pneumonia, Oral 
herpes simplex, 
Herpes zoster 

Diverticulitis  

Gastrointestinal 
disorders 

 Abdominal pain, 
Mouth ulceration, 
Gastritis 

Stomatitis, Gastric 
ulcer 

 

Skin and 
subcutaneous 
tissue disorders 

 Rash, Pruritus, 
Urticaria 

 Stevens-Johnson-
Syndrome3 

Nervous system 
disorders 

 Headache, 
Dizziness 

  

Investigations  Hepatic 
transaminases 
increased, Weight 
increased, Total 
bilirubin increased* 

  

Vascular 
disorders 

 Hypertension   

Blood and 
lymphatic 
system disorders 

 Leukopenia, 
Neutropenia, 
Hypofibrinogenaem
ia 

  

Immune system 
disorders 

   Anaphylaxis 
(fatal)1, 2 ,3 

Metabolism and 
nutrition 
disorders 

Hypercholesterolae
mia* 

 Hypertriglyceridae
mia 

 

General 
disorders and 
administration 
site conditions 

 Peripheral oedema, 
Hypersensitivity 
reactions 

  

Eye disorders  Conjunctivitis   
Respiratory, 
thoracic and 
mediastinal 
disorders 

 Cough, Dyspnoea   

Renal disorders   Nephrolithiasis  
Endocrine 
disorders 

  Hypothyroidism  

Hepatobiliary 
disorders 

   Drug-induced liver 
injury, Hepatitis, 
Jaundice,  
Very rare: Hepatic 
failure  

* 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 TCZ in clinical trials.  

 



15 

Infections  
In the 6-month controlled studies 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 RoActemra was 108 events per 100 patient years exposure. 
 
In 6-month controlled clinical studies, 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 study the rate of serious infections 
was 3.6 events per 100 patient years of exposure in the tocilizumab group and 1.5 events per 100 
patient years of exposure in the MTX group.  
 
In 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 tocilizumab were primarily reported as complications of diverticulitis 
including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess. 
 
Infusion 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 with tocilizumab during the controlled and open label 
clinical studies. 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.  
 
Haematological abnormalities: 
Neutrophils 
In the 6-month controlled trials decreases in neutrophil counts below 1 x 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 x 109/ l did so within 8 



16 

weeks after starting therapy. Decreases below 0.5 x 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 x 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 x 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 drugs (e.g. MTX) to tocilizumab monotherapy resulted in 
increased frequency of these elevations. Elevations of ALT/AST > 5 x 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 x ULN and 0.4% had an elevation 
of > 2 x 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 RoActemra 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. 
 
Malignancies 
The clinical data are insufficient to assess the potential incidence of malignancy following exposure to 
tocilizumab. Long-term safety evaluations are ongoing. 
 
Skin Reactions 
Rare reports of Stevens-Johnson Syndrome have occurred in the post marketing setting. 
 



17 

sJIA and pJIA Patients 
 
The safety profile of tocilizumab in the pediatric population is summarized in the sections on pJIA and 
sJIA below.  In general, the ADRs in pJIA and sJIA patients were similar in type to those seen in RA 
patients, see section 4.8.  
 
ADRs in the pJIA and sJIA patients treated with tocilizumab are listed in the Table 2 and presented by 
MedDRA system organ class. The corresponding frequency category for each ADR 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 2:  List of ADRs 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   
Gastrointestinal Disorders    
 Nausea  pJIA  
 Diarrhea  pJIA, sJIA  
General disorders and administration site 
conditions 

   

 Infusion related 
reactions 

 pJIA1, sJIA2  

Nervous system disorders    
 Headache pJIA sJIA  
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 
 
pJIA Patients 
The safety profile of intravenous RoActemra 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 ADRs in pJIA 
patients can be found in Table 2. The types of ADRs in pJIA patients were similar to those seen in RA 
and sJIA patients, see section 4.8. 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%). 
 



18 

Infusion 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 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 
drug 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 < 30kg group developed positive anti-tocilizumab antibodies without 
developing a hypersensitivity reaction and subsequently withdrew from the study.     
 
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 ≥ 3xULN occurred in 3.7% and <1% of patients, respectively. 
 
Lipid parameters 
During routine laboratory monitoring in the intravenous RoActemra study 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 study treatment, respectively. 
 
sJIA Patients 
The safety profile of intravenous RoActemra 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 to RoActemra, due to disease worsening, patients were treated in the open label extension 
phase. 
 
In general, the ADRs in sJIA patients were similar in type to those seen in RA patients, see section 
4.8. The frequency of ADRs in sJIA patients can be found in Table 2. When compared to the adult RA 
population, patients with sJIA experienced a higher frequency of nasopharyngitis, decrease in 
neutrophil counts, hepatic transaminases increased, and diarrhea. 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 RoActemra 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 RoActemra 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. 
 



19 

Infusion 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 study 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, diarrhea, 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 drug 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 x 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 x 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 x 103/µl. 
 
In the open label extension phase, decreases in platelet counts below 100 x 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 x 
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 x 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 study. 
 
Lipid parameters 
During routine laboratory monitoring in the 12 week controlled phase (study 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 study treatment, respectively. 
 
In the open label extension phase (study 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 study treatment, respectively.  



20 

 
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 authorization 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. 
 
4.9 Overdose 
 
There are limited data available on overdose with RoActemra. 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. 
 
Paediatric population 
 
No case of an overdose in the paediatric population has been observed. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic 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.  
 
RA Patients 
Pharmacodynamic effects 
In clinical studies 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 tocilizumab-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). 
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


21 

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 studies. Studies 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 Study I, tocilizumab was administered intravenously every four weeks as monotherapy. In Studies 
II, III and V, tocilizumab was administered intravenously every four weeks in combination with MTX 
vs. placebo and MTX. In Study 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 studies was the proportion of patients who achieved an ACR 20 response at week 24.  
 
Study I evaluated 673 patients who had not been treated with MTX within six months prior to 
randomisation and who had not discontinued previous MTX treatment as a result of clinically 
important toxic effects or lack of response. The majority (67%) of patients were MTX-naïve. Doses of 
8 mg/kg of tocilizumab were given every four weeks as monotherapy. The comparator group was 
weekly MTX (dose titrated from 7.5 mg to a maximum of 20 mg weekly over an eight week period).  
 
Study II, a two year study with planned analyses at week 24, week 52 and week 104, evaluated 1,196 
patients who had an inadequate clinical response to MTX. Doses of 4 or 8 mg/kg of tocilizumab or 
placebo were given every four weeks as blinded therapy for 52 weeks in combination with stable 
MTX (10 mg to 25 mg weekly). After week 52, all patients could receive open-label treatment with 
tocilizumab 8 mg/kg. Of the patients who completed the study who were originally randomised to 
placebo + MTX, 86% received open-label tocilizumab 8 mg/kg in year 2. The primary endpoint at 
week 24 was the proportion of patients who achieved an ACR 20 response. At week 52 and week 104 
the co-primary endpoints were prevention of joint damage and improvement in physical function. 
 
Study III evaluated 623 patients who had an inadequate clinical response to MTX. Doses of 4 or 
8 mg/kg tocilizumab or placebo were given every four weeks, in combination with stable MTX (10 mg 
to 25 mg weekly).  
 
Study IV evaluated 1,220 patients who had an inadequate response to their existing rheumatologic 
therapy, including one or more DMARDs. Doses of 8 mg/kg tocilizumab or placebo were given every 
four weeks in combination with stable DMARDs.  
 
Study V evaluated 499 patients who had an inadequate clinical response or were intolerant to one or 
more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomisation. 
Doses of 4 or 8 mg/kg tocilizumab or placebo were given every four weeks in combination with stable 
MTX (10 mg to 25 mg weekly).  
 
Clinical response 
In all studies, patients treated with tocilizumab 8 mg/kg had statistically significant higher ACR 20, 
50, 70 response rates at 6 months compared to control (Table 3). In study I, superiority of tocilizumab 
8 mg/kg was demonstrated against the active comparator MTX. 
 
The treatment effect was similar in patients independent of rheumatoid factor status, age, gender, race, 
number of prior treatments or disease status. Time to onset was rapid (as early as week 2) and the 
magnitude of response continued to improve with duration of treatment. Continued durable responses 
were seen for over 3 years in the open label extension studies I-V.  
 
In patients treated with tocilizumab 8 mg/kg, significant improvements were noted on all individual 
components of the ACR response including: tender and swollen joint counts; patients and physician 
global assessment; disability index scores; pain assessment and CRP compared to patients receiving 
placebo plus MTX or other DMARDs in all studies.  
 



22 

Patients in studies I – V had a mean Disease Activity Score (DAS28) of 6.5–6.8 at baseline. 
Significant reduction in DAS28 from baseline (mean improvement) of 3.1–3.4 were observed in 
tocilizumab-treated patients compared to control patients (1.3-2.1). The proportion of patients 
achieving a DAS28 clinical remission (DAS28 < 2.6) was significantly higher in patients receiving 
tocilizumab (28–34%) compared to 1–12% of control patients at 24 weeks. In study II, 65% of patients 
achieved a DAS28 < 2.6 at week 104 compared to 48% at 52 weeks and 33% of patients at week 24. 
 
In a pooled analysis of studies II, III and IV, the proportion of patients achieving an ACR 20, 50 and 
70 response was significantly higher (59% vs. 50%, 37% vs. 27%, 18% vs. 11%, respectively) in the 
tocilizumab 8 mg/kg plus DMARD vs. the tocilizumab 4 mg/kg plus DMARD group (p< 0.03). 
Similarly the proportion of patients achieving a DAS28 remission (DAS28 < 2.6) was significantly 
higher (31% vs. 16% respectively) in patients receiving tocilizumab 8 mg/kg plus DMARD than in 
patients receiving tocilizumab 4 mg/kg plus DMARD (p< 0.0001). 
 
Table 3. ACR responses in placebo-/MTX-/DMARDs-controlled studies (% patients) 
 

 Study I 
AMBITION 

Study II 
LITHE 

Study III 
OPTION 

Study IV 
TOWARD 

Study V 
RADIATE 

Week TCZ 
8 mg/kg 

MTX TCZ 
8 mg/kg 
+ MTX 

PBO 
+ MTX 

TCZ 
8 mg/kg 
+ MTX 

PBO 
+ MTX 

TCZ 
8 mg/kg 

+ 
DMARD 

PBO + 
DMARD 

TCZ 
8 mg/kg 
+ MTX 

PBO + 
MTX 

 

 N = 
286 

N = 
284 

N = 
398 

N = 
393 

N = 
205 

N = 
204 

N = 
803 

N = 
413 

N = 
170 

N = 
158 

ACR 20 
24 70%**

* 
52% 56%**

* 
27% 59%**

* 
26% 61%*** 24% 50%*** 10% 

52   56%**
* 

25%       

ACR 50 
24 44%** 33% 32%*** 10% 44%**

* 
11% 38%*** 9% 29%**

* 
4% 

52   36%*** 10%       
ACR 70 

24 28%** 15% 13%*** 2% 22%**
* 

2% 21%*** 3% 12%** 1% 

52   20%*** 4%       
TCZ   - Tocilizumab 
MTX  - Methotrexate 
PBO  - Placebo 
DMARD  - Disease modifying anti-rheumatic drug 
**   - p< 0.01, TCZ vs. PBO + MTX/DMARD 
***  - p< 0.0001, TCZ vs. PBO + MTX/DMARD 
 
Major Clinical Response 
After 2 years of treatment with tocilizumab plus MTX, 14% of patients achieved a major clinical 
response (maintenance of an ACR70 response for 24 weeks or more). 
 
Radiographic response 
In Study II, in patients with an inadequate response to MTX, inhibition of structural joint damage was 
assessed radiographically and expressed as change in modified Sharp score and its components, the 
erosion score and joint space narrowing score. Inhibition of joint structural damage was shown with 
significantly less radiographic progression in patients receiving tocilizumab compared to control 
(Table 4). 
 



23 

In the open-label extension of Study II the inhibition of progression of structural joint damage in 
tocilizumab plus MTX-treated patients was maintained in the second year of treatment. The mean 
change from baseline at week 104 in total Sharp-Genant score was significantly lower for patients 
randomised to tocilizumab 8 mg/kg plus MTX (p<0.0001) compared with patients who were 
randomised to placebo plus MTX.   
 
Table 4. Radiographic mean changes over 52 weeks in Study II 
 
 PBO + MTX  

(+ TCZ from week 24) 
N = 393 

TCZ 8 mg/kg + MTX 
 

N = 398 
Total Sharp-Genant score 1.13 0.29* 
Erosion score 0.71 0.17* 
JSN score 0.42 0.12** 
PBO  - Placebo 
MTX  - Methotrexate 
TCZ  - Tocilizumab 
JSN  - Joint space narrowing 
*  - p≤ 0.0001, TCZ vs. PBO + MTX 
**   - p< 0.005, TCZ vs. PBO + MTX 
 
Following 1 year of treatment with tocilizumab plus MTX, 85% of patients (n=348) had no 
progression of structural joint damage, as defined by a change in the Total Sharp Score of zero or less, 
compared with 67% of placebo plus MTX-treated patients (n=290) (p ≤ 0.001). This remained 
consistent following 2 years of treatment (83%; n=353). Ninety three percent (93%; n=271) of patients 
had no progression between week 52 and week 104. 
 
Health-related and quality of life outcomes 
Tocilizumab-treated patients reported an improvement in all patient-reported outcomes (Health 
Assessment Questionnaire Disability Index - HAQ-DI), Short Form-36 and Functional Assessment of 
Chronic Illness Therapy questionnaires. Statistically significant improvements in HAQ-DI scores were 
observed in patients treated with RoActemra compared with patients treated with DMARDs. During 
the open-label period of Study II, the improvement in physical function has been maintained for up to 
2 years. At Week 52, the mean change in HAQ-DI was -0.58 in the tocilizumab 8 mg/kg plus MTX 
group compared with -0.39 in the placebo + MTX group. The mean change in HAQ-DI was 
maintained at Week 104 in the tocilizumab 8 mg/kg plus MTX group (-0.61). 
 
Haemoglobin levels  
Statistically significant improvements in haemoglobin levels were observed with tocilizumab 
compared with DMARDs (p< 0.0001) at week 24. Mean haemoglobin levels increased by week 2 and 
remained within normal range through to week 24.  
 
Tocilizumab versus adalimumab in monotherapy 
Study VI (WA19924), a 24 week double-blinded study that compared tocilizumab monotherapy with 
adalimumab monotherapy, evaluated 326 patients with RA who were intolerant of MTX or where 
continued treatment with MTX was considered inappropriate (including MTX inadequate responders). 
Patients in the tocilizumab arm received an intravenous (IV) infusion of tocilizumab (8 mg/kg) every 4 
weeks (q4w) and a subcutaneous (SC) placebo injection every 2 weeks (q2w). Patients in the 
adalimumab arm received an adalimumab SC injection (40 mg) q2w plus an IV placebo infusion q4w. 
A statistically significant superior treatment effect was seen in favour of tocilizumab over adalimumab 
in control of disease activity from baseline to week 24 for the primary endpoint of change in DAS28 
and for all secondary endpoints (Table 5). 
 



24 

Table 5: Efficacy Results for Study VI (WA19924) 
 

 

ADA + Placebo (IV) 

N = 162 

TCZ + Placebo (SC) 

N = 163 p-value(a) 

Primary Endpoint - Mean Change from baseline at Week 24 

DAS28 (adjusted mean)  -1.8 -3.3   

Difference in adjusted mean (95% CI) -1.5 (-1.8, -1.1) <0.0001 

Secondary Endpoints - Percentage of Responders at Week 24 (b) 

DAS28 < 2.6, n (%) 17 (10.5) 65 (39.9) <0.0001 

DAS28 ≤ 3.2, n (%)  32 (19.8)  84 (51.5) <0.0001 

ACR20 response, n (%) 80 (49.4) 106 (65.0) 0.0038 

ACR50 response, n (%) 45 (27.8) 77 (47.2) 0.0002 

ACR70 response, n (%) 29 (17.9) 53 (32.5) 0.0023 
ap value is adjusted for region and duration of RA for all endpoints and additionally baseline value for all continuous  
endpoints. 
b Non-responder Imputation used for missing data. Multiplicity controlled using Bonferroni-Holm Procedure 
 
The overall clinical adverse event profile was similar between tocilizumab and adalimumab. The 
proportion of patients with serious adverse events was balanced between the treatment groups 
(tocilizumab 11.7% vs. adalimumab 9.9%). The types of adverse drug reactions in the tocilizumab arm 
were consistent with the known safety profile of tocilizumab and adverse drug reactions were reported 
at a similar frequency compared with Table 1. A higher incidence of infections and infestations was 
reported in the tocilizumab arm (48% vs. 42%), with no difference in the incidence of serious 
infections (3.1%). Both study treatments induced the same pattern of changes in laboratory safety 
parameters (decreases in neutrophil and platelet counts, increases in ALT, AST and lipids), however, 
the magnitude of change and the frequency of marked abnormalities was higher with tocilizumab 
compared with adalimumab. Four (2.5%) patients in the tocilizumab arm and two (1.2%) patients in 
the adalimumab arm experienced CTC grade 3 or 4 neutrophil count decreases.  Eleven (6.8%) 
patients in the tocilizumab arm and five (3.1%) patients in the adalimumab arm experienced ALT 
increases of CTC grade 2 or higher.  The mean LDL increase from baseline was 0.64 mmol/L 
(25 mg/dL) for patients in the tocilizumab arm and 0.19 mmol/L (7 mg/dL) for patients in the 
adalimumab arm.  The safety observed in the tocilizumab arm was consistent with the known safety 
profile of tocilizumab and no new or unexpected adverse drug reactions were observed (see Table 1).  
 
MTX naïve, Early RA 
Study VII (WA19926), a 2 year study with the planned primary analysis at week 52 evaluated 1162 
MTX-naïve adult patients with moderate to severe, active early RA (mean disease duration ≤ 6 
months). Approximately 20% of patients had received prior treatment with DMARDs other than 
MTX. This study evaluated the efficacy of IV tocilizumab 4 or 8 mg/kg every 4 weeks/MTX 
combination therapy, IV tocilizumab 8 mg/kg monotherapy and MTX monotherapy in reducing the 
signs and symptoms and rate of progression of joint damage for 104 weeks. The primary endpoint was 
the proportion of patients achieving DAS28 remission (DAS28 < 2.6) at week 24. A significantly 
higher proportion of patients in the tocilizumab 8 mg/kg + MTX and tocilizumab monotherapy groups 
met the primary endpoint compared with MTX alone. The tocilizumab 8 mg/kg + MTX group also 
showed statistically significant results across the key secondary endpoints. Numerically greater 
responses compared with MTX alone were observed in the tocilizumab 8 mg/kg monotherapy group in 
all secondary endpoints, including radiographic endpoints. In this study, ACR/EULAR remission 
(Boolean and Index) were also analysed as pre-specified exploratory endpoints, with higher responses 
observed in the tocilizumab groups. The results from study VII are shown in Table 6. 
 



25 

Table 6: Efficacy Results for Study VII (WA19926) on MTX-naïve, early RA patients 
 

 

TCZ 8 mg/kg + 
MTX 
N=290 

TCZ 8 mg/kg + 
placebo 
N=292 

TCZ 
4 mg/kg + 

MTX 
N=288 

Placebo + 
MTX 
N=287 

 Primary Endpoint 

DAS28 Remission                             

Week 24                        n (%) 130 (44.8)*** 113 (38.7)*** 92 (31.9) 43 (15.0) 

 Key Secondary Endpoints 

DAS 28 remission     

Week 52              n (%),  142 (49.0)*** 115 (39.4) 98 (34.0) 56 (19.5) 

ACR     

Week 24            ACR20, n (%) 216 (74.5)* 205 (70.2) 212 (73.6) 187 (65.2) 

ACR50, n (%) 165 (56.9)** 139 (47.6) 138 (47.9) 124 (43.2) 

ACR70, n (%) 112 (38.6)** 88 (30.1) 100 (34.7) 73 (25.4) 

Week 52            ACR20, n (%) 195 (67.2)* 184 (63.0) 181 (62.8) 164 (57.1) 

ACR50, n (%) 162 (55.9)** 144 (49.3) 151 (52.4) 117 (40.8) 

ACR70, n (%) 125 (43.1)** 105 (36.0) 107 (37.2) 83 (28.9) 

HAQ-DI (adjusted mean change from baseline)     

Week 52 -0.81* -0.67 -0.75 -0.64 

 Radiographic Endpoints (mean change from baseline) 

Week 52                          mTSS 0.08*** 0.26 0.42 1.14 

Erosion Score 0.05** 0.15 0.25 0.63 

JSN 0.03 0.11 0.17 0.51 

Radiographic Non-Progression n (%) (change from 
baseline in mTSS of ≤0)  

226 (83)‡ 226 (82)‡ 211 (79) 194 (73) 

 Exploratory Endpoints 

Week 24: ACR/EULAR Boolean Remission, n (%) 47 (18.4) ‡ 38 (14.2) 43 (16.7) ‡ 25 (10.0) 

      ACR/EULAR Index Remission, n (%) 73 (28.5) ‡ 60 (22.6) 58 (22.6) 41 (16.4) 

Week 52: ACR/EULAR Boolean Remission, n (%) 59 (25.7) ‡ 43 (18.7) 48 (21.1) 34 (15.5) 

                    ACR/EULAR Index Remission, n (%) 83 (36.1) ‡ 69 (30.0) 66 (29.3) 49 (22.4) 
mTSS  - modified Total Sharp Score 
JSN  - Joint space narrowing 
All efficacy comparisons vs Placebo + MTX. ***p≤0.0001; **p<0.001; *p<0.05;  
‡p-value < 0.05 vs. Placebo + MTX, but endpoint was exploratory (not included in the hierarchy of statistical testing and has 
therefore not been controlled for multiplicity) 
 
Paediatric population 
sJIA Patients 
Clinical efficacy 
The efficacy of tocilizumab for the treatment of active sJIA was assessed in a 12 week randomised, 
double blind, placebo-controlled, parallel group, two arm study. Patients included in the trial had a 
total disease duration of at least 6 months and active disease but were not experiencing an acute flare 
requiring corticosteroid doses of more than 0.5 mg/kg prednisone equivalent. Efficacy for the 
treatment of macrophage activation syndrome has not been investigated. 
 



26 

Patients (treated with or without MTX) were randomised (tocilizumab:placebo = 2:1) to one of two 
treatment groups, 75 patients received tocilizumab infusions every two weeks, either 8 mg/kg for 
patients ≥ 30 kg or 12 mg/kg for patients < 30 kg and 37 patients were assigned to receiving placebo 
infusions every two weeks. Corticosteroid tapering was permitted from week six for patients who 
achieved a JIA ACR70 response. After 12 weeks or at the time of escape, due to disease worsening, 
patients were treated in the open label phase at weight appropriate dosing. 
 
Clinical response 
The primary endpoint was the proportion of patients with at least 30% improvement in the JIA ACR 
core set (JIA ACR30 response) at week 12 and absence of fever (no temperature recording ≥ 37.5°C in 
the preceding 7 days). Eighty five percent (64/75) of tocilizumab treated patients and 24.3% (9/37) of 
placebo treated patients achieved this endpoint. These proportions were highly significantly different 
(p<0.0001). 
 
The percent of patients achieving JIA ACR 30, 50, 70 and 90 responses are shown in Table 7. 
 
Table 7. JIA ACR response rates at week 12 (% patients) 
 
Response Rate Tocilizumab 

N = 75 
Placebo 
N = 37 

JIA ACR 30 90.7%1 24.3% 
JIA ACR 50 85.3%1 10.8% 
JIA ACR 70 70.7%1 8.1% 
JIA ACR 90 37.3%1 5.4% 
1p<0.0001, tocilizumab vs. placebo 
 
Systemic Effects 
In the tocilizumab treated patients, 85% who had fever due to sJIA at baseline were free of fever (no 
temperature recording ≥ 37.5°C in the preceding 14 days) at week 12 versus 21% of placebo patients 
(p<0.0001).  
 
The adjusted mean change in the pain VAS after 12 weeks of tocilizumab treatment was a reduction of 
41 points on a scale of 0 - 100 compared to a reduction of 1 for placebo patients (p<0.0001).  
 
Corticosteroid Tapering 
Patients achieving a JIA ACR70 response were permitted corticosteroid dose reduction. Seventeen 
(24%) tocilizumab treated patients versus 1 (3%) placebo patient were able to reduce their dose of 
corticosteroid by at least 20% without experiencing a subsequent JIA ACR30 flare or occurrence of 
systemic symptoms to week 12 (p=0.028). Reductions in corticosteroids continued, with 44 patients 
off oral corticosteroids at week 44, while maintaining JIA ACR responses. 
 
Health related and quality of life outcomes 
At week 12, the proportion of tocilizumab treated patients showing a minimally clinically important 
improvement in the Childhood Health Assessment Questionnaire – Disability Index (defined as an 
individual total score decrease of ≥ 0.13) was significantly higher than in placebo treated patients, 77% 
versus 19% (p<0.0001).  
 
Laboratory Parameters 
Fifty out of seventy five (67%) tocilizumab treated patients had a haemoglobin < LLN at baseline. 
Forty (80%) of these patients had an increase in their haemoglobin to within the normal range at week 
12, in comparison to 2 out of 29 (7%) of placebo treated patients with haemoglobin < LLN at baseline 
(p<0.0001).  
 



27 

pJIA Patients 
Clinical efficacy 
The efficacy of tocilizumab was assessed in a three-part study WA19977 including an open-label 
extension in children with active pJIA. Part I consisted of a 16-week active tocilizumab treatment 
lead-in period (n=188) followed by Part II, a 24-week randomized double-blind placebo-controlled 
withdrawal period (n=163), followed by Part III, a 64-week open-label period. In Part 1, eligible 
patients ≥ 30 kg received tocilizumab at 8 mg/kg IV every 4 weeks for 4 doses. Patients < 30 kg were 
randomized 1:1 to receive either tocilizumab 8 mg/kg or 10 mg/kg IV every 4 weeks for 4 doses. 
Patients who completed Part I of the study and achieved at least a JIA ACR30 response at week 16 
compared to baseline were eligible to enter the blinded withdrawal period (Part II) of the study. In 
Part II, patients were randomized to tocilizumab (same dose received in Part I) or placebo in a 1:1 
ratio, stratified by concurrent MTX use and concurrent corticosteroid use. Each patient continued in 
Part II of the study until Week 40 or until the patient satisfied JIA ACR30 flare criteria (relative to 
Week 16) and qualified for escape to tocilizumab therapy (same dose received in Part I).   
 
Clinical response 
The primary endpoint was the proportion of patients with a JIA ACR30 flare at week 40 relative to 
week 16. Forty eight percent (48.1%, 39/81) of the patients treated with placebo flared compared with 
25.6% (21/82) of tocilizumab treated patients. These proportions were statistically significantly 
different (p=0.0024).  
 
At the conclusion of Part I, JIA ACR 30/50/70/90 responses were 89.4%, 83.0%, 62.2%, and 26.1%, 
respectively. 
 
During the withdrawal phase (Part II), the percentage of patients achieving JIA ACR 30, 50, and 70 
responses at Week 40 relative to baseline are shown in Table 8. In this statistical analysis, patients 
who flared (and escaped to TCZ) during Part II or who withdrew, were classified as non-responders.  
An additional analyses of JIA ACR responses, considering observed data at Week 40, regardless of 
flare status, showed that by Week 40, 95.1% of patients who had received continuous TCZ therapy, 
had achieved JIA ACR30 or higher. 
 
Table 8.  JIA ACR Response Rates at Week 40 Relative to baseline (Percentage of Patients) 
 
Response Rate Tocilizumab 

N=82 

Placebo 

N=81 

ACR 30 74.4%* 54.3%* 

ACR 50 73.2%* 51.9%* 

ACR 70 64.6%* 42.0%* 

* p<0.01, tocilizumab vs. placebo 
 
The number of active joints was significantly reduced compared to baseline in patients receiving 
tocilizumab compared to placebo (adjusted mean changes of -14.3 vs -11.4, p=0.0435). The 
physician’s global assessment of disease activity, as measured on a 0-100 mm scale, showed a greater 
reduction in disease activity for tocilizumab compared to placebo (adjusted mean changes of -45.2 mm 
vs -35.2 mm, p=0.0031).  
 
The adjusted mean change in the pain VAS after 40 weeks of tocilizumab treatment was 32.4 mm on a 
0-100 mm scale compared to a reduction of 22.3 mm for placebo patients (highly statistically 
significant; p=0.0076).  
 
The ACR response rates were numerically lower for patients with prior biologic treatment as shown in 
Table 9 below. 
 



28 

Table 9. Number and Proportion of Patients with a JIA ACR30 Flare and Proportion of Patients with 
JIA ACR30/50/70/90 Responses at Week 40, by Previous Biologic Use (ITT Population - Study Part II) 
 

 Placebo All TCZ 
Biologic Use Yes (N = 23) No (N = 58) Yes (N = 27) No (N = 55) 

JIA ACR30 Flare 18 (78.3) 21 (36.2) 12 (44.4) 9 (16.4) 

JIA ACR30 Response 6 (26.1) 38 (65.5) 15 (55.6) 46 (83.6) 

JIA ACR50 Response 5 (21.7) 37 (63.8) 14 (51.9) 46 (83.6) 

JIA ACR70 Response 2 (8.7) 32 (55.2) 13 (48.1) 40 (72.7) 

JIA ACR90 Response 2 (8.7) 17 (29.3) 5 (18.5) 32 (58.2) 
 
Patients randomized to tocilizumab had fewer ACR30 flares and higher overall ACR responses than 
patients receiving placebo regardless of a history of prior biologic use.  
 
CRS 
The efficacy of RoActemra for the treatment of CRS was assessed in a retrospective analysis of data 
from clinical trials of CAR T-cell therapies (tisagenlecleucel and axicabtagene ciloleucel) for 
hematological malignancies. Evaluable patients had been treated with tocilizumab 8 mg/kg (12 mg/kg 
for patients < 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening 
CRS; only the first episode of CRS was included in the analysis. The efficacy population for the 
tisagenlecleucel cohort included 28 males and 23 females (total 51 patients) of median age 17 years 
(range, 3–68 years). The median time from start of CRS to first dose of tocilizumab was 3 days (range, 
0–18 days). Resolution of CRS was defined as lack of fever and off vasopressors for at least 24 hours. 
Patients were considered responders if CRS resolved within 14 days of the first dose of tocilizumab, if 
no more than 2 doses of RoActemra were needed, and no drugs other than RoActemra and 
corticosteroids were used for treatment. Thirty-nine patients (76.5%; 95% CI: 62.5%–87.2%) achieved 
a response. In an independent cohort of 15 patients (range: 9–75 years old) with axicabtagene 
ciloleucel-induced CRS, 53% responded.  
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
RoActemra in all subsets of the paediatric population in treatment of cytokine release syndrome 
associated with chimeric antigen receptor (CAR) T cell therapy. 
 
5.2 Pharmacokinetic properties 
 
RA Patients 
 
Intravenous use 
The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on 
a database composed of 3552 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) = 38000 ± 13000 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 50000 ± 16800 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, 



29 

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). 
 
Distribution 
In RA patients the central volume of distribution was 3.72, the peripheral volume of distribution was 
3.35 resulting in a volume of distribution at steady state of 7.07.  
 
Elimination 
Following intravenous administration, tocilizumab undergoes biphasic elimination from the 
circulation. The total clearance of tocilizumab was concentration-dependent and is the sum of the 
linear and non-linear clearance. The linear clearance was estimated as a parameter in the population 
pharmacokinetic analysis and was 9.5 mL/h. The concentration-dependent non-linear clearance plays a 
major role at low tocilizumab concentrations. Once the non-linear clearance pathway is saturated, at 
higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.  
 
The t1/2 of tocilizumab was concentration-dependent. At steady-state following a dose of 8 mg/kg 
every 4 weeks, the effective t1/2 decreased with decreasing concentrations within a dosing interval 
from 18 days to 6 days. 
 
Linearity 
Pharmacokinetic parameters of tocilizumab did not change with time. A more than dose-proportional 
increase in the AUC and Cmin was observed for doses of 4 and 8 mg/kg every 4 weeks. Cmax increased 
dose-proportionally. At steady-state, predicted AUC and Cmin were 3.2 and 30 fold higher at 8 mg/kg 
as compared to 4 mg/kg, respectively. 
 
Special populations 
Renal impairment: No formal study of the effect of renal impairment on the pharmacokinetics of 
tocilizumab has been conducted. Most of the patients in the population pharmacokinetic analysis had 
normal renal function or mild renal impairment. Mild renal impairment (creatinine clearance based on 
Cockcroft-Gault < 80 mL/min and ≥ 50 mL/min) did not impact the pharmacokinetics of tocilizumab. 
 
Hepatic impairment: No formal study of the effect of hepatic impairment on the pharmacokinetics of 
tocilizumab has been conducted.  
 
Age, gender and ethnicity: Population pharmacokinetic analyses in RA patients, showed that age, 
gender and ethnic origin did not affect the pharmacokinetics of tocilizumab.  
 
sJIA Patients:  
The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on 
a database composed of 140 sJIA patients treated with 8 mg/kg IV every 2 weeks (patients with a body 
weight ≥ 30 kg ) 12 mg/kg IV every 2 weeks (patients with a body weight < 30 kg), 162 mg SC every 
week (patients weighing ≥ 30 kg), 162 mg SC every 10 days or every 2 weeks (patients weighing 
below 30 kg).  
 



30 

Table 10. Predicted mean ± SD PK parameters at steady-state after IV dosing in sJIA 
 

RoActemra PK Parameter 8 mg/kg Q2W ≥ 30 kg 12 mg/kg Q2W below 30 kg 

Cmax (µg/mL) 256 ± 60.8 274 ± 63.8 

Ctrough (µg/mL) 69.7 ± 29.1 68.4 ± 30.0 

Cmean (µg/mL) 119 ± 36.0 123 ±  36.0 

Accumulation Cmax 1.42 1.37 

Accumulation Ctrough 3.20 3.41 

Accumulation Cmean or AUCτ* 2.01 1.95 

*τ = 2 weeks for IV regimens  
 
After IV dosing, approximately 90% of the steady-state was reached by week 8 for both the 12 mg/kg 
(BW < 30 kg) and 8 mg/kg Q2W (BW ≥ 30 kg) regimens. 
 
In sJIA patients, the central volume of distribution was 1.87 L and the peripheral volume of 
distribution was 2.14 L resulting in a volume of distribution at a steady state of 4.01 L. The linear 
clearance estimated as a parameter in the population pharmacokinetic analysis, was 5.7 mL/h. 
 
The half life of tocilizumab in sJIA patients is up to 16 days for the two body weight categories 
(8 mg/kg for body weight ≥ 30 kg or 12 mg/kg for body weight < 30 kg) at week 12. 
 
pJIA Patients:  
The pharmacokinetics of tocilizumab in pJIA patients was characterized by a population 
pharmacokinetic analysis which included 237 patients who were treated with 8 mg/kg IV every 4 
weeks (patients weighing ≥ 30 kg ), 10 mg/kg IV every 4 weeks (patients weighing below 30 kg), 
162 mg SC every 2 weeks (patients weighing ≥ 30 kg), or 162 mg SC every 3 weeks (patients 
weighing below 30 kg).  
 
Table 11. Predicted mean ± SD PK parameters at steady-state after IV dosing in pJIA 
 

RoActemra PK Parameter 8 mg/kg Q4W ≥ 30 kg 10 mg/kg Q4W below 30 kg 

Cmax (µg/mL) 183 ± 42.3 168 ± 24.8 

Ctrough (µg/mL) 6.55 ± 7.93 1.47 ± 2.44 

Cmean (µg/mL) 42.2 ± 13.4 31.6 ±  7.84 

Accumulation Cmax 1.04 1.01 

Accumulation Ctrough 2.22 1.43 

Accumulation Cmean or AUCτ* 1.16 1.05 

*τ = 4 weeks for IV regimens  
 
After IV dosing, approximately 90% of the steady-state was reached by week 12 for the 10 mg/kg 
(BW < 30 kg), and by week 16 for the 8 mg/kg (BW ≥ 30 kg) dose. 
 
The half life of tocilizumab in pJIA patients is up to 16 days for the two body weight categories 
(8 mg/kg for body weight ≥ 30 kg or 10 mg/kg for body weight < 30 kg) during a dosing interval at 
steady state. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity and genotoxicity.  



31 

 
Carcinogenicity studies were not performed because IgG1 monoclonal antibodies are not deemed to 
have intrinsic carcinogenic potential.  
 
Available non-clinical data demonstrated the effect of IL-6 on malignant progression and apoptosis 
resistance to various cancer types. This data does not suggest a relevant risk for cancer initiation and 
progression under tocilizumab treatment. Additionally, proliferative lesions were not observed in a 
6-month chronic toxicity study in cynomolgus monkeys or in IL-6 deficient mice.  
 
Available non-clinical data do not suggest an effect on fertility under tocilizumab treatment. Effects on 
endocrine active and reproductive system organs were not observed in a chronic cynomolgus monkey 
toxicity study and reproductive performance was not affected in IL-6 deficient mice. Tocilizumab 
administered to cynomolgus monkeys during early gestation, was observed to have no direct or 
indirect harmful effect on pregnancy or embryonal-foetal development. However, a slight increase in 
abortion/embryonal-foetal death was observed with high systemic exposure (> 100 x human exposure) 
in the 50 mg/kg/day high-dose group compared to placebo and other low-dose groups. Although IL-6 
does not seem to be a critical cytokine for foetal growth or the immunological control of the 
maternal/foetal interface, a relation of this finding to tocilizumab cannot be excluded. 
 
Treatment with a murine analogue did not exert toxicity in juvenile mice. In particular, there was no 
impairment of skeletal growth, immune function and sexual maturation. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sucrose 
Polysorbate 80 
Disodium phosphate dodecahydrate 
Sodium dihydrogen phosphate dihydrate 
Water for injections 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vial: 30 months 
 
Diluted product: After dilution, the prepared solution for infusion is physically and chemically stable 
in sodium chloride 9 mg/mL (0.9%) solution for injection at 30ºC for 24 hours.  
 
From a microbiological point of view, the prepared solution for infusion should be used immediately. 
If not used immediately, in use storage times and conditions prior to use are the responsibility of the 
user and would normally not be longer than 24 hours at 2°C–8°C, unless dilution has taken place in 
controlled and validated aseptic conditions.  
 
6.4 Special precautions for storage 
 
Store vials in a refrigerator (2°C–8°C). Do not freeze.  
 
Keep the vial(s) in the outer carton in order to protect from light. 
 
For storage conditions of the diluted medicinal product see section 6.3. 



32 

 
6.5 Nature and contents of container 
 
RoActemra is supplied in a vial (type I glass) with a stopper (butyl rubber) containing 4 mL, 10 mL or 
20 mL concentrate. Pack sizes of 1 and 4 vials. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Instructions for dilution prior to administration 
Parenteral medicinal products should be inspected visually for particulate matter or discolouration 
prior to administration. Only solutions which are clear to opalescent, colourless to pale yellow and free 
of visible particles should be diluted. 
 
RA and CRS Patients (≥ 30 kg) 
Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) solution for injection 
from a 100 mL infusion bag, equal to the volume of RoActemra concentrate required for the patients 
dose, under aseptic conditions. The required amount of RoActemra concentrate (0.4 mL/kg) should be 
withdrawn from the vial and placed in the 100 mL infusion bag. This should be a final volume of 
100 mL. To mix the solution, gently invert the infusion bag to avoid foaming. 
 
Use in the paediatric population 
 
sJIA, pJIA and CRS Patients ≥ 30 kg 
Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) solution for injection 
from a 100 mL infusion bag, equal to the volume of RoActemra concentrate required for the patients 
dose, under aseptic conditions. The required amount of RoActemra concentrate (0.4 mL/kg) should be 
withdrawn from the vial and placed in the 100 mL infusion bag. This should be a final volume of 
100 mL. To mix the solution, gently invert the infusion bag to avoid foaming. 
 
sJIA and CRS Patients < 30 kg 
Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) solution for injection 
from a 50 mL infusion bag, equal to the volume of RoActemra concentrate required for the patients 
dose, under aseptic conditions. The required amount of RoActemra concentrate (0.6 mL/kg) should be 
withdrawn from the vial and placed in the 50 mL infusion bag. This should be a final volume of 
50 mL. To mix the solution, gently invert the infusion bag to avoid foaming. 
 
pJIA Patients < 30 kg 
Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) solution for injection 
from a 50 mL infusion bag, equal to the volume of RoActemra concentrate required for the patients 
dose, under aseptic conditions. The required amount of RoActemra concentrate (0.5 mL/kg) should be 
withdrawn from the vial and placed in the 50 mL infusion bag. This should be a final volume of 
50 mL. To mix the solution, gently invert the infusion bag to avoid foaming. 
 
RoActemra is for single-use only. 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 



33 

8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/492/001 
EU/1/08/492/002 
EU/1/08/492/003 
EU/1/08/492/004 
EU/1/08/492/005 
EU/1/08/492/006 
 
 
9. DATE OF FIRST AUTHORISATION/DATE OF LATEST RENEWAL  
 
Date of first authorisation: 16 January 2009 
Date of last renewal: 25 September 2013 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/. 
 

http://www.ema.europa.eu/


34 

1. NAME OF THE MEDICINAL PRODUCT 
 
RoActemra 162 mg solution for injection in pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe contains 162 mg of tocilizumab in 0.9 mL. 
 
Tocilizumab is a recombinant humanized, anti-human monoclonal antibody of the 
immunoglobulin G1 (IgG1) sub-class directed against soluble and membrane-bound interleukin 6 
receptors. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection in pre-filled syringe.  
 
A colourless to slightly yellowish solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
RoActemra, in combination with methotrexate (MTX), is indicated for 
 

• the treatment of severe, active and progressive rheumatoid arthritis (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. 
 
RoActemra is indicated for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in 
patients 1 year of age and older, who have responded inadequately to previous therapy with 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.  
 
RoActemra in combination with methotrexate (MTX) is indicated for the treatment of juvenile 
idiopathic polyarthritis (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. 
 
RoActemra is indicated for the treatment of Giant Cell Arteritis (GCA) in adult patients. 
 



35 

4.2 Posology and method of administration 
 
Tocilizumab SC formulation is administered with a single-use PFS+NSD.  Treatment should be 
initiated by healthcare professionals experienced in the diagnosis and treatment of RA, sJIA, pJIA and 
/ or GCA. The first injection should be performed under the supervision of a qualified health care 
professional. A patient or parent/guardian can self-inject RoActemra 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 IV therapy to SC administration should administer the first 
SC dose at the time of the next scheduled IV dose under the supervision of a qualified health care 
professional. 
 
All patients treated with RoActemra should be given the Patient Alert Card.  
 
Suitability of the patient or parent/guardian for subcutaneous home use should be assessed and patients 
or parent/guardian 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 
The recommended posology is subcutaneous 162 mg once every week. 
 
Limited information is available regarding switching patients from RoActemra intravenous 
formulation to RoActemra 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 
The recommended posology is subcutaneous 162 mg once every week in combination with a tapering 
course of glucocorticoids. RoActemra can be used alone following discontinuation of glucocorticoids. 
RoActemra monotherapy should not be used for the treatment of acute relapses (see 4.4). 
 
Based upon the chronic nature of GCA, treatment beyond 52 weeks should be guided by disease 
activity, physician discretion, and patient choice. 
 



36 

RA and GCA 
Dose adjustments due to laboratory abnormalities (see section 4.4).  
 
• Liver enzyme abnormalities 
 
Laboratory Value Action 

> 1 to 3 x Upper 
Limit of Normal 
(ULN) 

Dose modify concomitant DMARDs (RA) or immunomodulatory agents (GCA) 
if appropriate. 

For persistent increases in this range, reduce RoActemra dose frequency to 
every other week injection or interrupt RoActemra until alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) have normalised. 
 
Restart with weekly or every other week injection, as clinically appropriate. 

> 3 to 5 x ULN Interrupt RoActemra dosing until < 3 x ULN and follow recommendations 
above for > 1 to 3 x ULN. 

For persistent increases > 3 x ULN (confirmed by repeat testing, see 4.4.), 
discontinue RoActemra. 

> 5 x ULN Discontinue RoActemra. 

 
• Low absolute neutrophil count (ANC) 
 
In patients not previously treated with RoActemra, initiation is not recommended in patients with an 
absolute neutrophil count (ANC) below 2 x 109/L 
 
Laboratory Value 
(cells x 109/ L ) 

Action 

ANC > 1  Maintain dose. 

ANC 0.5 to 1 Interrupt RoActemra dosing. 

When ANC increases > 1 x 109/ L resume RoActemra dosing every other week 
and increase to every week injection, as clinically appropriate. 

ANC < 0.5 Discontinue RoActemra. 

 
• Low platelet count 
 
Laboratory Value 
(cells x 103/ μL) 

Action 

50 to 100 Interrupt RoActemra dosing. 

When platelet count > 100 x 103/ μL resume RoActemra dosing every other 
week and increase to every week injection as clinically appropriate. 

< 50 Discontinue RoActemra. 

 



37 

RA and GCA  
Missed dose 
If a patient misses a subcutaneous weekly injection of RoActemra 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 RoActemra 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. RoActemra has 
not been studied in patients with severe renal impairment (see section 5.2). Renal function should be 
monitored closely in these patients.  
 
Hepatic impairment:  
RoActemra has not been studied in patients with hepatic impairment. Therefore, no dose 
recommendations can be made.  
 
Paediatric patients  
The safety and efficacy of RoActemra 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.  
RoActemra 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 RoActemra 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.  
 
Dose adjustments due to laboratory abnormalities (sJIA and pJIA)  
 
If appropriate, the dose of concomitant MTX and/or other medications 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. 
 



38 

• Liver enzyme abnormalities 
 

Laboratory 
Value 

Action 

> 1 to 3 x ULN Modify the dose of the concomitant MTX if appropriate 

For persistent increases in this range, interrupt RoActemra until 
ALT/AST have normalized.  

> 3 x ULN to 5x 
ULN 

 

Modify the dose of the concomitant MTX if appropriate 

Interrupt RoActemra dosing until < 3x ULN and follow 
recommendations above for >1 to 3x ULN 

 

> 5x ULN Discontinue RoActemra.  

The decision to discontinue RoActemra in sJIA or pJIA for a 
laboratory abnormality should be based on the medical 
assessment of the individual patient. 

 
• Low absolute neutrophil count (ANC) 
 

Laboratory 
Value 
(cells x 
109/ L ) 

Action 

ANC > 1  Maintain dose 

ANC 0.5 to 
1 

Interrupt RoActemra dosing 

When ANC increases to > 1 x 109/ L resume RoActemra  

ANC < 0.5 Discontinue RoActemra 

The decision to discontinue RoActemra in sJIA or pJIA for a laboratory 
abnormality should be based on the medical assessment of the individual 
patient. 

 



39 

• Low platelet count  
 

Laboratory 
Value 

(cells x 103/µL) 

Action 

50 to 100 Modify the dose of the concomitant MTX if appropriate 

Interrupt RoActemra dosing 

When platelet count is > 100 x 103/µl resume RoActemra  

 

< 50  Discontinue RoActemra.  

The decision to discontinue RoActemra in sJIA or pJIA for a 
laboratory abnormality should be based on the medical 
assessment of the individual patient. 

 
Reduction of tocilizumab dosing frequency due to laboratory abnormalities has not been studied in 
sJIA or pJIA patients. 
 
The safety and efficacy of RoActemra subcutaneous formulation in children with conditions other than 
sJIA or pJIA have not been established.  
 
Available data with the IV formulation suggest that clinical improvement is observed within 12 weeks 
of initiation of treatment with RoActemra. Continued therapy should be carefully reconsidered in a 
patient exhibiting no improvement within this timeframe. 
 
Missed dose 
If a sJIA patient misses a subcutaneous weekly injection of RoActemra 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 2 week injection of RoActemra 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.  
 
If a pJIA patient misses a subcutaneous injection of RoActemra within 7 days of the scheduled dose, 
he/she should take the missed dose as soon as they remember and take the next dose at the regular 
scheduled time. If a patient misses a subcutaneous injection of RoActemra by more than 7 days of the 
scheduled dose or is unsure when to inject RoActemra, call the doctor or pharmacist. 
 
Method of administration 
RoActemra is for subcutaneous use.  
After proper training in injection technique, patients may self-inject with RoActemra if their physician 
determines that it is appropriate. The total content (0.9 mL) of the pre-filled syringe should be 
administered as a subcutaneous injection. The recommended injection sites (abdomen, thigh and upper 
arm) should be rotated and injections should never be given into moles, scars, or areas where the skin 
is tender, bruised, red, hard, or not intact. 
 
The pre-filled syringe should not be shaken.  
 
Comprehensive instructions for the administration of RoActemra in a pre-filled syringe are given in 
the package leaflet, see section 6.6. 
 



40 

4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Active, severe infections (see section 4.4). 
 
4.4 Special warnings and precautions for use 
 
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. 
 
Infections  
Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive 
agents including RoActemra (see section 4.8, Undesirable effects). RoActemra treatment must not be 
initiated in patients with active infections (see section 4.3). Administration of RoActemra should 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 RoActemra 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 RoActemra 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 should 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 RoActemra therapy. Patients with latent TB should be treated with 
standard anti-mycobacterial therapy before initiating RoActemra. 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 RoActemra.  
 
Viral reactivation 
Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinical 
studies with RoActemra, 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 RoActemra (see section 4.8). RoActemra 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 should be evaluated promptly for early 
identification of diverticulitis which can be associated with gastrointestinal perforation. 



41 

 
Hypersensitivity reactions 
Serious hypersensitivity reactions, including anaphylaxis have been reported in association with 
RoActemra (see section 4.8). Such reactions may be more severe, and potentially fatal in patients who 
have experienced hypersensitivity reactions during previous treatment with RoActemra even if they 
have received premedication with steroids and antihistamines. If an anaphylactic reaction or other 
serious hypersensitivity reaction occurs, administration of RoActemra should be stopped immediately, 
appropriate therapy initiated and tocilizumab should be permanently discontinued. 
 
Active hepatic disease and hepatic impairment 
Treatment with RoActemra, 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 RoActemra treatment (see section 4.8). An increased frequency of these elevations 
was observed when potentially hepatotoxic drugs (e.g. MTX) were used in combination with 
RoActemra. 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 RoActemra (see section 4.8). Serious hepatic injury occurred between 2 weeks to more 
than 5 years after initiation of RoActemra. Cases of liver failure resulting in liver transplantation have 
been reported. Patients should be advised to immediately seek medical help if they experience signs 
and symptoms of hepatic injury.  
 
Caution should be exercised when considering initiation of RoActemra treatment in patients with 
elevated ALT or AST > 1.5 x ULN. In patients with baseline ALT or AST > 5 x 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 RoActemra discontinuation, based on transaminases levels see section 4.2. For ALT or AST 
elevations > 3–5 x ULN, RoActemra 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 RoActemra, initiation is not recommended in patients with an 
ANC below 2 x 109/L. Caution should be exercised when considering initiation of RoActemra 
treatment in patients with a low platelet count (i.e. platelet count below 100 x 103/ μL). In patients who 
develop an ANC < 0.5 x 109/ L or a platelet count < 50 x 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 RoActemra 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. 
 



42 

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 RoActemra (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 
RoActemra 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 RoActemra is currently unknown. 
 
Malignancy 
The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products may 
increase the risk of malignancy. 
 
Vaccinations 
Live and live attenuated vaccines should not be given concurrently with RoActemra as clinical safety 
has not been established. In a randomized open-label study, adult RA patients treated with RoActemra 
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 
RoActemra therapy. The interval between live vaccinations and initiation of RoActemra therapy 
should be in accordance with current vaccination guidelines regarding immunosuppressive agents. 
 
Cardiovascular risk 
RA patients have an increased risk for cardiovascular disorders and should have risk factors (e.g. 
hypertension, hyperlipidaemia) managed as part of usual standard of care. 
 
Combination with TNF antagonists 
There is no experience with the use of RoActemra with TNF antagonists or other biological treatments 
for RA patients. RoActemra is not recommended for use with other biological agents.  
 
GCA 
RoActemra 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 
Macrophage activation syndrome (MAS) is a serious life-threatening disorder that may develop in 
sJIA patients. In clinical trials, RoActemra has not been studied in patients during an episode of active 
MAS.  
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction studies have only been performed in adults. 
 
Concomitant administration of a single dose of 10 mg/kg RoActemra with 10-25 mg MTX once 
weekly had no clinically significant effect on MTX exposure. 
 



43 

Population pharmacokinetic analyses did not detect any effect of MTX, non-steroidal  
anti-inflammatory drugs (NSAIDs) or corticosteroids on RoActemra  clearance in RA patients. In 
GCA patients, no effect of cumulative corticosteroid dose on RoActemra 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 RoActemra, is introduced. 
 
In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in 
CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. RoActemra normalises expression 
of these enzymes. 
 
In a study 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) should 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.  
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Women of childbearing potential must use effective contraception during and up to 3 months after 
treatment. 
 
Pregnancy  
 
There are no adequate data from the use of RoActemra in pregnant women. A study 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 breast milk. The excretion of RoActemra in 
milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or 
to continue/discontinue therapy with RoActemra should be made taking into account the benefit of 
breast-feeding to the child and the benefit of RoActemra therapy to the woman. 
 
Fertility 
 
Available non-clinical data do not suggest an effect on fertility under RoActemra treatment.  
 
4.7 Effects on ability to drive and use machines 
 
RoActemra has a minor influence on the ability to drive and use machines (see section 4.8, dizziness). 
 



44 

4.8 Undesirable effects 
 
Summary of the safety profile 
 
The safety profile comes from 4510 patients exposed to RoActemra in clinical trials; the majority of 
these patients were participating in adult RA studies (n=4009), while the remaining experience comes 
from GCA (n=149), pJIA (n=240) and sJIA (n=112) studies. The safety profile of RoActemra across 
these indications remains similar and undifferentiated. 
 
The most commonly reported Adverse Drug Reactions (ADRs) were upper respiratory tract infections, 
nasopharyngitis, headache, hypertension and increased ALT. 
 
The most serious ADRs were serious infections, complications of diverticulitis, and hypersensitivity 
reactions. 
 
Tabulated list of adverse reactions 
ADRs from clinical trials and/or post marketing experience with RoActemra based on spontaneous 
case reports, literature cases and cases from non-interventional study programs are listed in Table 1 
and are presented by MedDRA system organ class. The corresponding frequency category for each 
AR 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) or very rare (<1/10,000). Within each 
frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
 



45 

Table 1. List of ADRs occurring in patients treated with RoActemra.  
 

MedDRA 
System Organ 

Class 

Frequency categories with preferred terms 
Very Common 

  
Common 

  
Uncommon 

  
Rare 

 
Blood and 
lymphatic 
system disorders 

  Leukopenia, 
Neutropenia, 
Hypofibrinogenae
mia  

   

Endocrine 
disorders 

    Hypothyroidism  

Eye disorders   Conjunctivitis    
Gastrointestinal 
disorders 

  Abdominal pain, 
Mouth ulceration, 
Gastritis 

Stomatitis, Gastric 
ulcer 

 

General 
disorders and 
administration 
site conditions 

 Injection site 
reaction 

Peripheral oedema 
Hypersensitivity 
reaction,  

   

Hepatobiliary 
disorders 

   Drug-induced liver 
injury, Hepatitis, 
Jaundice,  
Very rare: Hepatic 
failure  

Immune system 
disorders 

   Anaphylaxis (fatal)1, 
2 ,3 

Infections and 
infestations 

Upper respiratory 
tract infections 

Cellulitis, 
Pneumonia, Oral 
herpes simplex, 
Herpes zoster 

Diverticulitis  

Investigations   Hepatic 
transaminases 
increased, Weight 
increased, Total 
bilirubin increased* 

   

Metabolism and 
nutrition 
disorders 

Hypercholesterolae
mia* 

  Hypertriglyceridae
mia 

 

Nervous system 
disorders 

  Headache, 
Dizziness 

   

Renal and 
urinary disorders 

    Nephrolithiasis  

Respiratory, 
thoracic and 
mediastinal 
disorders 

  Cough, Dyspnoea    

Skin and 
subcutaneous 
tissue disorders 

  Rash, Pruritus, 
Urticaria 

  Stevens-Johnson-
Syndrome3 

Vascular 
disorders 

  Hypertension    

* 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 TCZ in clinical trials.  

 



46 

Subcutaneous use 
RA 
The safety of subcutaneous RoActemra in RA includes a double-blind, controlled, multicenter study, 
SC-I. SC-I was a non-inferiority study that compared the efficacy and safety of RoActemra 162 mg 
administered every week versus 8 mg/kg intravenous in 1262 patients with RA. All patients received 
background non-biologic DMARD(s). The safety and immunogenicity observed for RoActemra 
administered subcutaneous was consistent with the known safety profile of intravenous RoActemra 
and no new or unexpected adverse drug 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 RoActemra 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 drug discontinuation. 
 
Immunogenicity 
In SC-I, a total of 625 patients treated with RoActemra 162mg weekly were tested for anti-RoActemra 
antibodies in the 6 month controlled period. Five patients (0.8%) developed positive anti-RoActemra 
antibodies; of these, all developed neutralizing anti-RoActemra antibodies. One patient was tested 
positive for IgE isotype (0.2%). 
 
In SC-II, a total of 434 patients treated with RoActemra 162mg every other week were tested for anti-
RoActemra antibodies in the 6 month controlled period. Seven patients (1.6%) developed positive 
antiRoActemra antibodies; of these, six (1.4%) developed neutralizing anti-RoActemra antibodies. 
Four patients were tested positive for IgE isotype (0.9%). 
 
No correlation of antibody development to clinical response or adverse events was observed. 
 
Haematological abnormalities: 
Neutrophils 
During routine laboratory monitoring in the RoActemra 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 x 109/L and the occurrence 
of serious infections. 
 
Platelets 
During routine laboratory monitoring in the RoActemra 6 month clinical trial SC-I, none of the 
patients on the SC weekly dose had a decrease in platelet count to ≤50 × 103 / μL. 
 
Hepatic transaminase elevations 
During routine laboratory monitoring in the RoActemra 6-month controlled clinical trial SC-I, 
elevation in ALT or AST ≥3 x ULN occurred in 6.5% and 1.4% of patients, respectively on the 
subcutaneous weekly dose.  
 
Lipid parameters 
During routine laboratory monitoring in the RoActemra 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.  
 



47 

sJIA (SC) 
The safety profile of subcutaneous RoActemra was evaluated in 51 paediatric patients (1 to 17 years of 
age) with sJIA. In general, the adverse drug reactions in patients with sJIA were similar in type to 
those seen in RA patients (see Undesirable Effects section above).  
 
Infections 
The rate of infection in sJIA patients treated with SC RoActemra was comparable to sJIA patients 
treated with IV RoActemra. 
 
Injection Site Reactions (ISRs)  
In the SC Study (WA28118), a total of 41.2% (21/51) sJIA patients experienced ISRs to RoActemra 
SC. 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 SC Study (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 SC Study (WA28118), neutrophil count decrease to below 1 × 109/L 
occurred in 23.5% of patients treated with RoActemra SC. Decreases in platelet counts to below 100 × 
103/μL occurred in 2% of the patients treated with RoActemra SC. An elevation in ALT or AST to ≥3 
x ULN occurred in 9.8% and 4.0% patients treated with RoActemra SC, respectively.  
 
Lipid parameters 
In the 52-week open-label SC Study (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 study treatment, respectively. 
 
pJIA (SC) 
The safety profile of subcutaneous RoActemra was also evaluated in 52 paediatric patients with pJIA. 
The total patient exposure to RoActemra in the pJIA all exposure population was 184.4 patient years 
for IV and 50.4 patient years for SC tocilizumab. In general, the safety profile observed in patients 
with pJIA was consistent with the known safety profile of RoActemra with the exception of ISRs (see 
Table 1). A higher frequency of pJIA patients experienced ISRs following SC RoActemra injections 
compared to adult RA. 
 
Infections 
In the SC RoActemra study, the rate of infection in pJIA patients treated with SC RoActemra was 
comparable with pJIA patients treated with IV RoActemra. 
 
Injection Site Reactions 
A total of 28.8% (15/52) pJIA patients experienced ISRs to RoActemra SC. 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, hematoma, 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 SC Study 5.8% [3/52] developed positive neutralizing anti-tocilizumab antibodies without 
developing a serious or clinically significant hypersensitivity reaction. Of these 3 patients, 1 
subsequently withdrew from the study. No correlation between antibody development and clinical 
response or adverse events was observed 
 



48 

Laboratory Abnormalities 
During routine laboratory monitoring in the RoActemra all exposure population, a decrease in 
neutrophil count below 1 × 109/L occurred in 15.4% of patients treated with SC RoActemra. An 
elevation in ALT or AST ≥3 x ULN occurred in 9.6% and 3.8% patients treated with RoActemra SC, 
respectively. No patients treated with SC RoActemra experienced a decrease in platelet count to ≤50 × 
103 / μL.  
 
Lipid parameters 
In the SC Study, 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 study 
treatment, respectively. 
 
GCA (SC) 
The safety of subcutaneous RoActemra has been studied in one Phase III study (WA28119) with 251 
GCA patients. The total patient years duration in the RoActemra all exposure population was 138.5 
patient years during the 12 month double blind, placebo controlled phase of the study. The overall 
safety profile observed in the RoActemra treatment groups was consistent with the known safety 
profile of RoActemra (see Table 1). 
 
Infections 
The rate of infection/serious infection events was balanced between the RoActemra 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 RoActemra 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 RoActemra subcutaneous weekly group, one patient (1.1%, 1/95) developed positive 
neutralizing anti-RoActemra antibodies, though not of the IgE isotype. This patient did not develop a 
hypersensitivity reaction or injection site reaction. 
 
Haematological abnormalities: 
Neutrophils 
During routine laboratory monitoring in the Roactemra 12 month controlled clinical trial, a decrease in 
neutrophil count below 1 × 109/L occurred in 4% of patients in the RoActemra subcutaneous weekly 
group. This was not observed in either of the placebo plus prednisone taper groups. 
 
Platelets 
During routine laboratory monitoring in the RoActemra 12 month controlled clinical trial, one patient 
(1%, 1/100) in the RoActemra 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 RoActemra 12 month controlled clinical trial, elevation in 
ALT ≥3 x ULN occurred in 3% of patients in the RoActemra 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 RoActemra 
subcutaneous weekly group, compared to no patients in either of the placebo plus prednisone taper 
groups. 
 



49 

Lipid parameters 
During routine laboratory monitoring in the RoActemra 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 RoActemra 
subcutaneous weekly group.  
 
Intravenous use 
RA 
The safety of RoActemra has been studied in 5 Phase III, double-blind controlled trials and their 
extension periods.  
 
The all control population includes all patients from the double-blind phases of each core study from 
randomization until either the first change in the treatment regimen, or two years is reached. The 
control period in 4 of the studies was 6 months and in 1 study was up to 2 years. In the double-blind 
controlled studies 774 patients received RoActemra 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 RoActemra either 
in the double-blind control period or open label extension phase in studies. Of the 4009 patients in this 
population, 3577 received treatment for at least 6 months, 3296 for at least one year; 2806 received 
treatment for at least 2 years and 1222 for 3 years. 
 
Description of selected adverse reactions 
 
Infections  
In the 6-month controlled studies the rate of all infections reported with RoActemra 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 RoActemra was 108 events per 100 patient years exposure. 
 
In 6-month controlled clinical studies, the rate of serious infections with RoActemra 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 study the rate of serious infections 
was 3.6 events per 100 patient years of exposure in the RoActemra group and 1.5 events per 
100 patient years of exposure in the MTX group.  
 
In the all exposure population the overall rate of serious infections was 4.7 events per 100 pt years. 
Reported serious infections, some with fatal outcome, included pneumonia, cellulitis, herpes zoster, 
gastroenteritis, diverticulitis, sepsis, 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 RoActemra 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 RoActemra were primarily reported as complications of diverticulitis 
including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess. 
 



50 

Infusion 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 6/3778patients, 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 RoActemra and requiring treatment discontinuation were reported in a total 
of  13 out of 3778 patients (0.3%) treated with RoActemra  during the controlled and open label 
clinical studies. 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 RoActemra (see section 4.4). 
 
Immunogenicity  
A total of 2,876 patients have been tested for anti-RoActemra antibodies in the 6-month controlled 
clinical trials. Of the 46 patients (1.6%) who developed anti-RoActemra 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.  
 
Haematological abnormalities: 
Neutrophils 
In the 6-month controlled trials decreases in neutrophil counts below 1 x 109/ L occurred in 3.4% of 
patients on RoActemra 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 x 109/ L did so within 8 
weeks after starting therapy. Decreases below 0.5 x 109/ L were reported in 0.3% patients receiving 
RoActemra 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 x 103/ μL occurred in 1.7% of 
patients on RoActemra 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 x ULN were observed in 
2.1% of patients on RoActemra  8 mg/kg compared to 4.9% of patients on MTX and in 6.5% of 
patients who received 8 mg/kg RoActemra  plus DMARDs compared to 1.5% of patients on placebo 
plus DMARDs. 
 
The addition of potentially hepatotoxic drugs (e.g. MTX) to RoActemra monotherapy resulted in 
increased frequency of these elevations. Elevations of ALT/AST > 5 x ULN were observed in 0.7% of 
RoActemra  monotherapy patients and 1.4% of RoActemra 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 RoActemra  + DMARD. A total of 



51 

5.8% of patients experienced an elevation of indirect bilirubin of > 1 to 2 x ULN and 0.4% had an 
elevation of > 2 x 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 RoActemra 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. 
 
Malignancies 
The clinical data are insufficient to assess the potential incidence of malignancy following exposure to 
RoActemra. Long-term safety evaluations are ongoing. 
 
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 authorization 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. 
 
4.9 Overdose 
 
There are limited data available on overdose with RoActemra. 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 
 
5.1 Pharmacodynamic 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.  
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


52 

Pharmacodynamic effects 
In clinical studies with RoActemra, 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 RoActemra was associated with reduction in platelet count within the normal 
range. Increases in haemoglobin levels were observed, through RoActemra decreasing the IL-6 driven 
effects on hepcidin production to increase iron availability. In RoActemra -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 study WA28119, similar rapid decreases in CRP and ESR were observed along with 
slight increases in mean corpuscular haemoglobin concentration. In healthy subjects administered 
RoActemra 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.   
 
Patients demonstrate a comparable (to healthy subjects) decrease of absolute neutrophil counts 
following RoActemra administration (see section 4.8). 
 
Subcutaneous use 
RA 
Clinical efficacy  
The efficacy of subcutaneous administered RoActemra in alleviating the signs and symptoms of RA 
and radiographic response, was assessed in two randomised, double-blind, controlled, multi-center 
studies. For study 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 study 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. 
 
Switching from 8 mg/kg intravenous once every 4 weeks to 162 mg subcutaneous once every week, 
will alter exposure in the patient. The extent varies with the patient’s body weight (increased in light 
body weight patients and decreased in heavy body weight patients) but clinical outcome is consistent 
with that observed in intravenous treated patients. 
 
Clinical response 
Study SC-I evaluated patients with moderate to severe active RA who had an inadequate clinical 
response to their existing rheumatologic therapy, including one or more DMARD(s) where 
approximately 20% had a history of inadequate response to at least one TNF inhibitor. In SC-I, 
1262 patients were randomized 1:1 to receive RoActemra subcutaneous 162 mg every week or 
RoActemra intravenous 8 mg/kg every four weeks in combination with non-biologic DMARD(s). The 
primary endpoint in the study was the difference in the proportion of patients who achieved an ACR20 
response at week 24. The results from study SC-I is shown in Table 2. 
 



53 

Table 2. ACR responses in study SC-I (% patients) at Week 24 
 
 SC-Ia 
 TCZ SC 162 mg 

every week 
+ DMARD 

N=558 

TCZ IV 8 mg/kg 
+ DMARD 

 
N=537 

ACR20 Week 24 69.4% 73.4% 
Weighted difference (95% 

CI) 
-4.0 (-9.2, 1.2) 

ACR50 Week 24 47.0% 48.6% 
Weighted difference (95% 

CI) 
-1.8 (-7.5, 4.0) 

ACR70 Week 24 24.0% 27.9% 
Weighted difference (95% 

CI) 
-3.8 (-9.0, 1.3) 

TCZ = tocilizumab 
a = Per Protocol Population 
 
Patients in study SC-I had a mean Disease Activity Score (DAS28) at baseline of 6.6 and 6.7 on the 
subcutaneous and intravenous arms, respectively. At week 24, a significant reduction in DAS28 from 
baseline (mean improvement) of 3.5 was observed on both treatment arms, and a comparable 
proportion of patients had achieved DAS28 clinical remission (DAS28 < 2.6) on the subcutaneous 
(38.4%) and IV (36.9%) arms. 
 
Radiographic response  
The radiographic response of subcutaneous administered RoActemra was assessed in a double-blind, 
controlled, multicenter study in patients with active RA (SC-II). Study SC-II evaluated patients with 
moderate to severe active RA who had an inadequate clinical response to their existing rheumatologic 
therapy, including one or more DMARD(s) where approximately 20% had a history of inadequate 
response to at least one TNF inhibitor. Patients were required to be >18 years of age with active RA 
diagnosed according to ACR criteria who had at least 8 tender and 6 swollen joints at baseline. In SC-
II, 656 patients were randomized 2:1 to RoActemra  subcutaneous 162 mg every other week or 
placebo, in combination with non-biologic DMARD(s). 
 
In study SC-II, inhibition of structural joint damage was assessed radiographically and expressed as a 
change from baseline in the van der Heijde modified mean total Sharp score (mTSS). At week 24, 
inhibition of structural damage was shown, with significantly less radiographic progression in patients 
receiving RoActemra subcutaneous compared to placebo (mean mTSS of 0.62 vs. 1.23, p=0.0149 (van 
Elteren). These results are consistent with those observed in patients treated with intravenous 
RoActemra. 
In study SC-II, at week 24 there was ACR20 of 60.9%, ACR50 of 39.8% and ACR70 of 19.7% for 
patients treated with RoActemra subcutaneous every other week versus placebo ACR20 of 31.5%, 
ACR50 of 12.3% and ACR70 of 5.0%. Patients had mean DAS28 at baseline of 6.7 on subcutaneous 
and 6.6 on placebo arms. At week 24, a significant reduction in DAS28 from baseline of 3.1 was 
observed on subcutaneous and 1.7 on placebo arm, and for DAS28 < 2.6, 32.0% was observed on 
subcutaneous and 4.0% on placebo arm. 
 
Health-related and quality of life outcomes 
In study SC-I, the mean decrease in HAQ-DI from baseline to week 24 was 0.6 on both the 
subcutaneous and intravenous arms. The proportion of patients achieving a clinically relevant 
improvement in HAQ-DI at week 24 (change from baseline of ≥ 0.3 units) was also comparable on the 
subcutaneous (65.2%) versus intravenous (67.4%) arms, with a weighted difference in proportions 
of - 2.3% (95% CI - 8.1, 3.4). For SF-36, the mean change from baseline at week 24 in the mental 
component score was 6.22 for the subcutaneous arm and 6.54 for the intravenous arm, and for the 



54 

physical component score was also similar with 9.49 for the subcutaneous arm and 9.65 for the 
intravenous arm. 
 
In study SC-II, mean decrease in HAQ-DI from baseline to week 24 was significantly greater for 
patients treated with RoActemra subcutaneous every other week (0.4) versus placebo (0.3). Proportion 
of patients achieving a clinically relevant improvement in HAQ-DI at week 24 (change from baseline 
of ≥ 0.3 units) was higher for RoActemra subcutaneous every other week (58%) versus placebo 
(46.8%). SF-36 (mean change in mental and physical component scores) was significantly greater with 
RoActemra subcutaneous group (6.5 and 5.3) versus placebo (3.8 and 2.9). 
 
sJIA (SC) 
Clinical Efficacy 
A 52-week, open-label, multi-centre, PK/PD and safety study (WA28118) was conducted in paediatric 
patients with sJIA, aged 1 to 17 years, to determine the appropriate SC dose of RoActemra that 
achieved comparable PK/PD and safety profiles to the IV regimen.  
 
Eligible patients received RoActemra dosed according to body weight (BW), with patients weighing 
≥30 kg (n=26) dosed with 162 mg of RoActemra every week (QW) and patients weighing below 
30 kg (n=25) dosed with 162 mg of RoActemra every 10 days (Q10D; n=8) or every 2 weeks (Q2W; 
n=17) for 52 weeks. Of these 51 patients, 26 (51%) were naive to RoActemra and 25 (49%) had been 
receiving RoActemra IV and switched to RoActemra SC at baseline.   
 
Exploratory efficacy results showed that RoActemra SC improved all exploratory efficacy parameters 
including Juvenile Arthritis Disease Activity Score (JADAS)-71, for TCZ naïve patients and 
maintained all exploratory efficacy parameters for patients who switched from RoActemra IV to 
RoActemra SC treatment over the entire course of the study for patients in both body weight groups 
(below 30 kg and ≥30 kg). 
 
pJIA (SC) 
A 52-week, open-label, multicenter, PK-PD and safety study was conducted in paediatric patients with 
pJIA, aged 1 to 17 years old, to determine the appropriate subcutaneous dose of RoActemra that 
achieved comparable PK/PD and safety profiles to the IV regimen. 
 
Eligible patients received tocilizumab dosed according to body weight (BW), with patients 
weighing  ≥30 kg (n = 25) dosed with 162 mg of RoActemra every 2 weeks (Q2W) and patients 
weighing below 30 kg (n = 27) dosed with 162 mg of RoActemra every 3 weeks (Q3W) for 52 weeks.  
Of these 52 patients, 37 (71%) were naive to RoActemra and 15 (29%) had been receiving RoActemra 
IV and switched to RoActemra SC at baseline.   
 
The RoActemra SC regimens of 162 mg Q3W for patients weighing below 30 kg and of 162 mg Q2W 
for patients weighing ≥ 30 kg respectively provide PK exposure and PD responses to support efficacy 
and safety outcomes similar to those achieved with the approved RoActemra IV regimens for pJIA. 
 
Exploratory efficacy results showed that RoActemra SC improved median Juvenile Arthritis Disease 
Activity Score (JADAS)-71 for RoActemra naïve patients and maintained the median JADAS-71 for 
patients who switched from IV to SC RoActemra treatment over the entire course of the study for 
patients in both body weight groups (below 30 kg and ≥ 30 kg). 
 
GCA (SC) 
Clinical efficacy 
Study WA28119 was a randomized, multi-center, double-blind placebo-controlled Phase III 
superiority study conducted to assess the efficacy and safety of RoActemra in patients with GCA.  
 
Two hundred and fifty one (251) patients with new-onset or relapsing GCA were enrolled and 
assigned to one of four treatment arms. The study consisted of a 52-week blinded period (Part 1), 
followed by a 104-week open-label extension (Part 2). The purpose of Part 2 was to describe the 
long-term safety and maintenance of efficacy after 52 weeks of RoActemra therapy, to explore the rate 



55 

of relapse and the requirement for RoActemra therapy beyond 52 weeks, and to gain insight into the 
potential long-term steroid-sparing effect of RoActemra. 
 
Two subcutaneous doses of RoActemra (162 mg every week and 162 mg every other week) were 
compared to two different placebo control groups randomised 2:1:1:1. 
 
All patients received background glucocorticoid (prednisone) therapy. Each of the RoActemra-treated 
groups and one of the placebo-treated groups followed a pre-specified prednisone-taper regimen over 
26 weeks, while the second placebo-treated group followed a pre-specified prednisone-taper regimen 
over 52 weeks, designed to be more in keeping with standard practice.  
 
The duration of glucocorticoid therapy during screening and before RoActemra (or placebo) was 
initiated, was similar in all 4 treatment groups (see Table 3). 
 
Table 3. Duration of Corticosteroid Therapy During Screening in Study WA28119  
 

 

Placebo + 26 
weeks prednisone 

taper 
N=50 

Placebo + 52 
weeks 

prednisone taper 
N=51 

RoActemra 162mg SC 
weekly + 26 weeks 
prednisone taper 

N=100 

RoActemra 162 mg SC 
every other weekly + 26 
weeks prednisone taper  

N=49 

Duration (days)                          

Mean 
(SD) 

35.7 (11.5) 36.3 (12.5) 35.6 (13.2) 37.4 (14.4) 

Median 42.0 41.0 41.0 42.0 

Min - 
Max 

6 - 63 12 – 82 1 - 87 9 - 87 

 
The primary efficacy endpoint assessed by the proportion of patients achieving steroid free sustained 
remission at week 52 on RoActemra plus 26 weeks prednisone taper compared with placebo plus 26 
weeks prednisone taper, was met (Table 4).  
 
The key secondary efficacy endpoint also based on the proportion of patients achieving sustained 
remission at week 52, comparing tocilizumab plus 26 weeks prednisone taper with placebo plus 52 
weeks prednisone taper, was also met (Table 4).   
 
A statistically significant superior treatment effect was seen in favour of RoActemra over placebo in 
achieving steroid-free sustained remission at week 52 on RoActemra plus 26 weeks prednisone taper 
compared with placebo plus 26 weeks prednisone taper and with placebo plus 52 weeks prednisone 
taper. 
 
The percentage of patients achieving sustained remission at week 52, are shown in the Table 4. 
 
Secondary Endpoints  
The assessment of the time to first GCA flare showed a significantly lower risk of flare for 
the RoActemra subcutaneous weekly group compared to placebo plus 26 weeks prednisone and 
placebo plus 52 weeks prednisone taper groups and for the RoActemra subcutaneous every other 
weekly group compared to placebo plus 26 weeks prednisone (when compared at a 0.01 significance 
level). RoActemra subcutaneous weekly dose also showed a clinically meaningful decrease in the risk 
for flare compared to placebo plus 26 weeks prednisone in patients who entered the trial with relapsing 
GCA as well as those with new-onset disease (Table 4).  
 



56 

Cumulative glucocorticoid dose  
The cumulative prednisone dose at week 52 was significantly lower in the two RoActemra dose 
groups compared to the two placebo groups (Table 4). In a separate analysis of the patients who 
received escape prednisone to treat GCA flare during the first 52 weeks, the cumulative prednisone 
dose varied greatly.  The median doses for escape patients in the RoActemra weekly and every other 
weekly groups were 3129.75 mg and 3847 mg, respectively. Both considerably lower than in the 
placebo plus 26 weeks and the placebo plus 52 weeks prednisone taper groups, 4023.5 mg and 
5389.5 mg respectively. 
 



57 

Table 4. Efficacy results from Study WA28119  
 

 

Placebo + 26 
weeks 

prednisone taper 
N=50 

Placebo + 52  
weeks 

prednisone 
taper 
N=51 

RoActemra 162mg 
SC weekly + 26 

weeks prednisone 
taper 

N=100 

RoActemra 162 mg 
SC every other 

weekly + 26 weeks 
prednisone taper  

N=49 

 Primary Endpoint 

****Sustained remission (Tocilizumab groups vs Placebo+26)                          

Responders at Week 52, n (%) 7 (14%) 9 (17.6%) 56 (56%) 26 (53.1%) 

Unadjusted difference in proportions 
(99.5% CI) 

N/A N/A 42%* 
(18.00, 66.00) 

39.06%* 
(12.46 , 65.66) 

 Key Secondary Endpoint  

Sustained remission  (Tocilizumab groups vs Placebo+52)                          

Responders at Week 52, n (%) 7 (14%) 9 (17.6%) 56 (56%) 26 (53.1%) 

Unadjusted difference in proportions 
(99.5% CI) 

N/A N/A 38.35%* 
(17.89 , 58.81) 

35.41%** 
(10.41 ,60.41) 

Other Secondary Endpoints     

Time to first GCA flare¹ (Tocilizumab groups vs 
Placebo+26) 

HR (99% CI) 
 Time to first GCA flare¹ (Tocilizumab groups vs 
Placebo+52) 
                                HR (99% CI) 
Time to first GCA flare¹ (Relapsing patients; 
Tocilizumab groups vs Placebo +26) HR (99% CI) 
Time to first GCA flare¹ (Relapsing patients; 
Tocilizumab groups vs Placebo + 52) HR (99% CI) 
Time to first GCA flare¹ (New-onset patients; 
Tocilizumab groups vs Placebo +26) HR (99% CI) 
Time to first GCA flare¹ (New-onset patients; 
Tocilizumab groups vs Placebo + 52) HR (99% CI) 

N/A 
 

N/A 
 
 

N/A 
 

N/A 
 

N/A 
 

N/A 

N/A 
 

N/A 
 
 

N/A 
 

N/A 
 

N/A 
 

N/A 

0.23* 
(0.11, 0.46) 

0.39** 
(0.18, 0.82)  

 
0.23*** 

(0.09,0.61) 
0.36 

(0.13, 1.00) 
0.25*** 

(0.09, 0.70) 
0.44 

(0.14, 1.32) 
 

0.28** 
(0.12, 0.66) 

0.48 
(0.20, 1.16)  

 
0.42 

(0.14, 1.28) 
0.67 

(0.21,2.10) 
0.20*** 

(0.05, 0.76) 
0.35 

(0.09, 1.42) 
 

Cumulative glucocorticoid dose (mg) 
median at Week 52 (Tocilizumab groups vs 
Placebo+262)                           
median at Week 52 (Tocilizumab groups vs 
Placebo +522)                          

 
3296.00 

 
N/A 

 
N/A 

 
3817.50 

 
1862.00* 

 
1862.00* 

 
1862.00* 

 
1862.00* 

 Exploratory Endpoints 

Annualized relapse rate, Week 52§ 
                
  Mean (SD) 

 
1.74  

(2.18) 

 
1.30  

(1.84) 

 
0.41 

 (0.78) 

 
0.67 

 (1.10) 
*  p<0.0001 
** p<0.005 (threshold for significance for primary and key secondary tests of superiority) 
***Descriptive p value <0.005 
****Flare: recurrence of GCA signs or symptoms and/or ESR ≥30 mm/h – Increase in the prednisone dose required 
Remission: absence of flare and normalization of the CRP 
Sustained remission: remission from week 12 to week 52 –Patients must adhere to the protocol-defined prednisone taper  
¹ analysis of the time (in days) between clinical remission and first disease flare 
2 p-values are determined using a Van Elteren analysis for non-parametric data 
§ statistical analyses has not been performed 
N/A= Not applicable 
HR = Hazard Ratio 
CI = Confidence Interval 



58 

 
Quality of Life Outcomes 
 
In study WA28119, the SF-36 results were separated into the physical and mental component 
summary scores (PCS and MCS, respectively). The PCS mean change from baseline to week 52 was 
higher (showing more improvement) in the RoActemra weekly and every other weekly dose groups 
[4.10, 2.76, respectively] than in the two placebo groups [placebo plus 26 weeks; -0.28, placebo plus 
52 weeks; -1.49], although only the comparison between RoActemra weekly plus 26 weeks 
prednisone taper group and placebo plus 52 weeks prednisone taper group (5.59, 99% CI: 8.6, 10.32) 
showed a statistically significant difference (p=0.0024).  For MCS, the mean change from baseline to 
week 52 for both RoActemra weekly and every other weekly dose groups [7.28, 6.12, respectively] 
were higher than the placebo plus 52 weeks prednisone taper group [2.84] (although the differences 
were not statistically significant [weekly p=0.0252 for weekly, p=0.1468 for every other weekly]) and 
similar to the placebo plus 26 weeks prednisone taper group [6.67].  
 
The Patient’s Global Assessment of disease activity was assessed on a 0-100mm Visual Analogue 
Scale (VAS). The mean change in Patient’s global VAS from baseline at week 52 was lower (showing 
greater improvement) in the RoActemra weekly and every other weekly dose groups [-19.0, -25.3, 
respectively] than in both placebo groups [placebo plus 26 weeks -3.4, placebo plus 52 weeks -7.2], 
although only the RoActemra every other weekly plus 26 weeks prednisone taper group showed a 
statistically significant difference compared to placebo [placebo plus 26 weeks taper p=0.0059, and 
placebo plus 52 weeks taper p=0.0081]. 
 
FACIT-Fatigue change from baseline to week 52 scores were calculated for all groups.  The mean 
[SD] change scores were as follows: RoActemra weekly plus 26 weeks 5.61 [10.115], RoActemra 
every other weekly plus 26 weeks 1.81 [8.836], placebo plus 26 weeks 0.26 [10.702], and placebo plus 
52 weeks -1.63 [6.753].  
 
Change in EQ5D scores from baseline to week 52 were RoActemra weekly plus 26 weeks 0.10 
[0.198], RoActemra every other weekly plus 26 weeks 0.05 [0.215], placebo plus 26 weeks 0.07 
[0.293], and placebo plus 52 weeks -0.02 [0.159]. 
 
Higher scores signal improvement in both FACIT-Fatigue and EQ5D. 
 
Intravenous use 
RA 
Clinical efficacy  
The efficacy of RoActemra in alleviating the signs and symptoms of RA was assessed in five 
randomised, double-blind, multi-centre studies. Studies 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 Study I, RoActemra was administered intravenously every four weeks as monotherapy. In Studies 
II, III and V, RoActemra was administered intravenously every four weeks in combination with MTX 
vs. placebo and MTX. In Study IV, RoActemra was administered intravenously every 4 weeks in 
combination with other DMARDs vs. placebo and other DMARDs. The primary endpoint for each of 
the five studies was the proportion of patients who achieved an ACR 20 response at week 24.  
 
Study I evaluated 673 patients who had not been treated with MTX within six months prior to 
randomisation and who had not discontinued previous MTX treatment as a result of clinically 
important toxic effects or lack of response. The majority (67%) of patients were MTX-naïve. Doses of 
8 mg/kg of RoActemra were given every four weeks as monotherapy. The comparator group was 
weekly MTX (dose titrated from 7.5 mg to a maximum of 20 mg weekly over an eight week period).  
 



59 

Study II, a two year study with planned analyses at week 24, week 52 and week 104, evaluated 
1196 patients who had an inadequate clinical response to MTX. Doses of 4 or 8 mg/kg of 
RoActemraor placebo were given every four weeks as blinded therapy for 52 weeks in combination 
with stable MTX (10 mg to 25 mg weekly). After week 52, all patients could receive open-label 
treatment with RoActemra 8 mg/kg. Of the patients who completed the study who were originally 
randomised to placebo + MTX, 86% received open-label RoActemra 8 mg/kg in year 2. The primary 
endpoint at week 24 was the proportion of patients who achieved an ACR 20 response. At week 52 
and week 104 the co-primary endpoints were prevention of joint damage and improvement in physical 
function. 
 
Study III evaluated 623 patients who had an inadequate clinical response to MTX. Doses of 4 or 
8 mg/kg RoActemra or placebo were given every four weeks, in combination with stable MTX (10 mg 
to 25 mg weekly).  
 
Study IV evaluated 1,220 patients who had an inadequate response to their existing rheumatologic 
therapy, including one or more DMARDs. Doses of 8 mg/kg RoActemra or placebo were given every 
four weeks in combination with stable DMARDs.  
 
Study V evaluated 499 patients who had an inadequate clinical response or were intolerant to one or 
more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomisation. 
Doses of 4 or 8 mg/kg RoActemra or placebo were given every four weeks in combination with stable 
MTX (10 mg to 25 mg weekly).  
 
Clinical response 
In all studies, patients treated with RoActemra 8 mg/kg had statistically significant higher ACR 20, 50, 
70 response rates at 6 months compared to control (Table 5). In study I, superiority of RoActemra 
8 mg/kg was demonstrated against the active comparator MTX. 
The treatment effect was similar in patients independent of rheumatoid factor status, age, gender, race, 
number of prior treatments or disease status. Time to onset was rapid (as early as week 2) and the 
magnitude of response continued to improve with duration of treatment. Continued durable responses 
were seen for over 3 years in the open label extension studies I-V.  
 
In patients treated with RoActemra 8 mg/kg, significant improvements were noted on all individual 
components of the ACR response including: tender and swollen joint counts; patients and physician 
global assessment; disability index scores; pain assessment and CRP compared to patients receiving 
placebo plus MTX or other DMARDs in all studies.  
 
Patients in studies I – V had a mean Disease Activity Score (DAS28) of 6.5–6.8 at baseline. 
Significant reduction in DAS28 from baseline (mean improvement) of 3.1–3.4 was observed in 
RoActemra-treated patients compared to control patients (1.3-2.1). The proportion of patients 
achieving a DAS28 clinical remission (DAS28 < 2.6) was significantly higher in patients receiving 
RoActemra (28–34%) compared to 1–12% of control patients at 24 weeks. In study II, 65% of patients 
achieved a DAS28 < 2.6 at week 104 compared to 48% at 52 weeks and 33% of patients at week 24. 
 
In a pooled analysis of studies II, III and IV, the proportion of patients achieving an ACR 20, 50 and 
70 response was significantly higher (59% vs. 50%, 37% vs. 27%, 18% vs. 11%, respectively) in the 
tocilizumab 8 mg/kg plus DMARD vs. the tocilizumab 4 mg/kg plus DMARD group (p< 0.03). 
Similarly the proportion of patients achieving a DAS 28 remission (DAS28 < 2.6) was significantly 
higher (31% vs. 16% respectively) in patients receiving RoActemra  8 mg/kg plus DMARD than in 
patients receiving RoActemra  4 mg/kg plus DMARD (p< 0.0001). 
 



60 

Table 5. ACR responses in placebo-/MTX-/DMARDs-controlled studies (% patients) 
 

 Study I 
AMBITION 

Study II 
LITHE 

Study III 
OPTION 

Study IV 
TOWARD 

Study V 
RADIATE 

Wee
k 

TCZ 
8 mg/k

g 

MT
X 

TCZ 
8 mg/k

g 
+ MT

X 

PBO 
+ MT

X 

TCZ 
8 mg/k

g 
+ MT

X 

PBO 
+ MT

X 

TCZ 
8 mg/kg 

+ 
DMAR

D 

PBO + 
DMAR

D 

TCZ 
8 mg/k

g 
+ MT

X 

PBO + 
MTX 

 

 N = 
286 

N = 
284 

N = 
398 

N = 
393 

N = 
205 

N = 
204 

N = 
803 

N = 
413 

N = 
170 

N = 
158 

ACR 20 
24 70%**

* 
52% 56%**

* 
27% 59%**

* 
26% 61%*** 24% 50%**

* 
10% 

52   56%**
* 

25%       

ACR 50 
24 44%** 33% 32%**

* 
10% 44%**

* 
11% 38%*** 9% 29%**

* 
4% 

52   36%**
* 

10%       

ACR 70 
24 28%** 15% 13%**

* 
2% 22%**

* 
2% 21%*** 3% 12%** 1% 

52   20%**
* 

4%       

TCZ   - Tocilizumab 
MTX  - Methotrexate 
PBO  - Placebo 
DMARD  - Disease modifying anti-rheumatic drug 
**   - p< 0.01, TCZ vs. PBO + MTX/DMARD 
***  - p< 0.0001, TCZ vs. PBO + MTX/DMARD 
 
Major clinical response 
After 2 years of treatment with RoActemra plus MTX, 14% of patients achieved a major clinical 
response (maintenance of an ACR70 response for 24 weeks or more). 
 
Radiographic response 
In Study II, in patients with an inadequate response to MTX, inhibition of structural joint damage was 
assessed radiographically and expressed as change in modified Sharp score and its components, the 
erosion score and joint space narrowing score. Inhibition of joint structural damage was shown with 
significantly less radiographic progression in patients receiving RoActemra  compared to control 
(Table 6). 
 
In the open-label extension of Study II the inhibition of progression of structural joint damage in 
RoActemra plus MTX-treated patients was maintained in the second year of treatment. The mean 
change from baseline at week 104 in total Sharp-Genant score was significantly lower for patients 
randomised to RoActemra  8 mg/kg plus MTX (p<0.0001) compared with patients who were 
randomised to placebo plus MTX. 
 



61 

Table 6. Radiographic mean changes over 52 weeks in Study II 
 
 PBO + MTX  

(+ TCZ from week 24) 
N = 393 

TCZ 8 mg/kg + MTX 
 

N = 398 
Total Sharp-Genant score 1.13 0.29* 
Erosion score 0.71 0.17* 
JSN score 0.42 0.12** 
PBO  - Placebo 
MTX  - Methotrexate 
TCZ  - Tocilizumab 
JSN  - Joint space narrowing 
*  - p≤ 0.0001, TCZ vs. PBO + MTX 
**   - p< 0.005, TCZ vs. PBO + MTX 
 
Following 1 year of treatment with RoActemra plus MTX, 85% of patients(n=348) had no progression 
of structural joint damage, as defined by a change in the Total Sharp Score of zero or less, compared 
with 67% of placebo plus MTX-treated patients(n=290) (p ≤ 0.001). This remained consistent 
following 2 years of treatment (83%; n=353). Ninety three percent (93%; n=271) of patients had no 
progression between week 52 and week 104. 
 
Health-related and quality of life outcomes 
RoActemra -treated patients reported an improvement in all patient-reported outcomes (Health 
Assessment Questionnaire Disability Index - HAQ-DI), Short Form-36 and Functional Assessment of 
Chronic Illness Therapy questionnaires. Statistically significant improvements in HAQ-DI scores were 
observed in patients treated with RoActemra compared with patients treated with DMARDs. During 
the open-label period of Study II, the improvement in physical function has been maintained for up to 
2 years. At Week 52, the mean change in HAQ-DI was -0.58 in the RoActemra 8 mg/kg plus MTX 
group compared with -0.39 in the placebo + MTX group. The mean change in HAQ-DI was 
maintained at Week 104 in the RoActemra 8 mg/kg plus MTX group (-0.61). 
 
Haemoglobin levels  
Statistically significant improvements in haemoglobin levels were observed with RoActemra 
compared with DMARDs (p< 0.0001) at week 24. Mean haemoglobin levels increased by week 2 and 
remained within normal range through to week 24.  
 
RoActemra versus adalimumab in monotherapy 
Study VI (WA19924), a 24 week double-blinded study that compared RoActemra  monotherapy with 
adalimumab monotherapy, evaluated 326 patients with RA who were intolerant of MTX or where 
continued treatment with MTX was considered inappropriate (including MTX inadequate responders). 
Patients in the RoActemra  arm received an intravenous (IV) infusion of RoActemra (8 mg/kg) every 
4 weeks (q4w) and a subcutaneous (SC) placebo injection every 2 weeks (q2w). Patients in the 
adalimumab arm received an adalimumab SC injection (40 mg) q2w plus an IV placebo infusion q4w. 
 
A statistically significant superior treatment effect was seen in favour of RoActemra over adalimumab 
in control of disease activity from baseline to week 24 for the primary endpoint of change in DAS28 
and for all secondary endpoints (Table 7). 
 



62 

Table 7: Efficacy Results for Study VI (WA19924) 
 

 

ADA + Placebo 
(IV) 

N = 162 

TCZ + Placebo 
(SC) 

N = 163 p-value(a) 
Primary Endpoint - Mean Change from baseline at Week 24 

DAS28 (adjusted mean)  -1.8 -3.3   
Difference in adjusted mean (95% 

CI) 
-1.5 (-1.8, -1.1) <0.0001 

Secondary Endpoints - Percentage of Responders at Week 24 (b) 
DAS28 < 2.6, n (%) 17 (10.5) 65 (39.9) <0.0001 
DAS28 ≤ 3.2, n (%)  32 (19.8)  84 (51.5) <0.0001 

ACR20 response, n (%) 80 (49.4) 106 (65.0) 0.0038 
ACR50 response, n (%) 45 (27.8) 77 (47.2) 0.0002 
ACR70 response, n (%) 29 (17.9) 53 (32.5) 0.0023 

ap value is adjusted for region and duration of RA for all endpoints and additionally baseline value for all continuous 
endpoints. 
b Non-responder Imputation used for missing data. Multiplicity controlled using Bonferroni-Holm Procedure 
 
The overall clinical adverse event profile was similar between RoActemra and adalimumab. The 
proportion of patients with serious adverse events was balanced between the treatment groups 
(RoActemra  11.7% vs. adalimumab 9.9%). The types of adverse drug reactions in the RoActemra arm 
were consistent with the known safety profile of RoActemra and adverse drug reactions were reported 
at a similar frequency compared with Table 1. A higher incidence of infections and infestations was 
reported in the RoActemra arm (48% vs. 42%), with no difference in the incidence of serious 
infections (3.1%). Both study treatments induced the same pattern of changes in laboratory safety 
parameters (decreases in neutrophil and platelet counts, increases in ALT, AST and lipids), however, 
the magnitude of change and the frequency of marked abnormalities was higher with RoActemra  
compared with adalimumab. Four (2.5%) patients in the RoActemra arm and two (1.2%) patients in 
the adalimumab arm experienced CTC grade 3 or 4 neutrophil count decreases. Eleven (6.8%) patients 
in the RoActemra arm and five (3.1%) patients in the adalimumab arm experienced ALT increases of 
CTC grade 2 or higher. The mean LDL increase from baseline was 0.64 mmol/L (25 mg/dL) for 
patients in the RoActemra  arm and 0.19 mmol/L (7 mg/dL) for patients in the adalimumab arm. The 
safety observed in the tocilizumab arm was consistent with the known safety profile of RoActemra and 
no new or unexpected adverse drug reactions were observed (see Table 1).  
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of RoActemra is characterized by nonlinear elimination which is a combination 
of linear clearance and Michaelis-Menten elimination.  The nonlinear part of RoActemra elimination 
leads to an increase in exposure that is more than dose-proportional.  The pharmacokinetic parameters 
of RoActemra do not change with time. Due to the dependence of total clearance on RoActemra serum 
concentrations, the half-life of RoActemra 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.  
 
RA 
Intravenous use 
The pharmacokinetics of RoActemra were determined using a population pharmacokinetic analysis on 
a database composed of 3552 RA patients treated with a one-hour infusion of 4 or 8 mg/kg RoActemra  
every 4 weeks for 24 weeks or with 162 mg tocilizumab given subcutaneously either once a week or 
every other week  for 24 weeks. 
 



63 

The following parameters (predicted mean ± SD) were estimated for a dose of 8 mg/kg RoActemra 
given every 4 weeks: steady-state area under curve (AUC) = 38000 ± 13000 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. RoActemra 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 RoActemra were 50000 ± 16800 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 RoActemra concentration 
such that clinically meaningful increases in efficacy were not demonstrated in patients treated with > 
800 mg of RoActemra. Therefore, RoActemra doses exceeding 800 mg per infusion are not 
recommended (see section 4.2). 
 
Distribution 
In RA patients the central volume of distribution was 3.72 L, the peripheral volume of distribution was 
3.35 L resulting in a volume of distribution at steady state of 7.07 L.  
 
Elimination 
Following intravenous administration, RoActemra undergoes biphasic elimination from the 
circulation. The total clearance of RoActemra was concentration-dependent and is the sum of the 
linear and non-linear clearance. The linear clearance was estimated as a parameter in the population 
pharmacokinetic analysis and was 9.5 mL/h. The concentration-dependent non-linear clearance plays a 
major role at low RoActemra concentrations. Once the non-linear clearance pathway is saturated, at 
higher RoActemra concentrations, clearance is mainly determined by the linear clearance.  
 
The t1/2 of RoActemra was concentration-dependent. At steady-state following a dose of 8 mg/kg 
every 4 weeks, the effective t1/2 decreased with decreasing concentrations within a dosing interval 
from 18 days to 6 days.  
 
Linearity 
Pharmacokinetic parameters of RoActemra did not change with time. A more than dose-proportional 
increase in the AUC and Cmin was observed for doses of 4 and 8 mg/kg every 4 weeks. Cmax increased 
dose-proportionally. At steady-state, predicted AUC and Cmin were 3.2 and 30 fold higher at 8 mg/kg 
as compared to 4 mg/kg, respectively. 
 
Subcutaneous use 
The pharmacokinetics of RoActemra were determined using a population pharmacokinetic analysis on 
a database composed of 3552 RA patients treated with 162 mg subcutaneous every week, 162 mg 
subcutaneous every other week, and or 4 or 8 mg/kg intravenous every 4 weeks for 24 weeks. 
 
The pharmacokinetic parameters of RoActemra did not change with time. For the 162 mg every week 
dose, the predicted mean (±SD) steady-state AUC1week, Cmin and Cmax of RoActemra were 
7970 ± 3432 µg•h/mL, 43.0 ± 19.8 µg/mL, and 49.8 ± 21.0 µg/mL, respectively. The accumulation 
ratios for AUC, Cmin, and Cmax were 6.32, 6.30, and 5.27, respectively. Steady state was reached after 
12 weeks for AUC, Cmin, and Cmax. 
 
For the 162 every other week dose, the predicted mean (±SD) steady-state AUC2week, Cmin, and Cmax of 
RoActemra were 3430 ± 2660 µg•h/mL, 5.7 ± 6.8 µg/mL, and 13.2 ± 8.8 µg/mL, respectively. The 
accumulation ratios for AUC, Cmin, and Cmax were 2.67, 6.02, and 2.12, respectively. Steady state was 
reached after 12 weeks for AUC and Cmin, and after 10 weeks for Cmax. 
 
Absorption 
Following subcutaneous dosing in RA patients, the time to peak serum RoActemra concentrations tmax 
was 2.8 days. The bioavailability for the subcutaneous formulation was 79%. 



64 

 
Elimination 
For subcutaneous administration, the effective t1/2 is up to 13 days for 162 mg every week and 5 days 
for 162 mg every other week in patients with RA at steady-state.  
 
sJIA 
Subcutaneous Use 
The pharmacokinetics of RoActemra in sJIA patients was characterized by a population 
pharmacokinetic analysis which included 140 patients who were treated with 8 mg/kg IV every 2 
weeks (patients weighing ≥30 kg), 12 mg/kg IV every 2 weeks (patients weighing below 30 kg), 
162 mg SC every week (patients weighing ≥30 kg), 162 mg SC every 10 days or every 2 weeks 
(patients weighing below 30 kg).  
 
Limited data are available regarding exposures following subcutaneous administration of RoActemra 
in sJIA patients below 2 years of age with a body weight less than 10 kg.  
Patients with sJIA must have a minimum body weight of 10 kg when receiving RoActemra 
subcutaneously (see section 4.2). 
 
Table 8. Predicted mean ± SD PK parameters at steady-state after SC dosing in sJIA 
 

RoActemra PK Parameter 162 mg QW ≥ 30 kg 162 mg Q2W below 30 kg 

Cmax (µg/mL) 99.8 ± 46.2 134 ± 58.6 

Cmin (µg/mL) 79.2 ± 35.6 65.9 ± 31.3 

Cmean (µg/mL) 91.3 ± 40.4 101 ± 43.2 

Accumulation Cmax 3.66 1.88 

Accumulation Cmin 4.39 3.21 

Accumulation Cmean or AUCτ* 4.28 2.27 

*τ = 1 week or 2 weeks for the two SC regimens 
 
After SC dosing, approximately 90% of the steady-state was reached by week 12 for both the 162 mg 
QW and Q2W regimens.  
 
Absorption 
Following SC dosing in sJIA patients, the absorption half-life was around 2 days, and the 
bioavailability for the SC formulation in sJIA patients was 95%.  
 
Distribution 
In paediatric patients with sJIA, the central volume of distribution was 1.87 L, the peripheral volume 
of distribution was 2.14 L resulting in a volume of distribution at steady state of 4.01 L 
 
Elimination 
The total clearance of tocilizumab was concentration-dependent and is the sum of the linear clearance 
and the nonlinear clearance. The linear clearance was estimated as a parameter in the population 
pharmacokinetic analysis and was 5.7 mL/h in paediatric patients with systemic juvenile idiopathic 
arthritis. Following subcutaneous administration, the effective t1/2 of RoActemra in sJIA patients is up 
to 14 days for both the 162 mg QW and Q2W regimens during a dosing interval at steady state.  
 
pJIA  
Subcutaneous use 
The pharmacokinetics of RoActemra in pJIA patients was characterized by a population 
pharmacokinetic analysis which included 237 patients who were treated with 8 mg/kg IV every 4 
weeks (patients weighing ≥ 30 kg), 10 mg/kg IV every 4 weeks (patients weighing below 30 kg), 
162 mg SC every 2 weeks (patients weighing   ≥ 30 kg), or 162 mg SC every 3 weeks (patients 
weighing   below 30 kg). 



65 

 
Table 9. Predicted mean ± SD PK parameters at steady-state after SC dosing in pJIA 
 
RoActemra PK Parameter 162 mg Q2W ≥ 30 kg 162 mg Q3W below 30 kg 

Cmax (µg/mL) 29.4 ± 13.5 75.5 ± 24.1 

Cmin (µg/mL) 11.8 ± 7.08 18.4 ± 12.9 

Cavg (µg/mL) 21.7 ± 10.4 45.5 ± 19.8 

Accumulation Cmax 1.72 1.32 

Accumulation Cmin 3.58 2.08 

Accumulation Cmean or AUCτ * 2.04 1.46 

*τ = 2 week or 3 week for the two SC regimens 
 
After IV dosing, approximately 90% of the steady-state was reached by Week 12 for the 10 mg/kg 
(BW < 30 kg), and by Week 16 for the 8 mg/kg (BW ≥ 30 kg) dose.  After SC dosing, approximately 
90% of the steady-state was reached by Week 12 for both the 162 mg SC Q2W and Q3W regimens. 
 
Absorption 
Following SC dosing in pJIA patients, the absorption half-life was around 2 days, and the 
bioavailability for the SC formulation in pJIA patients was 96%. 
 
Distribution 
In paediatric patients with pJIA, the central volume of distribution was 1.97 L, the peripheral volume 
of distribution was 2.03 L, resulting in a volume of distribution at steady state of 4.0 L. 
 
Elimination 
Population pharmacokinetic analysis for pJIA patients showed body size related impact on linear 
clearance so that body-weight based dosing should be taken into consideration (see Table 9).  
 
After subcutaneous administration, the effective t1/2 of RoActemra in pJIA patients is up to 10 days for 
patients < 30 kg (162 mg SC Q3W) and up to 7 days for patients >= 30 kg (162 mg SC Q2W)  during 
a dosing interval at steady state. Following intravenous administration, tocilizumab undergoes 
biphasic elimination from the circulation. The total clearance of tocilizumab was concentration-
dependent and is the sum of the linear and non-linear clearance. The linear clearance was estimated as 
a parameter in the population pharmacokinetic analysis and was 6.25 mL/h. The concentration-
dependent non-linear clearance plays a major role at low tocilizumab concentrations. Once the non-
linear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly 
determined by the linear clearance. 
 
GCA 
Subcutaneous use 
The PK of RoActemra in GCA patients were determined using a population PK model from an 
analysis dataset composed of 149 GCA patients treated with 162 mg subcutaneous every week or 
162 mg subcutaneous every other week.  The developed model had the same structure as the 
population PK model developed earlier based on data from RA patients (see Table 10). 
 



66 

Table 10. Predicted mean ± SD PK parameters at steady-state after subcutaneous dosing in GCA 
 

 
Subcutaneous 

Tocilizumab PK Parameter 162 mg every 
other weekly 

162 mg weekly 

Cmax (µg/mL) 19.3 ± 12.8 73 ± 30.4 

Cmin (µg/mL) 11.1 ± 10.3 68.1± 29.5 

Cmean (µg/mL)  16.2 ± 11.8 71.3 ± 30.1 

Accumulation Cmax 2.18  8.88 

Accumulation Cmin 5.61 9.59 

Accumulation Cmean or AUCτ * 2.81 10.91 

*τ = 2 week or 1 week for the two SC regimens 
 
The steady-state profile following the RoActemra weekly dose was almost flat, with very little 
fluctuations between trough and peak values, while there were substantial fluctuations for the 
RoActemra every other weekly dose. Approximately 90% of the steady-state (AUCτ) was reached by 
week 14 in the every other weekly and week 17 in the weekly dose groups. 
 
Based on the current characterization of PK, RoActemra trough concentration at steady state are 50% 
higher in this population relative to average concentrations in a large dataset from the RA population. 
These differences occur due to unknown reasons. PK differences are not accompanied by marked 
differences in PD parameters and so the clinical relevance is unknown.   
 
In GCA patients, higher exposure was observed in patients with lower body weight. For the 162 mg 
every week dosing regimen, the steady-state Cavg was 51% higher in patients with body weight less 
than 60 kg compared to patients weighing between 60 to 100 kg. For the 162 mg every other week 
regimen, the steady-state Cavg was 129% higher in patients with body weight less than 60 kg 
compared to patients weighing between 60 to 100 kg. There is limited data for patients above 100 kg 
(n=7). 
 
Absorption 
Following subcutaneous dosing in GCA patients, the absorption t½ was around 4 days.  The 
bioavailability for the SC formulation was 0.8. The median values of Tmax were 3 days after the 
RoActemra  weekly dose and 4.5 days after the tocilizumab every other week dose.   
 
Distribution 
In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distribution 
was 3.37 L, resulting in a volume of distribution at steady state of 7.46 L. 
 
Elimination 
The total clearance of RoActemra  was concentration-dependent and is the sum of the linear clearance 
and the nonlinear clearance. The linear clearance was estimated as a parameter in the population 
pharmacokinetic analysis and was 6.7 mL/h in GCA patients, 
 
In GCA patients, at steady state, the effective t ½ of RoActemra varied between 18.3 and 18.9 days for 
162 mg weekly regimen, and between 4.2 and 7.9 days for 162 mg every other weekly regimen. At 
high serum concentrations, when total clearance of RoActemra is dominated by linear clearance, an 
effective  t ½ of approximately 32 days was derived from the population parameter estimates. 
 
Special populations 
Renal impairment: No formal study of the effect of renal impairment on the pharmacokinetics of 
RoActemra  has been conducted. Most of the patients in the RA and GCA studies population 
pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment 



67 

(estimated creatinine clearance based on Cockcroft-Gault formula ) did not impact the 
pharmacokinetics of RoActemra. 
 
Approximately one-third of the patients in the GCA study had moderate renal impairment at baseline 
(estimated creatinine clearance of 30-59 mL/min). No impact on RoActemra exposure was noted in 
these patients. 
 
No dose adjustment is required in patients with mild or moderate renal impairment. 
 
Hepatic impairment: No formal study of the effect of hepatic impairment on the pharmacokinetics of 
RoActemra  has been conducted.  
 
Age, gender and ethnicity: Population pharmacokinetic analyses in RA and GCA patients, showed that 
age, gender and ethnic origin did not affect the pharmacokinetics of RoActemra.  
 
Results of the population PK analysis for sJIA and pJIA patients confirmed that body size is the only 
covariate which has an appreciable impact on the pharmacokinetics of RoActemra including 
elimination and absorption so that body-weight based dosing should be taken into consideration (see 
Tables 8 and 9). 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development. 
 
Carcinogenicity studies were not performed because IgG1 monoclonal antibodies are not deemed to 
have intrinsic carcinogenic potential.  
 
Available non-clinical data demonstrated the effect of IL-6 on malignant progression and apoptosis 
resistance to various cancer types. This data does not suggest a relevant risk for cancer initiation and 
progression under RoActemra treatment. Additionally, proliferative lesions were not observed in a 
6-month chronic toxicity study in cynomolgus monkeys or in IL-6 deficient mice.  
 
Available non-clinical data do not suggest an effect on fertility under RoActemra treatment. Effects on 
endocrine active and reproductive system organs were not observed in a chronic cynomolgus monkey 
toxicity study and reproductive performance was not affected in IL-6 deficient mice. RoActemra 
administered to cynomolgus monkeys during early gestation, was observed to have no direct or 
indirect harmful effect on pregnancy or embryonal-foetal development. However, a slight increase in 
abortion/embryonal-foetal death was observed with high systemic exposure (> 100 x human exposure) 
in the 50 mg/kg/day high-dose group compared to placebo and other low-dose groups. Although IL-6 
does not seem to be a critical cytokine for foetal growth or the immunological control of the 
maternal/foetal interface, a relation of this finding to RoActemra  cannot be excluded. 
 
Treatment with a murine analogue did not exert toxicity in juvenile mice. In particular, there was no 
impairment of skeletal growth, immune function and sexual maturation. 
 
The non-clinical safety profile of RoActemra  in the cynomolgus monkey does not suggest  
a difference between intravenous and subcutaneous routes of administration. 
 
 



68 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
L-Histidine 
L-Histidine monohydrochloride monohydrate 
L-Arginine hydrochloride 
L-Methionine 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatability studies, this medicinal product must not be mixed with other medicinal  
products. 
 
6.3 Shelf life 
 
24 months.  
 
Once removed from the refrigerator, RoActemra must be administered within 8 hours and should not 
be kept above 30°C. 
 
6.4 Special precautions for storage  
 
Store in a refrigerator (2°C – 8°C). Do not freeze.  
Keep the pre-filled syringe in the outer carton in order to protect from light and moisture. 
 
6.5 Nature and contents of container  
 
0.9 mL solution in a pre-filled syringe (type I glass) with a staked-in needle. The syringe is closed by a 
rigid needle shield (elastomer seal with a polypropylene shell) and a plunger stopper (butyl rubber 
with a fluororesin coating). 
 
Pack sizes of 4 pre-filled syringes and multipacks containing 12 (3 packs of 4) pre-filled syringes. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
RoActemra is supplied in a single use pre-filled syringe fitted into a needle safety device. After 
removing the pre-filled syringe from the refrigerator the pre-filled syringe should be allowed to reach 
room temperature (18°C to 28°C) by waiting for 25 to 30 minutes, before injecting RoActemra . The 
syringe should not be shaken. After removing the cap the injection  must be started within 5 minutes,  
to prevent the medicine from drying out and blocking the needle. If the pre-filled syringe is not used 
within 5 minutes of removing the cap, you must dispose of it in a puncture resistant container and use 
a new pre-filled syringe. 
If following insertion of the needle you cannot depress the plunger, you must dispose of the pre-filled 
syringe in a puncture resistant container and use a new pre-filled syringe. 
 
Do not use if the medicine is cloudy or contains particles, is any colour besides colourless to slightly 
yellowish, or any part of the pre-filled syringe appears to be damaged. 
 
Comprehensive instructions for the administration of RoActemra in a pre-filled syringe are given in 
the package leaflet. 
 



69 

Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/492/007 
EU/1/08/492/008 
 
 
9. DATE OF FIRST AUTHORISATION/DATE OF LATEST RENEWAL  
 
Date of first authorisation: 16 January 2009 
Date of last renewal: 25 September 2013 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/. 



70 

1. NAME OF THE MEDICINAL PRODUCT 
 
RoActemra 162 mg solution for injection in pre-filled pen. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled pen contains 162 mg of RoActemra (tocilizumab) in 0.9 mL. 
 
RoActemra is a recombinant humanized, anti-human monoclonal antibody of the 
immunoglobulin G1 (IgG1) sub-class directed against soluble and membrane-bound interleukin 6 
receptors. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection in pre-filled pen (ACTPen).  
 
A colourless to slightly yellowish solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
RoActemra, in combination with methotrexate (MTX), is indicated for 
 

• the treatment of severe, active and progressive rheumatoid arthritis (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. 
 
RoActemra is indicated for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in 
patients 12 years of age and older, who have responded inadequately to previous therapy with NSAIDs 
and systemic corticosteroids (see Section 4.2). 
RoActemra can be given as monotherapy (in case of intolerance to MTX or where treatment with 
MTX is inappropriate) or in combination with MTX.  
 
RoActemra in combination with methotrexate (MTX) is indicated for the treatment of juvenile 
idiopathic polyarthritis (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 
(see Section 4.2). 
RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment 
with MTX is inappropriate. 
 
RoActemra is indicated for the treatment of Giant Cell Arteritis (GCA) in adult patients. 
 



71 

4.2 Posology and method of administration 
 
Tocilizumab SC 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 should 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 should be performed under the supervision of a qualified health care professional. A 
patient or parent/guardian can inject RoActemra 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 IV therapy to SC administration should administer the first 
SC dose at the time of the next scheduled IV dose under the supervision of a qualified health care 
professional. 
 
All patients treated with RoActemra should be given the Patient Alert Card.  
 
Suitability of the patient or 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 
The recommended posology is subcutaneous 162 mg once every week. 
 
Limited information is available regarding switching patients from RoActemra intravenous 
formulation to RoActemra 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 
The recommended posology is subcutaneous 162 mg once every week in combination with a tapering 
course of glucocorticoids. RoActemra can be used alone following discontinuation of glucocorticoids. 
RoActemra monotherapy should not be used for the treatment of acute relapses (see 4.4). 
 
Based upon the chronic nature of GCA, treatment beyond 52 weeks should be guided by disease 
activity, physician discretion, and patient choice. 
 



72 

RA and GCA 
Dose adjustments due to laboratory abnormalities (see section 4.4).  
 
• Liver enzyme abnormalities 
 
Laboratory Value Action 

> 1 to 3 x Upper 
Limit of Normal 
(ULN) 

Dose modify concomitant DMARDs (RA) or immunomodulatory agents (GCA) 
if appropriate. 

For persistent increases in this range, reduce RoActemra dose frequency to 
every other week injection or interrupt RoActemra until alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) have normalised. 
 
Restart with weekly or every other week injection, as clinically appropriate. 

> 3 to 5 x ULN Interrupt RoActemra dosing until < 3 x ULN and follow recommendations 
above for > 1 to 3 x ULN. 

For persistent increases > 3 x ULN (confirmed by repeat testing, see 4.4.), 
discontinue RoActemra. 

> 5 x ULN Discontinue RoActemra. 

 
• Low absolute neutrophil count (ANC) 
 
In patients not previously treated with RoActemra, initiation is not recommended in patients with an 
absolute neutrophil count (ANC) below 2 x 109/L. 
 
Laboratory Value 
(cells x 109/ L ) 

Action 

ANC > 1  Maintain dose. 

ANC 0.5 to 1 Interrupt RoActemra dosing. 

When ANC increases > 1 x 109/ L resume RoActemra dosing every other week 
and increase to every week injection, as clinically appropriate. 

ANC < 0.5 Discontinue RoActemra. 

 
• Low platelet count 
 
Laboratory Value 
(cells x 103/ μL) 

Action 

50 to 100 Interrupt RoActemra dosing. 

When platelet count > 100 x 103/ μL resume RoActemra dosing every other 
week and increase to every week injection as clinically appropriate. 

< 50 Discontinue RoActemra. 

 



73 

RA and GCA  
Missed dose 
If a patient misses a subcutaneous weekly injection of RoActemra 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 RoActemra 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. RoActemra has 
not been studied in patients with severe renal impairment (see section 5.2). Renal function should be 
monitored closely in these patients.  
 
Hepatic impairment:  
RoActemra has not been studied in patients with hepatic impairment. Therefore, no dose 
recommendations can be made.  
 
Paediatric patients  
The safety and efficacy of RoActemra 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.  
RoActemra can be used alone or in combination with MTX. 
 
sJIA Patients 
The recommended posology in patients above 12 years of age is 162 mg subcutaneously once every 
week in patients weighing greater than or equal to 30 kg or 162 mg subcutaneously 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 RoActemra subcutaneously. 
 
pJIA Patients: 
The recommended posology in patients above 12 years of age is 162 mg subcutaneously once every 2 
weeks in patients weighing greater than or equal to 30 kg or 162 mg subcutaneously 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. 
 
Dose adjustments due to laboratory abnormalities (sJIA and pJIA)  
 
If appropriate, the dose of concomitant MTX and/or other medications 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. 
 



74 

• Liver enzyme abnormalities 
 

Laboratory 
Value 

Action 

> 1 to 3 x ULN Modify the dose of the concomitant MTX if appropriate 
 
For persistent increases in this range, interrupt RoActemra until 
ALT/AST have normalized.  

> 3 x ULN to 5x 
ULN 
 

Modify the dose of the concomitant MTX if appropriate 
 
Interrupt RoActemra dosing until < 3x ULN and follow 
recommendations above for >1 to 3x ULN 
 

> 5x ULN Discontinue RoActemra.  
 
The decision to discontinue RoActemra in sJIA or pJIA for a 
laboratory abnormality should be based on the medical 
assessment of the individual patient. 

 
• Low absolute neutrophil count (ANC) 
 

Laboratory 
Value 
(cells x 
109/ L ) 
 

Action 

ANC > 1  Maintain dose 
 

ANC 0.5 to 
1 

Interrupt RoActemra dosing 
 
When ANC increases to > 1 x 109/ L resume RoActemra  
 

ANC < 0.5 Discontinue RoActemra 
 
The decision to discontinue RoActemra in sJIA or pJIA for a laboratory 
abnormality should be based on the medical assessment of the individual 
patient. 
 

 
• Low platelet count  
 

Laboratory 
Value 
(cells x 103/µL) 

Action 

50 to 100 Modify the dose of the concomitant MTX if appropriate 
 
Interrupt RoActemra dosing 
 
When platelet count is > 100 x 103/µl resume RoActemra  
 

< 50  Discontinue RoActemra.  
 
The decision to discontinue RoActemra in sJIA or pJIA for a 
laboratory abnormality should be based on the medical 
assessment of the individual patient. 
 



75 

 
Reduction of tocilizumab dosing frequency due to laboratory abnormalities has not been studied in 
sJIA or pJIA patients. 
 
The safety and efficacy of RoActemra subcutaneous formulation in children with conditions other than 
sJIA or pJIA have not been established.  
 
Available data with the IV formulation suggest that clinical improvement is observed within 12 weeks 
of initiation of treatment with RoActemra. Continued therapy should be carefully reconsidered in a 
patient exhibiting no improvement within this timeframe. 
 
Missed dose 
If a sJIA patient misses a subcutaneous weekly injection of RoActemra 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 2 week injection of RoActemra 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.  
 
If a pJIA patient misses a subcutaneous injection of RoActemra within 7 days of the scheduled dose, 
he/she should take the missed dose as soon as they remember and take the next dose at the regular 
scheduled time. If a patient misses a subcutaneous injection of RoActemra by more than 7 days of the 
scheduled dose or is unsure when to inject RoActemra, call the doctor or pharmacist. 
 
Method of administration 
 
RoActemra is for subcutaneous use.  
After proper training in injection technique, patients may self-inject with RoActemra if their physician 
determines that it is appropriate. The total content (0.9 mL) of the pre-filled pen should be 
administered as a subcutaneous injection. The recommended injection sites (abdomen, thigh and upper 
arm) should be rotated and injections should never be given into moles, scars, or areas where the skin 
is tender, bruised, red, hard, or not intact. 
 
The pre-filled pen should not be shaken.  
 
Comprehensive instructions for the administration of RoActemra in a pre-filled pen are given in the 
package leaflet, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Active, severe infections (see section 4.4). 
 
4.4 Special warnings and precautions for use 
 
RoActemra subcutaneous formulation is not intended for intravenous administration. 
 
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. 
 
Infections  
Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive 
agents including RoActemra (see section 4.8, Undesirable effects). RoActemra treatment must not be 
initiated in patients with active infections (see section 4.3). Administration of RoActemra should 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 RoActemra in patients 



76 

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 RoActemra as signs and symptoms of acute inflammation may be 
lessened, due to suppression of the acute phase reactants. The effects of RoActemra on C-reactive 
protein (CRP), neutrophils and signs and symptoms of infection should be considered when evaluating 
a patient for a potential infection. Patients, 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 RoActemra therapy. Patients with latent TB should be treated with 
standard anti-mycobacterial therapy before initiating RoActemra. 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 RoActemra.  
 
Viral reactivation 
Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinical 
studies with RoActemra, 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 RoActemra (see section 4.8). RoActemra 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 should 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 
RoActemra (see section 4.8). Such reactions may be more severe, and potentially fatal in patients who 
have experienced hypersensitivity reactions during previous treatment with RoActemra even if they 
have received premedication with steroids and antihistamines. If an anaphylactic reaction or other 
serious hypersensitivity reaction occurs, administration of RoActemra should be stopped immediately, 
appropriate therapy initiated and RoActemra should be permanently discontinued. 
 
Active hepatic disease and hepatic impairment 
Treatment with RoActemra, 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 RoActemra treatment (see section 4.8). An increased frequency of these elevations 
was observed when potentially hepatotoxic drugs (e.g. MTX) were used in combination with 
RoActemra. When clinically indicated, other liver function tests including bilirubin should be 
considered. 
 



77 

Serious drug-induced liver injury, including acute liver failure, hepatitis and jaundice, have been 
observed with RoActemra (see section 4.8). Serious hepatic injury occurred between 2 weeks to more 
than 5 years after initiation of RoActemra. Cases of liver failure resulting in liver transplantation have 
been reported. Patients should be advised to immediately seek medical help if they experience signs 
and symptoms of hepatic injury.  
 
Caution should be exercised when considering initiation of RoActemra treatment in patients with 
elevated ALT or AST > 1.5 x ULN. In patients with baseline ALT or AST > 5 x 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 RoActemra discontinuation, based on transaminases levels see section 4.2. For ALT or AST 
elevations > 3–5 x ULN, RoActemra treatment should be interrupted.  
 
Haematological abnormalities 
Decreases in neutrophil and platelet counts have occurred following treatment with RoActemra 
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 RoActemra, initiation is not recommended in patients with an 
ANC below 2 x 109/L. Caution should be exercised when considering initiation of RoActemra 
treatment in patients with a low platelet count (i.e. platelet count below 100 x 103/ μL). In patients who 
develop an ANC < 0.5 x 109/L or a platelet count < 50 x 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 RoActemra 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 RoActemra (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 and GCA patients, assessment of lipid parameters should be performed 4 to 8 weeks following 
initiation of RoActemra 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 RoActemra is currently unknown. 
 
Malignancy 
The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products may 
increase the risk of malignancy. 
 



78 

Vaccinations 
Live and live attenuated vaccines should not be given concurrently with RoActemra as clinical safety 
has not been established. In a randomized open-label study, adult RA patients treated with RoActemra 
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 elderly patients, be brought up to date with 
all immunisations in agreement with current immunisation guidelines prior to initiating RoActemra 
therapy. The interval between live vaccinations and initiation of RoActemra therapy should be in 
accordance with current vaccination guidelines regarding immunosuppressive agents. 
 
Cardiovascular risk 
RA patients have an increased risk for cardiovascular disorders and should have risk factors (e.g. 
hypertension, hyperlipidaemia) managed as part of usual standard of care. 
 
Combination with TNF antagonists 
There is no experience with the use of RoActemra with TNF antagonists or other biological treatments 
for RA patients. RoActemra is not recommended for use with other biological agents.  
 
GCA 
RoActemra 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 
Macrophage activation syndrome (MAS) is a serious life-threatening disorder that may develop in 
sJIA patients. In clinical trials, RoActemra has not been studied in patients during an episode of active 
MAS.  
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction studies have only been performed in adults. 
 
Concomitant administration of a single dose of 10 mg/kg RoActemra 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, non-steroidal anti-
inflammatory drugs (NSAIDs) or corticosteroids on RoActemra clearance in RA patients. In GCA 
patients, no effect of cumulative corticosteroid dose on RoActemra 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 RoActemra, is introduced. 
 
In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in 
CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. RoActemra normalises expression 
of these enzymes. 
 
In a study in RA patients, levels of simvastatin (CYP3A4) were decreased by 57% one week following 
a single dose of RoActemra, to the level similar to, or slightly higher than, those observed in healthy 
subjects.  
 
When starting or stopping therapy with RoActemra, 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) should be monitored as doses may need to be increased to maintain therapeutic 



79 

effect. Given its long elimination half-life (t1/2), the effect of RoActemra on CYP450 enzyme activity 
may persist for several weeks after stopping therapy.  
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Women of childbearing potential must use effective contraception during and up to 3 months after 
treatment. 
 
Pregnancy  
 
There are no adequate data from the use of RoActemra in pregnant women. A study 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 RoActemra is excreted in human breast milk. The excretion of RoActemra in 
milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or 
to continue/discontinue therapy with RoActemra should be made taking into account the benefit of 
breast-feeding to the child and the benefit of RoActemra therapy to the woman. 
 
Fertility 
 
Available non-clinical data do not suggest an effect on fertility under RoActemra treatment.  
 
4.7 Effects on ability to drive and use machines 
 
RoActemra has a minor influence on the ability to drive and use machines (see section 4.8, dizziness). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The safety profile comes from 4510 patients exposed to RoActemra in clinical trials; the majority of 
these patients were participating in RA studies (n=4009), while the remaining experience comes from 
GCA (n=149), pJIA (n=240) and sJIA (n=112)  studies. The safety profile of RoActemra across these 
indications remains similar and undifferentiated. 
 
The most commonly reported Adverse Drug Reactions (ADRs) were upper respiratory tract infections, 
nasopharyngitis, headache, hypertension and increased ALT. 
 
The most serious ADRs were serious infections, complications of diverticulitis, and hypersensitivity  
reactions. 
 
Tabulated list of adverse reactions 
ADRs from clinical trials and/or post marketing experience with RoActemra based on spontaneous 
case reports, literature cases and cases from non-interventional study 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) or very rare (<1/10,000). Within each frequency grouping, 
undesirable effects are presented in order of decreasing seriousness. 
 



80 

Table 1. List of ADRs occurring in patients treated with RoActemra 
 

MedDRA 
System Organ 

Class  

Frequency category with preferred term 
Very Common 

  
Common 

  
Uncommon 

  
Rare 

 
Blood and 
lymphatic 
system disorders 

  Leukopenia, 
Neutropenia, 
Hypofibrinogenae
mia  

   

Endocrine 
disorders 

    Hypothyroidism  

Eye disorders   Conjunctivitis    
Gastrointestinal 
disorders 

  Abdominal pain, 
Mouth ulceration, 
Gastritis 

Stomatitis, Gastric 
ulcer 

 

General 
disorders and 
administration 
site conditions 

 Injection site 
reaction 

Peripheral oedema 
Hypersensitivity 
reaction,  

   

Hepatobiliary 
disorders 

   Drug-induced liver 
injury, Hepatitis, 
Jaundice,  
Very rare: Hepatic 
failure  

Immune system 
disorders 

   Anaphylaxis (fatal)1, 
2 ,3 

Infections and 
infestations 

Upper respiratory 
tract infections 

Cellulitis, 
Pneumonia, Oral 
herpes simplex, 
Herpes zoster 

Diverticulitis  

Investigations   Hepatic 
transaminases 
increased, Weight 
increased, Total 
bilirubin increased* 

   

Metabolism and 
nutrition 
disorders 

Hypercholesterolae
mia* 

  Hypertriglyceridae
mia 

 

Nervous system 
disorders 

  Headache, 
Dizziness 

   

Renal and 
urinary disorders 

    Nephrolithiasis  

Respiratory, 
thoracic and 
mediastinal 
disorders 

  Cough, Dyspnoea    

Skin and 
subcutaneous 
tissue disorders 

  Rash, Pruritus, 
Urticaria 

  Stevens-Johnson-
Syndrome3 

Vascular 
disorders 

  Hypertension    

* 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 TCZ in clinical trials.  

 



81 

Subcutaneous use 
RA 
The safety of subcutaneous RoActemra in RA includes a double-blind, controlled, multicenter study, 
SC-I. SC-I was a non-inferiority study that compared the efficacy and safety of RoActemra162 mg 
administered every week versus 8 mg/kg intravenous in 1262 patients with RA. All patients received 
background non-biologic DMARD(s). The safety and immunogenicity observed for RoActemra 
administered subcutaneous was consistent with the known safety profile of intravenous RoActemra 
and no new or unexpected adverse drug 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 RoActemra 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 drug discontinuation. 
 
Immunogenicity 
In SC-I, a total of 625 patients treated with RoActemra 162mg weekly were tested for anti-RoActemra 
antibodies in the 6 month controlled period. Five patients (0.8%) developed positive anti-RoActemra 
antibodies; of these, all developed neutralizing anti-RoActemra antibodies. One patient was tested 
positive for IgE isotype (0.2%). 
 
In SC-II, a total of 434 patients treated with RoActemra 162mg every other week were tested for anti-
RoActemra antibodies in the 6 month controlled period. Seven patients (1.6%) developed positive 
anti-RoActemra antibodies; of these, six (1.4%) developed neutralizing anti-RoActemra antibodies. 
Four patients were tested positive for IgE isotype (0.9%). 
 
No correlation of antibody development to clinical response or adverse events was observed. 
 
Haematological abnormalities: 
Neutrophils 
During routine laboratory monitoring in the RoActemra 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 x 109/L and the occurrence 
of serious infections. 
 
Platelets 
During routine laboratory monitoring in the RoActemra 6 month clinical trial SC-I, none of the 
patients on the SC weekly dose had a decrease in platelet count to ≤50 × 103 / μL. 
 
Hepatic transaminase elevations 
During routine laboratory monitoring in the RoActemra 6-month controlled clinical trial SC-I, 
elevation in ALT or AST ≥3 x ULN occurred in 6.5% and 1.4% of patients, respectively on the 
subcutaneous weekly dose.  
 



82 

Lipid parameters 
During routine laboratory monitoring in the RoActemra 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.  
 
Subcutaneous Use  
sJIA  
The safety profile of subcutaneous RoActemra was evaluated in 51 paediatric patients (1 to 17 years of 
age) with sJIA. In general, the adverse drug reactions in patients with sJIA were similar in type to 
those seen in RA patients (see Undesirable Effects section above).  
 
Infections 
The rate of infection in sJIA patients treated with SC RoActemra was comparable to sJIA patients 
treated with IV RoActemra. 
 
Injection Site Reactions (ISRs)  
In the SC Study (WA28118), a total of 41.2% (21/51) sJIA patients experienced ISRs to RoActemra 
SC. 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 SC Study (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 SC Study (WA28118), neutrophil count decrease to below 1 × 109/L 
occurred in 23.5% of patients treated with RoActemra SC. Decreases in platelet counts to below 100 × 
103/μL occurred in 2% of the patients treated with RoActemra SC. An elevation in ALT or AST to ≥3 
x ULN occurred in 9.8% and 4.0% patients treated with RoActemra SC, respectively.  
 
Lipid parameters 
In the 52-week open-label SC Study (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 study treatment, respectively. 
 
Subcutaneous use 
pJIA  
The safety profile of subcutaneous RoActemra was also evaluated in 52 paediatric patients with pJIA. 
The total patient exposure to RoActemra in the pJIA all exposure population was 184.4 patient years 
for IV and 50.4 patient years for SC tocilizumab. In general, the safety profile observed in patients 
with pJIA was consistent with the known safety profile of RoActemra with the exception of ISRs (see 
Table 1). A higher frequency of pJIA patients experienced ISRs following SC RoActemra injections 
compared to adult RA. 
 
Infections 
In the SC RoActemra study, the rate of infection in pJIA patients treated with SC RoActemra was 
comparable with pJIA patients treated with IV RoActemra. 
 
Injection Site Reactions 
A total of 28.8% (15/52) pJIA patients experienced ISRs to RoActemra SC. 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, hematoma, 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. 
 



83 

Immunogenicity 
In the SC Study 5.8% [3/52] developed positive neutralizing anti-tocilizumab antibodies without 
developing a serious or clinically significant hypersensitivity reaction. Of these 3 patients, 1 
subsequently withdrew from the study. No correlation between antibody development and clinical 
response or adverse events was observed 
 
Laboratory Abnormalities 
During routine laboratory monitoring in the RoActemra all exposure population, a decrease in 
neutrophil count below 1 × 109/L occurred in 15.4% of patients treated with SC RoActemra. An 
elevation in ALT or AST ≥3 x ULN occurred in 9.6% and 3.8% patients treated with RoActemra SC, 
respectively. No patients treated with SC RoActemra experienced a decrease in platelet count to ≤50 × 
103 / μL.  
 
Lipid parameters 
In the SC Study, 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 study 
treatment, respectively. 
 
Subcutaneous Use 
GCAThe safety of subcutaneous RoActemra has been studied in one Phase III study (WA28119) with 
251 GCA patients. The total patient years duration in the RoActemra all exposure population was 
138.5 patient years during the 12 month double blind, placebo controlled phase of the study. The 
overall safety profile observed in the RoActemra treatment groups was consistent with the known 
safety profile of RoActemra (see Table 1). 
 
Infections 
The rate of infection/serious infection events was balanced between the RoActemra 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 RoActemra 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 RoActemra subcutaneous weekly group, one patient (1.1%, 1/95) developed positive 
neutralizing anti-RoActemra antibodies, though not of the IgE isotype. This patient did not develop a 
hypersensitivity reaction or injection site reaction. 
 
Haematological abnormalities: 
Neutrophils 
During routine laboratory monitoring in the Roactemra 12 month controlled clinical trial, a decrease in 
neutrophil count below 1 × 109/L occurred in 4% of patients in the RoActemra subcutaneous weekly 
group. This was not observed in either of the placebo plus prednisone taper groups. 
 
Platelets 
During routine laboratory monitoring in the RoActemra 12 month controlled clinical trial, one patient 
(1%, 1/100) in the RoActemra 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. 
 



84 

Hepatic transaminase elevations 
During routine laboratory monitoring in the RoActemra 12 month controlled clinical trial, elevation in 
ALT ≥3 x ULN occurred in 3% of patients in the RoActemra 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 RoActemra 
subcutaneous weekly group, compared to no patients in either of the placebo plus prednisone taper 
groups. 
 
Lipid parameters 
During routine laboratory monitoring in the RoActemra 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 RoActemra 
subcutaneous weekly group.  
 
Intravenous use 
RA 
The safety of RoActemra has been studied in 4 placebo-controlled studies (studies II, III, IV and V), 1 
MTX-controlled study (study I) and their extension periods (see section 5.1).  
 
The double-blind controlled period was 6 months in four studies (studies I, III, IV and V) and was up 
to 2 years in one study (study II). In the double-blind controlled studies, 774 patients received 
RoActemra 4 mg/kg in combination with MTX, 1870 patients received RoActemra 8 mg/kg in 
combination with MTX or other DMARDs and 288 patients received RoActemra 8 mg/kg 
monotherapy.  
 
The long-term exposure population includes all patients who received at least one dose of RoActemra 
either in the double-blind control period or open label extension phase in the studies. Of the 4009 
patients in this population, 3577 received treatment for at least 6 months, 3296 for at least one year, 
2806 received treatment for at least 2 years and 1222 for 3 years. 
 
Description of selected adverse reactions 
 
Infections  
In the 6-month controlled studies the rate of all infections reported with RoActemra8 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 RoActemra was 108 events per 100 patient years exposure. 
 
In 6-month controlled clinical studies, the rate of serious infections with RoActemra8 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 study the rate of serious infections 
was 3.6 events per 100 patient years of exposure in the RoActemra 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. 
 



85 

Gastrointestinal perforation 
During the 6-month controlled clinical trials, the overall rate of gastrointestinal perforation was 
0.26 events per 100 patient years with RoActemra 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 RoActemrawere primarily reported as complications of diverticulitis 
including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess. 
 
Infusion 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 RoActemra 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 RoActemra and requiring treatment discontinuation were reported in a total 
of 56 out of 4,009 patients (1.4%) treated with RoActemra during the controlled and open label 
clinical studies. These reactions were generally observed during the second to fifth infusions of 
RoActemra (see section 4.4). Fatal anaphylaxis has been reported after marketing authorisation during 
treatment with intravenous RoActemra (see section 4.4). 
 
Immunogenicity  
A total of 2,876 patients have been tested for anti-RoActemra antibodies in the 6-month controlled 
clinical trials. Of the 46 patients (1.6%) who developed anti-RoActemra 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.  
 
Haematological abnormalities: 
Neutrophils 
In the 6-month controlled trials decreases in neutrophil counts below 1 x 109/ L occurred in 3.4% of 
patients on RoActemra 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 x 109/ L did so within 8 
weeks after starting therapy. Decreases below 0.5 x 109/ L were reported in 0.3% patients receiving 
RoActemra8 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 x 103/ μL occurred in 1.7% of 
patients on RoActemra 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 x ULN were observed in 
2.1% of patients on RoActemra 8 mg/kg compared to 4.9% of patients on MTX and in 6.5% of 
patients who received 8 mg/kg RoActemra plus DMARDs compared to 1.5% of patients on placebo 
plus DMARDs. 
 



86 

The addition of potentially hepatotoxic drugs (e.g. MTX) to RoActemra monotherapy resulted in 
increased frequency of these elevations. Elevations of ALT/AST > 5 x ULN were observed in 0.7% of 
RoActemra monotherapy patients and 1.4% of RoActemra plus DMARD patients, the majority of 
whom were discontinued permanently from RoActemra 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 RoActemra+ DMARD. A total of 5.8% 
of patients experienced an elevation of indirect bilirubin of > 1 to 2 x ULN and 0.4% had an elevation 
of > 2 x 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 RoActemra 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. 
 
Malignancies 
The clinical data are insufficient to assess the potential incidence of malignancy following exposure to 
RoActemra. Long-term safety evaluations are ongoing. 
 
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 authorization 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. 
 
4.9 Overdose 
 
There are limited data available on overdose with RoActemra. 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 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunosupressants, Interleukin inhibitors; ATC code: L04AC07. 
 
Mechanism of action 
RoActemra binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and 
mIL-6R). RoActemra 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, 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


87 

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 studies with RoActemra, 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 RoActemra was associated with reduction in platelet count within the normal 
range. Increases in haemoglobin levels were observed, through RoActemra decreasing the IL-6 driven 
effects on hepcidin production to increase iron availability. In RoActemra-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 study WA28119, similar rapid decreases in CRP and ESR were observed along with 
slight increases in mean corpuscular haemoglobin concentration. In healthy subjects administered 
RoActemra 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 
RoActemra administration (see section 4.8). 
 
Subcutaneous use 
RA 
Clinical efficacy  
The efficacy of subcutaneous administered RoActemra in alleviating the signs and symptoms of RA 
and radiographic response, was assessed in two randomised, double-blind, controlled, multi-center 
studies. For study 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 study 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. 
 
Switching from 8 mg/kg intravenous once every 4 weeks to 162 mg subcutaneous once every week, 
will alter exposure in the patient. The extent varies with the patient’s body weight (increased in light 
body weight patients and decreased in heavy body weight patients) but clinical outcome is consistent 
with that observed in intravenous treated patients. 
 
Clinical response 
Study SC-I evaluated patients with moderate to severe active RA who had an inadequate clinical 
response to their existing rheumatologic therapy, including one or more DMARD(s) where 
approximately 20% had a history of inadequate response to at least one TNF inhibitor. In SC-I, 
1262 patients were randomized 1:1 to receive RoActemra subcutaneous 162 mg every week or 
RoActemra intravenous 8 mg/kg every four weeks in combination with non-biologic DMARD(s). The 
primary endpoint in the study was the difference in the proportion of patients who achieved an ACR20 
response at week 24. The results from study SC-I is shown in Table 2. 
 



88 

Table 2. ACR responses in study SC-I (% patients) at Week 24 
 
 SC-Ia 
 TCZ SC 162 mg 

every week 
+ DMARD 

N=558 

TCZ IV 8 mg/kg 
+ DMARD 

 
N=537 

ACR20 Week 24 69.4% 73.4% 
Weighted difference (95% 

CI) 
-4.0 (-9.2, 1.2) 

ACR50 Week 24 47.0% 48.6% 
Weighted difference (95% 

CI) 
-1.8 (-7.5, 4.0) 

ACR70 Week 24 24.0% 27.9% 
Weighted difference (95% 

CI) 
-3.8 (-9.0, 1.3) 

TCZ = tocilizumab 
a = Per Protocol Population 
 
Patients in study SC-I had a mean Disease Activity Score (DAS28) at baseline of 6.6 and 6.7 on the 
subcutaneous and intravenous arms, respectively. At week 24, a significant reduction in DAS28 from 
baseline (mean improvement) of 3.5 was observed on both treatment arms, and a comparable 
proportion of patients had achieved DAS28 clinical remission (DAS28 < 2.6) on the subcutaneous 
(38.4%) and IV (36.9%) arms. 
 
Radiographic response  
The radiographic response of subcutaneous administered RoActemra was assessed in a double-blind, 
controlled, multicenter study in patients with active RA (SC-II). Study SC-II evaluated patients with 
moderate to severe active RA who had an inadequate clinical response to their existing rheumatologic 
therapy, including one or more DMARD(s) where approximately 20% had a history of inadequate 
response to at least one TNF inhibitor. Patients were required to be >18 years of age with active RA 
diagnosed according to ACR criteria who had at least 8 tender and 6 swollen joints at baseline. In SC-
II, 656 patients were randomized 2:1 to RoActemra subcutaneous 162 mg every other week or 
placebo, in combination with non-biologic DMARD(s). 
 
In study SC-II, inhibition of structural joint damage was assessed radiographically and expressed as a 
change from baseline in the van der Heijde modified mean total Sharp score (mTSS). At week 24, 
inhibition of structural damage was shown, with significantly less radiographic progression in patients 
receiving RoActemra subcutaneous compared to placebo (mean mTSS of 0.62 vs. 1.23, p=0.0149 (van 
Elteren). These results are consistent with those observed in patients treated with intravenous 
RoActemra. 
 
In study SC-II, at week 24 there was ACR20 of 60.9%, ACR50 of 39.8% and ACR70 of 19.7% for 
patients treated with RoActemra subcutaneous every other week versus placebo ACR20 of 31.5%, 
ACR50 of 12.3% and ACR70 of 5.0%. Patients had mean DAS28 at baseline of 6.7 on subcutaneous 
and 6.6 on placebo arms. At week 24, a significant reduction in DAS28 from baseline of 3.1 was 
observed on subcutaneous and 1.7 on placebo arm, and for DAS28 < 2.6, 32.0% was observed on 
subcutaneous and 4.0% on placebo arm. 
 
Health-related and quality of life outcomes 
In study SC-I, the mean decrease in HAQ-DI from baseline to week 24 was 0.6 on both the 
subcutaneous and intravenous arms. The proportion of patients achieving a clinically relevant 
improvement in HAQ-DI at week 24 (change from baseline of ≥ 0.3 units) was also comparable on the 
subcutaneous (65.2%) versus intravenous (67.4%) arms, with a weighted difference in proportions 
of - 2.3% (95% CI - 8.1, 3.4). For SF-36, the mean change from baseline at week 24 in the mental 



89 

component score was 6.22 for the subcutaneous arm and 6.54 for the intravenous arm, and for the 
physical component score was also similar with 9.49 for the subcutaneous arm and 9.65 for the 
intravenous arm. 
 
In study SC-II, mean decrease in HAQ-DI from baseline to week 24 was significantly greater for 
patients treated with RoActemra subcutaneous every other week (0.4) versus placebo (0.3). Proportion 
of patients achieving a clinically relevant improvement in HAQ-DI at week 24 (change from baseline 
of ≥ 0.3 units) was higher for RoActemra subcutaneous every other week (58%) versus placebo 
(46.8%). SF-36 (mean change in mental and physical component scores) was significantly greater with 
RoActemra subcutaneous group (6.5 and 5.3) versus placebo (3.8 and 2.9). 
 
Subcutaneous Use 
sJIA 
Clinical Efficacy 
A 52-week, open-label, multi-centre, PK/PD and safety study (WA28118) was conducted in paediatric 
patients with sJIA, aged 1 to 17 years, to determine the appropriate SC dose of RoActemra that 
achieved comparable PK/PD and safety profiles to the IV regimen.  
 
Eligible patients received RoActemra dosed according to body weight (BW), with patients weighing 
≥30 kg (n=26) dosed with 162 mg of RoActemra every week (QW) and patients weighing below 
30 kg (n=25) dosed with 162 mg of RoActemra every 10 days (Q10D; n=8) or every 2 weeks (Q2W; 
n=17) for 52 weeks. Of these 51 patients, 26 (51%) were naive to RoActemra and 25 (49%) had been 
receiving RoActemra IV and switched to RoActemra SC at baseline.   
 
Exploratory efficacy results showed that RoActemra SC improved all exploratory efficacy parameters 
including Juvenile Arthritis Disease Activity Score (JADAS)-71, for TCZ naïve patients and 
maintained all exploratory efficacy parameters for patients who switched from RoActemra IV to 
RoActemra SC treatment over the entire course of the study for patients in both body weight groups 
(below 30 kg and ≥30 kg). 
 
Subcutaneous Use 
pJIA  
Clinical Efficacy 
A 52-week, open-label, multicenter, PK-PD and safety study was conducted in paediatric patients with 
pJIA, aged 1 to 17 years old, to determine the appropriate subcutaneous dose of RoActemra that 
achieved comparable PK/PD and safety profiles to the IV regimen. 
 
Eligible patients received tocilizumab dosed according to body weight (BW), with patients 
weighing  ≥30 kg (n = 25) dosed with 162 mg of RoActemra every 2 weeks (Q2W) and patients 
weighing below 30 kg (n = 27) dosed with 162 mg of RoActemra every 3 weeks (Q3W) for 52 weeks.  
Of these 52 patients, 37 (71%) were naive to RoActemra and 15 (29%) had been receiving RoActemra 
IV and switched to RoActemra SC at baseline.   
 
The RoActemra SC regimens of 162 mg Q3W for patients weighing below 30 kg and of 162 mg Q2W 
for patients weighing ≥ 30 kg respectively provide PK exposure and PD responses to support efficacy 
and safety outcomes similar to those achieved with the approved RoActemra IV regimens for pJIA. 
 
Exploratory efficacy results showed that RoActemra SC improved median Juvenile Arthritis Disease 
Activity Score (JADAS)-71 for RoActemra naïve patients and maintained the median JADAS-71 for 
patients who switched from IV to SC RoActemra treatment over the entire course of the study for 
patients in both body weight groups (below 30 kg and ≥ 30 kg). 
 
Subcutaneous Use 
GCA  
Clinical efficacy 
Study WA28119 was a randomized, multi-center, double-blind placebo-controlled Phase III 
superiority study conducted to assess the efficacy and safety of RoActemra in patients with GCA.  



90 

 
Two hundred and fifty one (251) patients with new-onset or relapsing GCA were enrolled and 
assigned to one of four treatment arms. The study consisted of a 52-week blinded period (Part 1), 
followed by a 104-week open-label extension (Part 2). The purpose of Part 2 was  to describe the 
long-term safety and maintenance of efficacy after 52 weeks of RoActemra therapy, to explore the rate 
of relapse and the requirement for RoActemra therapy beyond 52 weeks, and to gain insight into the 
potential long-term steroid-sparing effect of RoActemra. 
 
Two subcutaneous doses of RoActemra (162 mg every week and 162 mg every other week) were 
compared to two different placebo control groups randomised 2:1:1:1. 
 
All patients received background glucocorticoid (prednisone) therapy. Each of the RoActemra-treated 
groups and one of the placebo-treated groups followed a pre-specified prednisone-taper regimen over 
26 weeks, while the second placebo-treated group followed a pre-specified prednisone-taper regimen 
over 52 weeks, designed to be more in keeping with standard practice.  
 
The duration of glucocorticoid therapy during screening and before RoActemra (or placebo) was 
initiated, was similar in all 4 treatment groups (see Table 3). 
 
Table 3. Duration of Corticosteroid Therapy During Screening in Study WA28119  
 

 

Placebo + 26 weeks 
prednisone taper 

N=50 

Placebo + 52 weeks 
prednisone taper 

N=51 

RoActemra 162mg SC 
weekly + 26 weeks 
prednisone taper 

N=100 

RoActemra 162 mg SC every 
other weekly + 26 weeks 

prednisone taper  
N=49 

Duration (days)                          

Mean 
(SD) 

35.7 (11.5) 36.3 (12.5) 35.6 (13.2) 37.4 (14.4) 

Median 42.0 41.0 41.0 42.0 

Min - 
Max 

6 - 63 12 – 82 1 - 87 9 - 87 

The primary efficacy endpoint assessed by the proportion of patients achieving steroid free  sustained 
remission at week 52 on RoActemra plus 26 weeks prednisone taper compared with placebo plus 26 
weeks prednisone taper, was met (Table 4).  
 
The key secondary efficacy endpoint also based on the proportion of patients achieving sustained 
remission at week 52, comparing tocilizumab plus 26 weeks prednisone taper with placebo plus 52 
weeks prednisone taper, was also met (Table 4).   
 
A statistically significant superior treatment effect was seen in favour of RoActemra over placebo in 
achieving steroid-free sustained remission at week 52 on RoActemra plus 26 weeks prednisone taper 
compared with placebo plus 26 weeks prednisone taper and with placebo plus 52 weeks prednisone 
taper. 
 
The percentage of patients achieving sustained remission at week 52, are shown in the Table 4. 
 
Secondary Endpoints  
The assessment of the time to first GCA flare showed a significantly lower risk of flare for 
the RoActemra subcutaneous weekly group compared to placebo plus 26 weeks prednisone and 
placebo plus 52 weeks prednisone taper groups and for the RoActemra subcutaneous every other 
weekly group compared to placebo plus 26 weeks prednisone (when compared at a 0.01 significance 
level). RoActemra subcutaneous weekly dose also showed a clinically meaningful decrease in the risk 
for flare compared to placebo plus 26 weeks prednisone in patients who entered the trial with relapsing 
GCA as well as those with new-onset disease (Table 4).   
 



91 

Cumulative glucocorticoid dose  
The cumulative prednisone dose at week 52 was significantly lower in the two RoActemra dose 
groups compared to the two placebo groups (Table 4). In a separate analysis of the patients who 
received escape prednisone to treat GCA flare during the first 52 weeks, the cumulative prednisone 
dose varied greatly.  The median doses for escape patients in the RoActemra weekly and every other 
weekly groups were 3129.75 mg and 3847 mg, respectively. Both considerably lower than in the 
placebo plus 26 weeks and the placebo plus 52 weeks prednisone taper groups, 4023.5 mg and 
5389.5 mg respectively. 
 



92 

Table 4. Efficacy results from Study WA28119  
 

 

Placebo + 26 
weeks 

prednisone taper 
N=50 

Placebo + 52  
weeks 

prednisone 
taper 
N=51 

RoActemra 162mg 
SC weekly + 26 

weeks prednisone 
taper 

N=100 

RoActemra 162 mg 
SC every other 

weekly + 26 weeks 
prednisone taper  

N=49 

 Primary Endpoint 

****Sustained remission (Tocilizumab groups vs Placebo+26)                          

Responders at Week 52, n (%) 7 (14%) 9 (17.6%) 56 (56%) 26 (53.1%) 

Unadjusted difference in proportions 
(99.5% CI) 

N/A N/A 42%* 
(18.00, 66.00) 

39.06%* 
(12.46 , 65.66) 

 Key Secondary Endpoint  

Sustained remission  (Tocilizumab groups vs Placebo+52)                          

Responders at Week 52, n (%) 7 (14%) 9 (17.6%) 56 (56%) 26 (53.1%) 

Unadjusted difference in proportions 
(99.5% CI) 

N/A N/A 38.35%* 
(17.89 , 58.81) 

35.41%** 
(10.41 ,60.41) 

Other Secondary Endpoints     

Time to first GCA flare¹ (Tocilizumab groups vs 
Placebo+26) 

HR (99% CI) 
 Time to first GCA flare¹ (Tocilizumab groups vs 
Placebo+52) 
                                HR (99% CI) 
Time to first GCA flare¹ (Relapsing patients; 
Tocilizumab groups vs Placebo +26) HR (99% CI) 
Time to first GCA flare¹ (Relapsing patients; 
Tocilizumab groups vs Placebo + 52) HR (99% CI) 
Time to first GCA flare¹ (New-onset patients; 
Tocilizumab groups vs Placebo +26) HR (99% CI) 
Time to first GCA flare¹ (New-onset patients; 
Tocilizumab groups vs Placebo + 52) HR (99% CI) 

N/A 
 

N/A 
 
 

N/A 
 

N/A 
 

N/A 
 

N/A 

N/A 
 

N/A 
 
 

N/A 
 

N/A 
 

N/A 
 

N/A 

0.23* 
(0.11, 0.46) 

0.39** 
(0.18, 0.82)  

 
0.23*** 

(0.09,0.61) 
0.36 

(0.13, 1.00) 
0.25*** 

(0.09, 0.70) 
0.44 

(0.14, 1.32) 
 

0.28** 
(0.12, 0.66) 

0.48 
(0.20, 1.16)  

 
0.42 

(0.14, 1.28) 
0.67 

(0.21,2.10) 
0.20*** 

(0.05, 0.76) 
0.35 

(0.09, 1.42) 
 

Cumulative glucocorticoid dose (mg) 
median at Week 52 (Tocilizumab groups vs 
Placebo+262)                           
median at Week 52 (Tocilizumab groups vs 
Placebo +522)                          

 
3296.00 

 
N/A 

 
N/A 

 
3817.50 

 
1862.00* 

 
1862.00* 

 
1862.00* 

 
1862.00* 

 Exploratory Endpoints 

Annualized relapse rate, Week 52§ 
                
  Mean (SD) 

 
1.74  

(2.18) 

 
1.30  

(1.84) 

 
0.41 

 (0.78) 

 
0.67 

 (1.10) 
*  p<0.0001 
** p<0.005 (threshold for significance for primary and key secondary tests of superiority) 
***Descriptive p value <0.005 
****Flare: recurrence of GCA signs or symptoms and/or ESR ≥30 mm/h – Increase in the prednisone dose required 
Remission: absence of flare and normalization of the CRP 
Sustained remission: remission from week 12 to week 52 –Patients must adhere to the protocol-defined prednisone taper  
¹ analysis of the time (in days) between clinical remission and first disease flare 
2 p-values are determined using a Van Elteren analysis for non-parametric data 
§ statistical analyses has not been performed 
N/A= Not applicable 
HR = Hazard Ratio 
CI = Confidence Interval 



93 

 
Quality of Life Outcomes 
 
In study WA28119, the SF-36 results were separated into the physical and mental component 
summary scores (PCS and MCS, respectively). The PCS mean change from baseline to week 52 was 
higher (showing more improvement) in the RoActemra weekly and every other weekly dose groups 
[4.10, 2.76, respectively] than in the two placebo groups [placebo plus 26 weeks; -0.28, placebo plus 
52 weeks; -1.49], although only the comparison between RoActemra weekly plus 26 weeks 
prednisone taper group and placebo plus 52 weeks prednisone taper group (5.59, 99% CI: 8.6, 10.32) 
showed a statistically significant difference (p=0.0024).  For MCS, the mean change from baseline to 
week 52 for both RoActemra weekly and every other weekly dose groups [7.28, 6.12, respectively] 
were higher than the placebo plus 52 weeks prednisone taper group [2.84] (although the differences 
were not statistically significant [weekly p=0.0252 for weekly, p=0.1468 for every other weekly]) and 
similar to the placebo plus 26 weeks prednisone taper group [6.67].  
 
The Patient’s Global Assessment of disease activity was assessed on a 0-100mm Visual Analogue 
Scale (VAS). The mean change in Patient’s global VAS from baseline at week 52 was lower (showing 
greater improvement) in the RoActemra weekly and every other weekly dose groups [-19.0, -25.3, 
respectively] than in both placebo  groups [placebo plus 26 weeks -3.4, placebo plus 52 weeks -7.2], 
although only the RoActemra every other weekly plus 26 weeks prednisone taper group showed a 
statistically significant difference compared to placebo [placebo plus 26 weeks taper p=0.0059, and 
placebo plus 52 weeks taper p=0.0081]. 
 
FACIT-Fatigue change from baseline to week 52 scores were calculated for all groups.  The mean 
[SD] change scores were as follows: RoActemra weekly plus 26 weeks 5.61 [10.115], RoActemra 
every other weekly plus 26 weeks 1.81 [8.836], placebo plus 26 weeks 0.26 [10.702], and placebo plus 
52 weeks -1.63 [6.753].  
 
Change in EQ5D scores from baseline to week 52 were RoActemra weekly plus 26 weeks 0.10 
[0.198], RoActemra every other weekly plus 26 weeks 0.05 [0.215], placebo plus 26 weeks 0.07 
[0.293], and placebo plus 52 weeks -0.02 [0.159]. 
 
Higher scores signal improvement in both FACIT-Fatigue and EQ5D. 
 
Intravenous use 
RA 
Clinical efficacy  
The efficacy of RoActemra in alleviating the signs and symptoms of RA was assessed in five 
randomised, double-blind, multi-centre studies. Studies 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 Study I, RoActemra was administered intravenously every four weeks as monotherapy. In Studies 
II, III and V, RoActemra was administered intravenously every four weeks in combination with MTX 
vs. placebo and MTX. In Study IV, RoActemra was administered intravenously every 4 weeks in 
combination with other DMARDs vs. placebo and other DMARDs. The primary endpoint for each of 
the five studies was the proportion of patients who achieved an ACR 20 response at week 24.  
 
Study I evaluated 673 patients who had not been treated with MTX within six months prior to 
randomisation and who had not discontinued previous MTX treatment as a result of clinically 
important toxic effects or lack of response. The majority (67%) of patients were MTX-naïve. Doses of 
8 mg/kg of RoActemra were given every four weeks as monotherapy. The comparator group was 
weekly MTX (dose titrated from 7.5 mg to a maximum of 20 mg weekly over an eight week period).  
 



94 

Study II, a two year study with planned analyses at week 24, week 52 and week 104, evaluated 
1196 patients who had an inadequate clinical response to MTX. Doses of 4 or 8 mg/kg of RoActemra 
or placebo were given every four weeks as blinded therapy for 52 weeks in combination with stable 
MTX (10 mg to 25 mg weekly). After week 52, all patients could receive open-label treatment with 
RoActemra 8 mg/kg. Of the patients who completed the study who were originally randomised to 
placebo + MTX, 86% received open-label RoActemra 8 mg/kg in year 2. The primary endpoint at 
week 24 was the proportion of patients who achieved an ACR 20 response. At week 52 and week 104 
the co-primary endpoints were prevention of joint damage and improvement in physical function. 
 
Study III evaluated 623 patients who had an inadequate clinical response to MTX. Doses of 4 or 
8 mg/kg RoActemra or placebo were given every four weeks, in combination with stable MTX (10 mg 
to 25 mg weekly).  
 
Study IV evaluated 1,220 patients who had an inadequate response to their existing rheumatologic 
therapy, including one or more DMARDs. Doses of 8 mg/kg RoActemra or placebo were given every 
four weeks in combination with stable DMARDs.  
 
Study V evaluated 499 patients who had an inadequate clinical response or were intolerant to one or 
more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomisation. 
Doses of 4 or 8 mg/kg RoActemra or placebo were given every four weeks in combination with stable 
MTX (10 mg to 25 mg weekly).  
 
Clinical response 
In all studies, patients treated with RoActemra 8 mg/kg had statistically significant higher ACR 20, 50, 
70 response rates at 6 months compared to control (Table 5). In study I, superiority of RoActemra 
8 mg/kg was demonstrated against the active comparator MTX. 
 
The treatment effect was similar in patients independent of rheumatoid factor status, age, gender, race, 
number of prior treatments or disease status. Time to onset was rapid (as early as week 2) and the 
magnitude of response continued to improve with duration of treatment. Continued durable responses 
were seen for over 3 years in the ongoing open label extension studies I-V.  
 
In patients treated with RoActemra 8 mg/kg, significant improvements were noted on all individual 
components of the ACR response including: tender and swollen joint counts; patients and physician 
global assessment; disability index scores; pain assessment and CRP compared to patients receiving 
placebo plus MTX or other DMARDs in all studies.  
 
Patients in studies I – V had a mean Disease Activity Score (DAS28) of 6.5–6.8 at baseline. 
Significant reduction in DAS28 from baseline (mean improvement) of 3.1–3.4 were observed in 
RoActemra-treated patients compared to control patients (1.3-2.1). The proportion of patients 
achieving a DAS28 clinical remission (DAS28 < 2.6) was significantly higher in patients receiving 
RoActemra (28–34%) compared to 1–12% of control patients at 24 weeks. In study II, 65% of patients 
achieved a DAS28 < 2.6 at week 104 compared to 48% at 52 weeks and 33% of patients at week 24. 
 
In a pooled analysis of studies II, III and IV, the proportion of patients achieving an ACR 20, 50 and 
70 response was significantly higher (59% vs. 50%, 37% vs. 27%, 18% vs. 11%, respectively) in the 
RoActemra 8 mg/kg plus DMARD vs. the RoActemra 4 mg/kg plus DMARD group (p< 0.03). 
Similarly the proportion of patients achieving a DAS 28 remission (DAS28 < 2.6) was significantly 
higher (31% vs. 16% respectively) in patients receiving RoActemra 8 mg/kg plus DMARD than in 
patients receiving RoActemra 4 mg/kg plus DMARD (p< 0.0001). 
 



95 

Table 5. ACR responses in placebo-/MTX-/DMARDs-controlled studies (% patients) 
 

 Study I 
AMBITION 

Study II 
LITHE 

Study III 
OPTION 

Study IV 
TOWARD 

Study V 
RADIATE 

Wee
k 

TCZ 
8 mg/k

g 

MT
X 

TCZ 
8 mg/k

g 
+ MT

X 

PBO 
+ MT

X 

TCZ 
8 mg/k

g 
+ MT

X 

PBO 
+ MT

X 

TCZ 
8 mg/kg 

+ 
DMAR

D 

PBO + 
DMAR

D 

TCZ 
8 mg/k

g 
+ MT

X 

PBO + 
MTX 

 

 N = 
286 

N = 
284 

N = 
398 

N = 
393 

N = 
205 

N = 
204 

N = 
803 

N = 
413 

N = 
170 

N = 
158 

ACR 20 
24 70%**

* 
52% 56%**

* 
27% 59%**

* 
26% 61%*** 24% 50%**

* 
10% 

52   56%**
* 

25%       

ACR 50 
24 44%** 33% 32%**

* 
10% 44%**

* 
11% 38%*** 9% 29%**

* 
4% 

52   36%**
* 

10%       

ACR 70 
24 28%** 15% 13%**

* 
2% 22%**

* 
2% 21%*** 3% 12%** 1% 

52   20%**
* 

4%       

TCZ   - Tocilizumab 
MTX  - Methotrexate 
PBO  - Placebo 
DMARD  - Disease modifying anti-rheumatic drug 
**   - p< 0.01, TCZ vs. PBO + MTX/DMARD 
***  - p< 0.0001, TCZ vs. PBO + MTX/DMARD 
 
Major clinical response 
After 2 years of treatment with RoActemra plus MTX, 14% of patients achieved a major clinical 
response (maintenance of an ACR70 response for 24 weeks or more). 
 
Radiographic response 
In Study II, in patients with an inadequate response to MTX, inhibition of structural joint damage was 
assessed radiographically and expressed as change in modified Sharp score and its components, the 
erosion score and joint space narrowing score. Inhibition of joint structural damage was shown with 
significantly less radiographic progression in patients receiving RoActemra compared to control 
(Table 6). 
 
In the open-label extension of Study II the inhibition of progression of structural joint damage in 
RoActemra plus MTX-treated patients was maintained in the second year of treatment. The mean 
change from baseline at week 104 in total Sharp-Genant score was significantly lower for patients 
randomised to RoActemra 8 mg/kg plus MTX (p<0.0001) compared with patients who were 
randomised to placebo plus MTX. 
 



96 

Table 6. Radiographic mean changes over 52 weeks in Study II 
 
 PBO + MTX  

(+ TCZ from week 24) 
N = 393 

TCZ 8 mg/kg + MTX 
 

N = 398 
Total Sharp-Genant score 1.13 0.29* 
Erosion score 0.71 0.17* 
JSN score 0.42 0.12** 
PBO  - Placebo 
MTX  - Methotrexate 
TCZ  - Tocilizumab 
JSN  - Joint space narrowing 
*  - p≤ 0.0001, TCZ vs. PBO + MTX 
**   - p< 0.005, TCZ vs. PBO + MTX 
 
Following 1 year of treatment with RoActemra plus MTX, 85% of patients(n=348) had no progression 
of structural joint damage, as defined by a change in the Total Sharp Score of zero or less, compared 
with 67% of placebo plus MTX-treated patients(n=290) (p ≤ 0.001). This remained consistent 
following 2 years of treatment (83%; n=353). Ninety three percent (93%; n=271) of patients had no 
progression between week 52 and week 104. 
 
Health-related and quality of life outcomes 
RoActemra-treated patients reported an improvement in all patient-reported outcomes (Health 
Assessment Questionnaire Disability Index - HAQ-DI), Short Form-36 and Functional Assessment of 
Chronic Illness Therapy questionnaires. Statistically significant improvements in HAQ-DI scores were 
observed in patients treated with RoActemra compared with patients treated with DMARDs. During 
the open-label period of Study II, the improvement in physical function has been maintained for up to 
2 years. At Week 52, the mean change in HAQ-DI was -0.58 in the RoActemra 8 mg/kg plus MTX 
group compared with -0.39 in the placebo + MTX group. The mean change in HAQ-DI was 
maintained at Week 104 in the RoActemra 8 mg/kg plus MTX group (-0.61). 
 
Haemoglobin levels  
Statistically significant improvements in haemoglobin levels were observed with RoActemra 
compared with DMARDs (p< 0.0001) at week 24. Mean haemoglobin levels increased by week 2 and 
remained within normal range through to week 24.  
 
Tocilizumab versus adalimumab in monotherapy 
Study VI (WA19924), a 24 week double-blinded study that compared RoActemra monotherapy with 
adalimumab monotherapy, evaluated 326 patients with RA who were intolerant of MTX or where 
continued treatment with MTX was considered inappropriate (including MTX inadequate responders). 
Patients in the RoActemra arm received an intravenous (IV) infusion of RoActemra (8 mg/kg) every 
4 weeks (q4w) and a subcutaneous (SC) placebo injection every 2 weeks (q2w). Patients in the 
adalimumab arm received an adalimumab SC injection (40 mg) q2w plus an IV placebo infusion q4w. 
A statistically significant superior treatment effect was seen in favour of RoActemra over adalimumab 
in control of disease activity from baseline to week 24 for the primary endpoint of change in DAS28 
and for all secondary endpoints (Table 7). 
 



97 

Table 7: Efficacy Results for Study VI (WA19924) 
 

 

ADA + Placebo 
(IV) 

N = 162 

TCZ + Placebo 
(SC) 

N = 163 p-value(a) 
Primary Endpoint - Mean Change from baseline at Week 24 

DAS28 (adjusted mean)  -1.8 -3.3   
Difference in adjusted mean (95% 

CI) 
-1.5 (-1.8, -1.1) <0.0001 

Secondary Endpoints - Percentage of Responders at Week 24 (b) 
DAS28 < 2.6, n (%) 17 (10.5) 65 (39.9) <0.0001 
DAS28 ≤ 3.2, n (%)  32 (19.8)  84 (51.5) <0.0001 

ACR20 response, n (%) 80 (49.4) 106 (65.0) 0.0038 
ACR50 response, n (%) 45 (27.8) 77 (47.2) 0.0002 
ACR70 response, n (%) 29 (17.9) 53 (32.5) 0.0023 

ap value is adjusted for region and duration of RA for all endpoints and additionally baseline value for all continuous 
endpoints. 
b Non-responder Imputation used for missing data. Multiplicity controlled using Bonferroni-Holm Procedure 
 
The overall clinical adverse event profile was similar between RoActemra and adalimumab. The 
proportion of patients with serious adverse events was balanced between the treatment groups 
(RoActemra 11.7% vs. adalimumab 9.9%). The types of adverse drug reactions in the RoActemra arm 
were consistent with the known safety profile of RoActemra and adverse drug reactions were reported 
at a similar frequency compared with Table 1. A higher incidence of infections and infestations was 
reported in the RoActemra arm (48% vs. 42%), with no difference in the incidence of serious 
infections (3.1%). Both study treatments induced the same pattern of changes in laboratory safety 
parameters (decreases in neutrophil and platelet counts, increases in ALT, AST and lipids), however, 
the magnitude of change and the frequency of marked abnormalities was higher with RoActemra 
compared with adalimumab. Four (2.5%) patients in the RoActemra arm and two (1.2%) patients in 
the adalimumab arm experienced CTC grade 3 or 4 neutrophil count decreases. Eleven (6.8%) patients 
in the RoActemra arm and five (3.1%) patients in the adalimumab arm experienced ALT increases of 
CTC grade 2 or higher. The mean LDL increase from baseline was 0.64 mmol/L (25 mg/dL) for 
patients in the RoActemra arm and 0.19 mmol/L (7 mg/dL) for patients in the adalimumab arm. The 
safety observed in the RoActemra arm was consistent with the known safety profile of RoActemra and 
no new or unexpected adverse drug reactions were observed (see Table 1).  
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of RoActemra is characterized by nonlinear elimination which is a combination 
of linear clearance and Michaelis-Menten elimination.  The nonlinear part of RoActemra elimination 
leads to an increase in exposure that is more than dose-proportional.  The pharmacokinetic parameters 
of RoActemra do not change with time. Due to the dependence of total clearance on RoActemra serum 
concentrations, the half-life of RoActemra 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.  
 
RA 
Intravenous use 
The pharmacokinetics of RoActemra were determined using a population pharmacokinetic analysis on 
a database composed of 3552 RA patients treated with a one-hour infusion of 4 or 8 mg/kg RoActemra 
every 4 weeks for 24 weeks or with 162 mg RoActemra given subcutaneously either once a week or 
every other week for 24 weeks. 
 



98 

The following parameters (predicted mean ± SD) were estimated for a dose of 8 mg/kg RoActemra 
given every 4 weeks: steady-state area under curve (AUC) = 38000 ± 13000 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. RoActemra 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 RoActemra were 50000 ± 16800 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 RoActemra flattens at higher 
exposure, resulting in smaller efficacy gains for each incremental increase in RoActemra concentration 
such that clinically meaningful increases in efficacy were not demonstrated in patients treated with > 
800 mg of RoActemra. Therefore, RoActemra doses exceeding 800 mg per infusion are not 
recommended (see section 4.2). 
 
Distribution 
In RA patients the central volume of distribution was 3.72, the peripheral volume of distribution was 
3.35 resulting in a volume of distribution at steady state of 7.07.  
 
Elimination 
Following intravenous administration, RoActemra undergoes biphasic elimination from the 
circulation. The total clearance of RoActemra was concentration-dependent and is the sum of the 
linear and non-linear clearance. The linear clearance was estimated as a parameter in the population 
pharmacokinetic analysis and was 9.5 mL/h. The concentration-dependent non-linear clearance plays a 
major role at low RoActemra concentrations. Once the non-linear clearance pathway is saturated, at 
higher RoActemra concentrations, clearance is mainly determined by the linear clearance.  
The t1/2 of RoActemra was concentration-dependent. At steady-state following a dose of 8 mg/kg 
every 4 weeks, the effective t1/2 decreased with decreasing concentrations within a dosing interval 
from 18 days to 6 days. 
 
Linearity 
Pharmacokinetic parameters of RoActemra did not change with time. A more than dose-proportional 
increase in the AUC and Cmin was observed for doses of 4 and 8 mg/kg every 4 weeks. Cmax increased 
dose-proportionally. At steady-state, predicted AUC and Cmin were 3.2 and 30 fold higher at 8 mg/kg 
as compared to 4 mg/kg, respectively. 
 
Subcutaneous use 
The pharmacokinetics of RoActemra were determined using a population pharmacokinetic analysis on 
a database composed of 3552 RA patients treated with 162 mg subcutaneous every week, 162 mg 
subcutaneous every other week, and or 4 or 8 mg/kg intravenous every 4 weeks for 24 weeks. 
 
The pharmacokinetic parameters of RoActemra did not change with time. For the 162 mg every week 
dose, the predicted mean (±SD) steady-state AUC1week, Cmin and Cmax of RoActemra were 
7970 ± 3432 µg•h/mL, 43.0 ± 19.8 µg/mL, and 49.8 ± 21.0 µg /mL, respectively. The accumulation 
ratios for AUC, Cmin, and Cmax were 6.32, 6.30, and 5.27, respectively. Steady state was reached after 
12 weeks for AUC, Cmin, and Cmax. 
 
For the 162 every other week dose, the predicted mean (±SD) steady-state AUC2week, Cmin, and 
Cmax of RoActemra were 3430 ± 2660 µg•h/mL, 5.7 ± 6.8 µg/mL, and 13.2 ± 8.8 µg/mL, 
respectively. The accumulation ratios for AUC, Cmin, and Cmax were 2.67, 6.02, and 2.12, respectively. 
Steady state was reached after 12 weeks for AUC and Cmin, and after 10 weeks for Cmax. 
 
Absorption 
Following subcutaneous dosing in RA patients, the time to peak serum RoActemra concentrations tmax 
was 2.8 days. The bioavailability for the subcutaneous formulation was 79%. 
 



99 

Elimination 
For subcutaneous administration, the concentration-dependent apparent t 1/2 is up to 12 days for 
162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state. 
 
sJIA 
Subcutaneous Use 
The pharmacokinetics of RoActemra in sJIA patients was characterized by a population 
pharmacokinetic analysis which included 140 patients who were treated with 8 mg/kg IV every 2 
weeks (patients weighing ≥30 kg), 12 mg/kg IV every 2 weeks (patients weighing below 30 kg), 
162 mg SC every week (patients weighing ≥30 kg), 162 mg SC every 10 days or every 2 weeks 
(patients weighing below 30 kg).  
 
Limited data are available regarding exposures following subcutaneous administration of RoActemra 
in sJIA patients below 2 years of age with a body weight less than 10 kg.  
 
Patients with sJIA must have a minimum body weight of 10 kg when receiving RoActemra 
subcutaneously (see section 4.2). 
 
Table 8. Predicted mean ± SD PK parameters at steady-state after SC dosing in sJIA 
 

RoActemra PK Parameter 162 mg QW ≥ 30 kg 162 mg Q2W below 30 kg 

Cmax (µg/mL) 99.8 ± 46.2 134 ± 58.6 

Cmin (µg/mL) 79.2 ± 35.6 65.9 ± 31.3 

Cmean (µg/mL) 91.3 ± 40.4 101 ± 43.2 

Accumulation Cmax 3.66 1.88 

Accumulation Cmin 4.39 3.21 

Accumulation Cmean or AUCτ* 4.28 2.27 

*τ = 1 week or 2 weeks for the two SC regimens 
 
After SC dosing, approximately 90% of the steady-state was reached by week 12 for both the 162 mg 
QW and Q2W regimens.  
 
Absorption 
Following SC dosing in sJIA patients, the absorption half-life was around 2 days, and the 
bioavailability for the SC formulation in sJIA patients was 95%.  
 
Distribution 
In paediatric patients with sJIA, the central volume of distribution was 1.87 L, the peripheral volume 
of distribution was 2.14 L resulting in a volume of distribution at steady state of 4.01 L 
 
Elimination 
The total clearance of tocilizumab was concentration-dependent and is the sum of the linear clearance 
and the nonlinear clearance. The linear clearance was estimated as a parameter in the population 
pharmacokinetic analysis and was 5.7 mL/h in paediatric patients with systemic juvenile idiopathic 
arthritis. Following subcutaneous administration, the effective t1/2 of RoActemra in sJIA patients is up 
to 14 days for both the 162 mg QW and Q2W regimens during a dosing interval at steady state.  
 
pJIA  
Subcutaneous use 
The pharmacokinetics of RoActemra in pJIA patients was characterized by a population 
pharmacokinetic analysis which included 237 patients who were treated with 8 mg/kg IV every 4 
weeks (patients weighing ≥ 30 kg), 10 mg/kg IV every 4 weeks (patients weighing below 30 kg), 
162 mg SC every 2 weeks (patients weighing   ≥ 30 kg), or 162 mg SC every 3 weeks (patients 
weighing   below 30 kg). 



100 

 
Table 9. Predicted mean ± SD PK parameters at steady-state after SC dosing in pJIA 
RoActemra PK Parameter 162 mg Q2W ≥ 30 kg 162 mg Q3W below 30 kg 

Cmax (µg/mL) 29.4 ± 13.5 75.5 ± 24.1 

Cmin (µg/mL) 11.8 ± 7.08 18.4 ± 12.9 

Cavg (µg/mL) 21.7 ± 10.4 45.5 ± 19.8 

Accumulation Cmax 1.72 1.32 

Accumulation Cmin 3.58 2.08 

Accumulation Cmean or AUCτ * 2.04 1.46 

*τ = 2 week or 3 week for the two SC regimens 
 
After IV dosing, approximately 90% of the steady-state was reached by Week 12 for the 10 mg/kg 
(BW < 30 kg), and by Week 16 for the 8 mg/kg (BW ≥ 30 kg) dose.  After SC dosing, approximately 
90% of the steady-state was reached by Week 12 for both the 162 mg SC Q2W and Q3W regimens. 
 
Absorption 
Following SC dosing in pJIA patients, the absorption half-life was around 2 days, and the 
bioavailability for the SC formulation in pJIA patients was 96%. 
 
Distribution 
In paediatric patients with pJIA, the central volume of distribution was 1.97 L, the peripheral volume 
of distribution was 2.03 L, resulting in a volume of distribution at steady state of 4.0 L. 
 
Elimination 
Population pharmacokinetic analysis for pJIA patients showed body size related impact on linear 
clearance so that body-weight based dosing should be taken into consideration (see Table 9).  
 
After subcutaneous administration, the effective t1/2 of RoActemra in pJIA patients is up to 10 days for 
patients < 30 kg (162 mg SC Q3W) and up to 7 days for patients >= 30 kg (162 mg SC Q2W)  during 
a dosing interval at steady state. Following intravenous administration, tocilizumab undergoes 
biphasic elimination from the circulation. The total clearance of tocilizumab was concentration-
dependent and is the sum of the linear and non-linear clearance. The linear clearance was estimated as 
a parameter in the population pharmacokinetic analysis and was 6.25 mL/h. The concentration-
dependent non-linear clearance plays a major role at low tocilizumab concentrations. Once the non-
linear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly 
determined by the linear clearance. 
 
GCA 
Subcutaneous use 
The PK of RoActemra  in GCA patients were determined using a population PK model from an 
analysis dataset composed of 149 GCA patients treated with 162 mg subcutaneous every week or 
162 mg subcutaneous every other week.  The developed model had the same structure as the 
population PK model developed earlier based on data from RA patients (see Table 10). 

 



101 

Table 10. Predicted mean ± SD PK parameters at steady-state after subcutaneous dosing in GCA 
 

 
Subcutaneous 

Tocilizumab PK Parameter 162 mg every other weekly 162 mg weekly 

Cmax (µg/mL) 19.3 ± 12.8 73 ± 30.4 

Ctrough (µg/mL) 11.1 ± 10.3 68.1± 29.5 

Cmean (µg/mL)  16.2 ± 11.8 71.3 ± 30.1 

Accumulation Cmax 2.18  8.88 

Accumulation Ctrough 5.61 9.59 

Accumulation Cmean or AUCτ * 2.81 10.91 

*τ = 2 week or 1 week for the two SC regimens 
 
The steady-state profile following the RoActemra weekly dose was almost flat, with very little 
fluctuations between trough and peak values, while there were substantial fluctuations for the 
RoActemra every other weekly dose. Approximately 90% of the steady-state (AUCτ) was reached by 
week 14 in the every other weekly and week 17 in the weekly dose groups. 
 
Based on the current characterization of PK, RoActemra trough concentration at steady state are 50% 
higher in this population relative to average concentrations in a large dataset from the RA population. 
These differences occur due to unknown reasons. PK differences are not accompanied by marked 
differences in PD parameters and so the clinical relevance is unknown.    
 
In GCA patients, higher exposure was observed in patients with lower body weight. For the 162 mg 
every week dosing regimen, the steady-state Cavg was 51% higher in patients with body weight less 
than 60 kg compared to patients weighing between 60 to 100 kg. For the 162 mg every other week 
regimen, the steady-state Cavg was 129% higher in patients with body weight less than 60 kg 
compared to patients weighing between 60 to 100 kg. There is limited data for patients above 100 kg 
(n=7). 
 
Absorption 
 
Following subcutaneous dosing in GCA patients, the absorption t½ was around 4 days.  The 
bioavailability for the SC formulation was 0.8. The median values of Tmax were 3 days after the 
RoActemra  weekly dose and 4.5 days after the tocilizumab every other week dose.   
 
Distribution 
 
In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distribution 
was 3.37 L, resulting in a volume of distribution at steady state of 7.46 L. 
 
Elimination 
 
The total clearance of RoActemra was concentration-dependent and is the sum of the linear clearance 
and the nonlinear clearance. The linear clearance was estimated as a parameter in the population 
pharmacokinetic analysis and was 6.7 mL/h in GCA patients, 
 
In GCA patients, at steady state, the effective t ½ of RoActemra varied between 18.3 and 18.9 days for 
162 mg weekly regimen, and between 4.2 and 7.9 days for 162 mg every other weekly regimen. At 
high serum concentrations, when total clearance of RoActemra is dominated by linear clearance, an 
effective t ½ of approximately 32 days was derived from the population parameter estimates. 
 



102 

Special populations 
Renal impairment: No formal study of the effect of renal impairment on the pharmacokinetics of 
RoActemra has been conducted. Most of the patients in the RA and GCA studies population 
pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment 
(estimated creatinine clearance based on Cockcroft-Gault formula) did not impact the 
pharmacokinetics of RoActemra. 
 
Approximately one-third of the patients in the GCA study had moderate renal impairment at baseline 
(estimated creatinine clearance of 30-59 mL/min). No impact on RoActemra exposure was noted in 
these patients. 
 
No dose adjustment is required in patients with mild or moderate renal impairment. 
 
Hepatic impairment: No formal study of the effect of hepatic impairment on the pharmacokinetics of 
RoActemra has been conducted.  
 
Age, gender and ethnicity: Population pharmacokinetic analyses in RA and GCA patients, showed that 
age, gender and ethnic origin did not affect the pharmacokinetics of RoActemra.  
 
Results of the population PK analysis for sJIA and pJIA patients confirmed that body size is the only 
covariate which has an appreciable impact on the pharmacokinetics of RoActemra including 
elimination and absorption so that body-weight based dosing should be taken into consideration (see 
Tables 8 and 9). 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development. 
 
Carcinogenicity studies were not performed because IgG1 monoclonal antibodies are not deemed to 
have intrinsic carcinogenic potential.  
 
Available non-clinical data demonstrated the effect of IL-6 on malignant progression and apoptosis 
resistance to various cancer types. This data does not suggest a relevant risk for cancer initiation and 
progression under RoActemra treatment. Additionally, proliferative lesions were not observed in a 
6-month chronic toxicity study in cynomolgus monkeys or in IL-6 deficient mice.  
 
Available non-clinical data do not suggest an effect on fertility under RoActemra treatment. Effects on 
endocrine active and reproductive system organs were not observed in a chronic cynomolgus monkey 
toxicity study and reproductive performance was not affected in IL-6 deficient mice. RoActemra 
administered to cynomolgus monkeys during early gestation, was observed to have no direct or 
indirect harmful effect on pregnancy or embryonal-foetal development. However, a slight increase in 
abortion/embryonal-foetal death was observed with high systemic exposure (> 100 x human exposure) 
in the 50 mg/kg/day high-dose group compared to placebo and other low-dose groups. Although IL-6 
does not seem to be a critical cytokine for foetal growth or the immunological control of the 
maternal/foetal interface, a relation of this finding to RoActemra cannot be excluded. 
 
Treatment with a murine analogue did not exert toxicity in juvenile mice. In particular, there was no 
impairment of skeletal growth, immune function and sexual maturation. 
 
The non-clinical safety profile of RoActemra in the cynomolgus monkey does not suggest a difference 
between intravenous and subcutaneous routes of administration. 
 
 



103 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
L-Histidine 
L-Histidine monohydrochloride monohydrate 
L-Arginine hydrochloride 
L-Methionine 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
24 months.  
 
Once removed from the refrigerator, RoActemra must be administered within 8 hours and should not 
be kept above 30°C. 
 
6.4 Special precautions for storage  
 
Store in a refrigerator (2°C – 8°C). Do not freeze.  
Keep the pre-filled pen in the outer carton in order to protect from light and moisture. 
 
6.5 Nature and contents of container  
 
0.9 mL solution in a pre-filled syringe (type I glass) with a staked-in needle containing 162 mg 
RoActemra assembled into a pre-filled pen. The syringe is closed by a rigid needle shield (elastomer 
seal with a polypropylene shell) and a plunger stopper (butyl rubber with a fluororesin coating). 
 
Pack sizes of 4 pre-filled pens and multipacks containing 12 (3 packs of 4) pre-filled pens. Not all 
pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
RoActemra is supplied in a single use pre-filled pen. After removing the pre-filled pen from the 
refrigerator the pre-filled pen should be allowed to reach room temperature (18°C to 28°C) by waiting 
for 45 minutes, before injecting RoActemra. The pen should not be shaken. After removing the cap the 
injection  must be started within 3 minutes,  to prevent the medicine from drying out and blocking the 
needle. If the pre-filled pen is not used within 3 minutes of removing the cap, you must dispose of it in 
a puncture resistant container and use a new pre-filled pen. 
 
If following pressing the activation button the purple indicator does not move, you must dispose of the 
pre-filled pen in a puncture resistant container. Do not try to re-use the pre-filled pen. Do not repeat 
the injection with another pre-filled pen. Call your healthcare provider for help. 
 
Do not use if the medicine is cloudy or contains particles, is any colour besides colourless to slightly 
yellowish, or any part of the pre-filled pen appears to be damaged. 
 
Comprehensive instructions for the administration of RoActemra in a pre-filled pen are given in the 
package leaflet. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 



104 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/492/009 
EU/1/08/492/010 
 
 
9. DATE OF FIRST AUTHORISATION/DATE OF LATEST RENEWAL  
 
Date of first authorisation: 16 January 2009 
Date of last renewal: 25 September 2013 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/. 
 

  



105 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE 
SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE 
FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

  C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



106 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER  RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 
 
Genentech, Inc.  
1000 New Horizons Way  
Vacaville, CA  
95688  
United States 
 
Name and address of the manufacturer responsible for batch release 
 
Roche Pharma AG 
Emil-Barell-Strasse 1 
D-79639 Grenzach-Wyhlen 
Germany 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 

• Periodic Safety Update Reports 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency;  
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at 

the same time. 
• Additional risk minimisation measures   
The Marketing Authorisation Holder (MAH) shall provide an educational pack covering the therapeutic 
indications RA, sJIA, pJIA and GCA, targeting all physicians who are expected to prescribe/use 
RoActemra containing the following: 
 

• Physician Information Pack 



107 

• Nurse Information Pack 
• Patient Information Pack 

 
The MAH must agree the content and format of the educational material, together with a 
communication plan (including means of distribution), with the national competent authority prior to 
distribution of the educational material. 
 
The Physician Information pack should contain the following key elements: 

• Reference to the Summary of Product Characteristics (e.g., link to EMA website) 
• Dose calculation (RA, sJIA and pJIA patients), preparation of infusion and infusion rate 
• Risk of serious infections 

• The product must not be given to patients with active or suspected infection 
• The product may lessen signs and symptoms of acute infection delaying the diagnosis 

• Risk of Hepatotoxicity 
• Caution should be exercised when considering initiation of tocilizumab treatment in 

patients with elevated transaminases ALT or AST above 1.5x ULN. In patients with 
elevated ALT or AST above 5x ULN treatment is not recommended. 

• In RA, GCA, pJIA and sJIA, ALT/AST should be monitored every 4 to 8 weeks for 
the first 6 months of treatment followed by every 12 weeks thereafter. The 
recommended dose modifications, including tocilizumab discontinuation, based on 
transaminases levels, in line with SmPC section 4.2. 

• Serious injection/infusion reaction and their management 
• Serious hypersensitivity reactions and their management 
• Risk of gastrointestinal perforations especially in patients with history of diverticulitis or 

intestinal ulcerations 
• Details on how to report serious adverse drug reactions 
• The Patient Information Packs (to be given to patients by healthcare professionals) 
• Guidance on how to diagnose Macrophage Activation Syndrome in sJIA patients 
• Recommendations for dose interruptions in sJIA and pJIA patients 

 
The Nurse Information Pack should contain the following key elements: 

• Prevention of medical errors and injection/infusion reactions  
• Preparation of injection/infusion 
• Infusion rate 

• Monitoring of the patient for injection/infusion reactions 
• Details on how to report serious adverse reactions 

 
The Patient Information Pack should contain the following key elements: 

• Package leaflet (with instructions for use for SC) (e.g., link to EMA website) 
• Patient alert card 
- to address the risk of getting infections which can become serious if not treated. In addition, 

some previous infections may reappear. 
- to address the risk that patients using RoActemra may develop complications of diverticulitis 

which can become serious if not treated. 
- to address the risk that patients using RoActemra may develop serious hepatic injury. Patients 

would be monitored for liver function tests. Patients should inform their doctor immediately 
if they experience signs and symptoms of liver toxicity including tiredness, abdominal pain 
and jaundice. 

- to address the risk of allergic reactions. 
 
  



108 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



109 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 

  



110 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RoActemra 20 mg/mL concentrate for solution for infusion 
Tocilizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial contains 80 mg tocilizumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Polysorbate 80, sucrose, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate 
and water for injections. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
80 mg/4 mL  
1 vial of 4 mL 
4 vials of 4 mL 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous infusion after dilution 
The diluted product should be used immediately 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 



111 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
Do not freeze 
Keep the vial in the outer carton in order to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/492/001 
EU/1/08/492/002 
 
 
13. BATCH NUMBER 
 
Batch  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
  



112 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RoActemra 20 mg/mL concentrate for solution for infusion 
Tocilizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial contains 200 mg tocilizumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Polysorbate 80, sucrose, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate 
and water for injections. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
200 mg/10 mL 
1 vial of 10 mL 
4 vials of 10 mL 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous infusion after dilution 
The diluted product should be used immediately 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 



113 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
Do not freeze 
Keep the vial in the outer carton, in order to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/492/003 
EU/1/08/492/004 
 
 
13. BATCH NUMBER 
 
Batch  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
  



114 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RoActemra 20 mg/mL concentrate for solution for infusion 
Tocilizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial contains 400 mg tocilizumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Polysorbate 80, sucrose, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate 
and water for injections. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
400 mg/20 mL 
1 vial of 20 mL 
4 vials of 20 mL 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous infusion after dilution 
The diluted product should be used immediately 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 



115 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
Do not freeze 
Keep the vial in the outer carton, in order to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/492/005 
EU/1/08/492/006 
 
 
13. BATCH NUMBER 
 
Batch  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:   



116 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
PRE-FILLED SYRINGE CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RoActemra 162 mg solution for injection in pre-filled syringe 
 
Tocilizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 pre-filled syringe contains 162 mg tocilizumab 
 
 
3. LIST OF EXCIPIENTS 
 
L-Histidine, L-Histidine monohydrochloride monohydrate, L-Arginine hydrochloride, L- 
Methionine, Polysorbate 80, Water for injections.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection in pre-filled syringe 
4 pre-filled syringes  
162 mg/0.9 mL  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use  
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Allow the syringe to sit at room temperature outside the box for 25 to 30 minutes before use 
 
 
8. EXPIRY DATE 
 
EXP  
 
Once removed from the refrigerator, RoActemra must be administered within 8 hours and should not 
be kept above 30 °C 
 
 



117 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2°C – 8°C) 
Do not freeze. 
Keep the pre-filled syringe in the outer carton in order to protect from light and moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/492/007 
 
 
13. BATCH NUMBER 
 
Batch  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
roactemra 162 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:   



118 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
PRE-FILLED SYRINGE CARTON (WITH BLUE BOX) - Multipack 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RoActemra 162 mg solution for injection in pre-filled syringe 
 
Tocilizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 pre-filled syringe contains 162 mg tocilizumab 
 
 
3. LIST OF EXCIPIENTS 
 
L-Histidine, L-Histidine monohydrochloride monohydrate, L-Arginine hydrochloride, L- 
Methionine, Polysorbate 80, Water for injections.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection in pre-filled syringe 
Multipack: 12 (3 packs of 4) pre-filled syringes. 
162 mg/0.9 mL  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use  
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Allow the syringe to sit at room temperature outside the box for 25 to 30 minutes before use 
 
 
8. EXPIRY DATE 
 
EXP  
 
Once removed from the refrigerator, RoActemra must be administered within 8 hours and should not 
be kept above 30 °C 
 
 



119 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2°C–8°C) 
Do not freeze. 
Keep the pre-filled syringe in the outer carton in order to protect from light and moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/492/008 
 
 
13. BATCH NUMBER 
 
Batch  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
roactemra 162 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:   



120 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
PRE-FILLED SYRINGE CARTON (WITHOUT BLUE BOX) - Multipack 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RoActemra 162 mg solution for injection in pre-filled syringe 
 
Tocilizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 pre-filled syringe contains 162 mg tocilizumab 
 
 
3. LIST OF EXCIPIENTS 
 
L-Histidine, L-Histidine monohydrochloride monohydrate, L-Arginine hydrochloride, L- 
Methionine, Polysorbate 80, Water for injections.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection in pre-filled syringe 
4 pre-filled syringes. Component of a multipack, can’t be sold separately.  
162 mg/0.9 mL  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use  
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Allow the syringe to sit at room temperature outside the box for 25 to 30 minutes before use 
 
 
8. EXPIRY DATE 
 
EXP  
 
Once removed from the refrigerator, RoActemra must be administered within 8 hours and should not 
be kept above 30 °C 
 
 



121 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2°C – 8°C) 
Do not freeze. 
Keep the pre-filled syringe in the outer carton in order to protect from light and moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/492/008 
 
 
13. BATCH NUMBER 
 
Batch  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
roactemra 162 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:   



122 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
PRE-FILLED PEN CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RoActemra 162 mg solution for injection in pre-filled pen 
 
Tocilizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 pre-filled pen contains 162 mg tocilizumab 
 
 
3. LIST OF EXCIPIENTS 
 
L-Histidine, L-Histidine monohydrochloride monohydrate, L-Arginine hydrochloride, L- 
Methionine, Polysorbate 80, Water for injections.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection in pre-filled pen, ACTPen® 
4 pre-filled pens  
162 mg/0.9 mL  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use  
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Allow the pre-filled pen to sit at room temperature outside the box for 45 minutes before use 
 
 
8. EXPIRY DATE 
 
EXP  
 
Once removed from the refrigerator, RoActemra must be administered within 8 hours and should not 
be kept above 30 °C 
 
 



123 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2°C–8°C) 
Do not freeze. 
Keep the pre-filled pen in the outer carton in order to protect from light and moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/492/009 
 
 
13. BATCH NUMBER 
 
Batch  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
roactemra 162 mg pen  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
  



124 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
PRE-FILLED PEN CARTON (WITH BLUE BOX) - Multipack 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RoActemra 162 mg solution for injection in pre-filled pen 
 
Tocilizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 pre-filled pen contains 162 mg tocilizumab 
 
 
3. LIST OF EXCIPIENTS 
 
L-Histidine, L-Histidine monohydrochloride monohydrate, L-Arginine hydrochloride, L- 
Methionine, Polysorbate 80, Water for injections.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection in pre-filled pen, ACTPen® 
Multipack: 12 (3 packs of 4) pre-filled pens. 
162 mg/0.9 mL  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use  
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children 
  
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Allow the pre-filled pen to sit at room temperature outside the box for 45 minutes before use 
 
 
8. EXPIRY DATE 
 
EXP  
 
Once removed from the refrigerator, RoActemra must be administered within 8 hours and should not 
be kept above 30 °C 
 
 



125 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2°C–8°C) 
Do not freeze. 
Keep the pre-filled pen in the outer carton in order to protect from light and moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/492/010 
 
 
13. BATCH NUMBER 
 
Batch  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
roactemra 162 mg pen 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
  



126 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
PRE-FILLED PEN CARTON (WITHOUT BLUE BOX) - Multipack 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RoActemra 162 mg solution for injection in pre-filled pen 
 
Tocilizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 pre-filled pen contains 162 mg tocilizumab 
 
 
3. LIST OF EXCIPIENTS 
 
L-Histidine, L-Histidine monohydrochloride monohydrate, L-Arginine hydrochloride, L- 
Methionine, Polysorbate 80, Water for injections.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection in pre-filled pen, ACTPen® 
4 pre-filled pens. Component of a multipack, can’t be sold separately.  
162 mg/0.9 mL  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use  
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Allow the pre-filled pen to sit at room temperature outside the box for 45 minutes before use 
 
 
8. EXPIRY DATE 
 
EXP  
 
Once removed from the refrigerator, RoActemra must be administered within 8 hours and should not 
be kept above 30 °C 
 
 



127 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2°C–8°C) 
Do not freeze. 
Keep the pre-filled pen in the outer carton in order to protect from light and moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/492/010 
 
 
13. BATCH NUMBER 
 
Batch  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
roactemra 162 mg pen 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
  



128 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
RoActemra 20 mg/mL sterile concentrate 
Tocilizumab 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
IV infusion 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
80 mg/4 mL  
 
 
6. OTHER 
 
  



129 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
RoActemra 20 mg/mL sterile concentrate 
Tocilizumab 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
IV infusion  
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
200 mg/10 mL 
 
 
6. OTHER 
 
  



130 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
RoActemra 20 mg/mL sterile concentrate 
Tocilizumab 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
IV infusion 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
400 mg/20 mL 
 
 
6. OTHER 
 
  



131 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PRE-FILLED SYRINGE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
RoActemra 162 mg injection 
Tocilizumab 
SC 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
162 mg/0.9 mL  
 
 
6. OTHER 
 



132 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PRE-FILLED PEN LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
RoActemra 162 mg injection 
Tocilizumab 
SC 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
162 mg/0.9 mL  
 
 
6. OTHER 
 

 
  



133 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



134 

Package Leaflet: Information for the user 
 

RoActemra 20 mg/mL concentrate for solution for infusion 
Tocilizumab 

 
Read all of this leaflet carefully before you are given this medicine because it contains important 

information for you. 
 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor or nurse. 
• This medicine has been prescribed for you only.  
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
In addition to this leaflet, you will be given a Patient Alert Card, which contains important safety 
information that you need to be aware of before and during treatment with RoActemra. 
 
What is in this leaflet:  
1. What RoActemra is and what it is used for 
2. What you need to know before you are given RoActemra 
3. How RoActemra is given 
4. Possible side effects 
5. How to store RoActemra 
6. Contents of the pack and other information 
 
 
1. What RoActemra is and what it is used for 
 
RoActemra contains the active substance tocilizumab, which is a protein made from specific immune 
cells (monoclonal antibody), that blocks the action of a specific protein (cytokine) called interleukin-6. 
This protein is involved in inflammatory processes of the body, and blocking it can reduce the 
inflammation in your body. RoActemra helps to reduce symptoms such as pain and swelling in your 
joints and can also improve your performance of daily tasks. RoActemra has been shown to slow the 
damage to the cartilage and bone of the joints caused by the disease and to improve your ability to do 
normal daily activities. 

 
• RoActemra is used to treat adults with moderate to severe active rheumatoid arthritis (RA), 

an autoimmune disease, if previous therapies did not work well enough. RoActemra is usually 
given in combination with methotrexate. However, RoActemra can be given alone if your 
doctor determines that methotrexate is inappropriate. 

 
• RoActemra can also be used to treat adults who have not had previous methotrexate treatment 

if they have severe, active and progressive rheumatoid arthritis. 
 

• RoActemra is used to treat children with sJIA. RoActemra is used for children aged 2 years 
and over who have active systemic juvenile idiopathic arthritis (sJIA), an inflammatory 
disease that causes pain and swelling in one or more joints as well as fever and rash. 
RoActemra is used to improve the symptoms of sJIA and can be given in combination with 
methotrexate or alone. 

 
• RoActemra is used to treat children with pJIA. RoActemra is used for children aged 2 

years and over with active polyarticular juvenile idiopathic arthritis (pJIA), an inflammatory 
disease that causes pain and swelling in one or more joints. RoActemra is used to improve the 
symptoms of pJIA and can be given in combination with methotrexate or alone. 

 



135 

• RoActemra is used to treat adults and children aged 2 years and over with severe or life-
threatening cytokine release syndrome (CRS), a side-effect in patients treated with chimeric 
antigen receptor (CAR) T-cell therapies used to treat certain types of cancer.  

 
 
2. What you need to know before you are given RoActemra 
 
You are not to be given RoActemra 

• if you are allergic  to tocilizumab or any of the other ingredients of this medicine (listed in 
Section 6). 

• if you have an active, severe infection. 
If any of these applies to you, tell the doctor or nurse giving you the infusion. 
 
Warnings and precautions  
Talk to your doctor or nurse before you are given RoActemra. 
 

• If you experience allergic reactions such as chest tightness, wheezing, severe dizziness or 
light-headedness, swelling of the lips or skin rash during or after the infusion, then tell your 
doctor immediately. 

 
• If you have any kind of infection, short- or long-term, or if you often get infections. Tell your 

doctor immediately if you feel unwell. RoActemra can reduce your body’s ability to respond 
to infections and may make an existing infection worse or increase the chance of getting a new 
infection. 

 
• If you have had tuberculosis, tell your doctor. Your doctor will check for signs and symptoms 

of tuberculosis before starting RoActemra. If symptoms of tuberculosis (persistent cough, 
weight loss, listlessness, mild fever), or any other infection appear during or after therapy tell 
your doctor immediately. 

 
• If you have had intestinal ulcers or diverticulitis, tell your doctor. Symptoms would include 

abdominal pain and unexplained changes in bowel habits with a fever. 
 

• If you have liver disease, tell your doctor. Before you use RoActemra, your doctor may do a 
blood test to measure your liver function. 

 
• If any patient has recently been vaccinated (either adult or child), or is planning a 

vaccination, tell your doctor. All patients, especially children, should be up-to-date with all 
their vaccinations before they start treatment with RoActemra. Certain types of vaccines 
should not be used while receiving RoActemra. 

 
• If you have cancer, tell your doctor. Your doctor will have to decide if you can still be given 

RoActemra. 
 

• If you have cardiovascular risk factors such as raised blood pressure and raised cholesterol 
levels, tell your doctor. These factors need to be monitored while receiving RoActemra. 

 
• If you have moderate to severe kidney function problems, your doctor will monitor you. 
 
• If you have persistent headaches. 

 
Your doctor will perform blood tests before you are given RoActemra, and during your treatment, to 
determine if you have a low white blood cell count, low platelet count or high liver enzymes. 
 



136 

Children and adolescents 
RoActemra is not recommended for use in children under 2 years of age. 
 
If a child has a history of macrophage activation syndrome, (activation and uncontrolled proliferation 
of specific blood cells), tell your doctor. Your doctor will have to decide if they can still be given 
RoActemra. 
 
Other medicines and RoActemra 
Tell your doctor if you are taking any other medicines (or your child is, if they are the patient), or have 
recently taken any. This includes medicines obtained without a prescription.  RoActemra can affect the 
way some medicines work, and the dose of these may require adjustment. If you are using medicines 
containing any of the following active substances, tell your doctor: 
 
• methylprednisolone, dexamethasone, used to reduce inflammation 
• simvastatin or atorvastatin, used to reduce cholesterol levels 
• calcium channel blockers (e.g. amlodipine), used to treat raised blood pressure 
• theophylline, used to treat asthma 
• warfarin or phenprocoumon, used as a blood thinning agents 
• phenytoin, used to treat convulsions 
• ciclosporin, used to suppress your immune system during organ transplants 
• benzodiazepines (e.g. temazepam), used to relieve anxiety. 
 
Due to lack of clinical experience, RoActemra is not recommended for use with other biological 
medicines for the treatment of RA, sJIA or pJIA. 
 
Pregnancy, breast-feeding and fertility 
RoActemra is not to be used in pregnancy unless clearly necessary. Talk to your doctor if you are 
pregnant, may be pregnant, or intend to become pregnant.  
 
Women of childbearing potential must use effective contraception during and up to 3 months after 
treatment.  
 
Stop breast-feeding if you are to be given RoActemra, and talk to your doctor. Leave a gap of at 
least 3 months after your last treatment before you start breast-feeding. It is not known whether 
RoActemra is passed into breast milk.  
 
The data available so far does not suggest any effect on fertility from this treatment. 
 
Driving and using machines 
This medicine can cause dizziness. If you feel dizzy, do not drive or use machines.  
 
RoActemra contains sodium 
This medicine contains 26.55 mg sodium per maximum dose of 1200 mg. Take this into account if 
you are on a low-sodium diet. However, doses below 1025 mg of this medicine contain less than 
23 mg sodium, so they are virtually sodium free. 
 
 
3. How RoActemra is given 
 
This medicine is subject to restricted medical prescription by your doctor. 
 
RoActemra will be given to you as a drip into a vein, by a doctor or a nurse. They will dilute the 
solution, set up the intravenous infusion and monitor you during and after the treatment. 
 



137 

Adult patients with RA 
The usual dose of RoActemra is 8 mg per kg of body weight. Depending on your response, your 
doctor may decrease your dose to 4 mg/kg then increase back to 8 mg/kg when appropriate. 
 
Adults will be given RoActemra once every 4 weeks through a drip in the vein (intravenous infusion) 
over one hour.  
 
Children with sJIA (aged 2 and over) 
The usual dose of RoActemra depends on your weight. 

• If you weigh less than 30 kg: the dose is 12 mg for every kilogram of body weight 
• If you weigh 30 kg or more, the dose is 8 mg for every kilogram of body weight 

The dose is calculated based on your body weight at each administration.  
 
Children with sJIA will be given RoActemra once every 2 weeks through a drip in the vein 
(intravenous infusion) over one hour.  
 
Children with pJIA (aged 2 and over) 
The usual dose of RoActemra depends on your weight. 

• If you weigh less than 30 kg: the dose is 10mg for every kilogram of body weight  
• If you weigh 30 kg or more: the dose is 8 mg for every kilogram of body weight  

The dose is calculated based on your body weight at each administration.  
 
Children with pJIA will be given RoActemra once every 4 weeks through a drip in the vein 
(intravenous infusion) over one hour.  
 
Patients with CRS 
The usual dose of RoActemra is 8 mg for every kg of body weight if you weigh 30 kg or more.  
The dose is 12 mg for every kg of body weight if you weigh less than 30 kg.  
RoActemra can be given alone or in combination with corticosteroids.  
 
If you are given more RoActemra than you should 
Since RoActemra is given by a doctor or nurse, it is unlikely that you will be given too much. 
However, if you are worried, talk to your doctor.  
 
If you miss a dose of RoActemra 
Since RoActemra is given by a doctor or nurse, it is unlikely that you will miss a dose. However, if 
you are worried, talk to your doctor or nurse. 
 
If you stop being given RoActemra 
You should not stop using RoActemra without discussing with your doctor first. 
 
If you have any further questions on the use of this medicine, ask your doctor or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, RoActemra can cause side effects, although not everybody gets them. Side effects 
could occur at least up to 3 months after your last dose of RoActemra. 
 
Possible serious side effects: tell a doctor straight away. 
These are common: they may affect up to 1 in every 10 users 
 
Allergic reactions during or after infusion: 
• difficulty with breathing, chest tightness or light-headedness 
• rash, itching, hives, swelling of the lips, tongue or face 
If you notice any of these, tell your doctor immediately. 



138 

 
Signs of serious infections 

• fever and chills  
• mouth or skin blisters  
• stomach ache 
 

Signs and symptoms of liver toxicity 
These may affect up to 1 in every 1000 users 
• tiredness,  
• abdominal pain,  
• jaundice (yellow discoloration of skin or eyes) 

 
If you notice any of these, tell your doctor as soon as possible. 
 
Very common side effects:  
These may affect more than 1 in every 10 users 
• upper respiratory tract infections with typical symptoms such as cough, blocked nose, runny 

nose, sore throat and headache 
• high blood fat (cholesterol) levels. 
 
Common side effects:  
These may affect up to 1 in every 10 users 
• lung infection (pneumonia) 
• shingles (herpes zoster) 
• cold sores (oral herpes simplex), blisters 
• skin infection (cellulitis) sometimes with fever and chills 
• rash and itching, hives 
• allergic (hypersensitivity) reactions 
• eye infection (conjunctivitis) 
• headache, dizziness, high blood pressure 
• mouth ulcers, stomach pain 
• fluid retention (oedema) in the lower legs, weight increase 
• cough, shortness of breath  
• low white blood cell counts shown by blood tests (neutropenia, leucopenia) 
• abnormal liver function tests (increased transaminases) 
• increased bilirubin shown by blood tests 
• low fibrinogen levels in the blood (a protein involved in blood clotting). 
 
Uncommon side effects:  
These may affect up to 1 in every 100 users 
• diverticulitis (fever, nausea, diarrhoea, constipation, stomach pain) 
• red swollen areas in the mouth 
• high blood fat (triglycerides) 
• stomach ulcer 
• kidney stones  
• underactive thyroid. 
 
Rare side effects: 
These may affect up to 1 in every 1,000 users 
• Stevens-Johnson syndrome (skin rash, which may lead to severe blistering and peeling of the 

skin) 
• Fatal Allergic Reactions (Anaphylaxis [fatal]) 
• inflammation of the liver (hepatitis), jaundice   
 



139 

Very rare side effects: 
These may affect up to 1 in every 10,000 users 
• low counts for white blood cells, red blood cells and platelets in blood tests. 
• liver failure 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. 

You can also report side effects directly via the national reporting system listed in Appendix V. By 
reporting side effects you can help provide more information on the safety of this medicine. 
 
Children with sJIA  
In general, side effects in sJIA patients were of a similar type to those in adults with RA. Some side 
effects were seen more often: inflamed nose and throat, diarrhoea, lower white blood cell counts and 
higher liver enzymes. 
 
Children with pJIA  
In general, side effects in pJIA patients were of a similar type to those in adults with RA. Some side 
effects were seen more often: inflamed nose and throat, headache, feeling sick (nausea) and lower 
white blood cell counts.  
 
 
5. How to store RoActemra 
 
Keep RoActemra out of the sight and reach of children. 
 
Store in a refrigerator (2°C - 8°C). Do not freeze.  
 
Keep the vial in the outer carton in order to protect from light. 
 
Do not use this medicine after the expiry date which is stated on the carton. 
 
 
6. Contents of the pack and other information 
 
What RoActemra contains 

• The active substance is tocilizumab.  
  Each 4 mL vial contains 80 mg tocilizumab (20 mg/mL). 
  Each 10 mL vial contains 200 mg tocilizumab (20 mg/mL).  
  Each 20 mL vial contains 400 mg tocilizumab (20 mg/mL).  
 

• The other ingredients are sucrose, polysorbate 80, disodium phosphate dodecahydrate, sodium 
dihydrogen phosphate dihydrate and water for injections. 

 
What RoActemra looks like and contents of the pack 
RoActemra is a concentrate for solution for infusion. The concentrate is a clear to opalescent, 
colourless to pale yellow liquid. 
RoActemra is supplied as vials containing 4 mL, 10 mL and 20 mL concentrate for solution for 
infusion. Pack size of 1 and 4 vials. Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


140 

Manufacturer 
Roche Pharma AG 
Emil-Barell-Str. 1 
D-79639 Grenzach-Wyhlen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
N.V. Roche S.A. 
Tél/Tel: +32 (0) 2 525 82 11 
 

Luxembourg/Luxemburg 
(Voir/siehe Belgique/Belgien) 
 

България 
Рош България ЕООД 
Тел: +359 2 818 44 44 
 

Magyarország 
Roche (Magyarország) Kft. 
Tel: +36 - 23 446 800 
 

Česká republika 
Roche s. r. o. 
Tel: +420 - 2 20382111 

Malta  
(See Ireland)  

Danmark 
Roche a/s 
Tlf: +45 - 36 39 99 99 
 

Nederland 
Roche Nederland B.V. 
Tel: +31 (0) 348 438050 
 

Deutschland 
Roche Pharma AG 
Tel: +49 (0) 7624 140  
oder 
Chugai Pharma Europe  
Zweigniederlassung Deutschland 
Tel: +49 (0) 69 663000 0 
 

Norge 
Roche Norge AS 
Tlf: +47 - 22 78 90 00 
 

Eesti 
Roche Eesti OÜ 
Tel: + 372 - 6 177 380 
 

Österreich 
Roche Austria GmbH 
Tel: +43 (0) 1 27739 
 

Ελλάδα 
Roche (Hellas) A.E.  
Τηλ: +30 210 61 66 100 
 

Polska 
Roche Polska Sp.z o.o. 
Tel: +48 - 22 345 18 88 
 

España 
Roche Farma S.A. 
Tel: +34 - 91 324 81 00 
 

Portugal 
Roche Farmacêutica Química, Lda 
Tel: +351 - 21 425 70 00 
 

France 
Roche 
Tél: +33 (0) 1 47 61 40 00 
ou 
Chugai Pharma France 
Tél: +33 (0) 1 56 37 05 20 
 
Hrvatska 
Roche d.o.o 
Tel: +385 1 47 22 333 

România 
Roche România S.R.L. 
Tel: +40 21 206 47 01 
 



141 

 
Ireland 
Roche Products (Ireland) Ltd. 
Tel: +353 (0) 1 469 0700 
 

 
Slovenija 
Roche farmacevtska družba d.o.o. 
Tel: +386 - 1 360 26 00 
 

Ísland  
Roche a/s 
c/o Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika  
Roche Slovensko, s.r.o. 
Tel: +421 - 2 52638201 
 

Italia 
Roche S.p.A. 
Tel: +39 - 039 2471 

Suomi/Finland 
Roche Oy  
Puh/Tel: +358 (0) 10 554 500 
 

Kύπρος  
Γ.Α.Σταμάτης & Σια Λτδ. 
Τηλ: +357 - 22 76 62 76 
 

Sverige 
Roche AB 
Tel: +46 (0) 8 726 1200 
 

Latvija 
Roche Latvija SIA 
Tel: +371 - 6 7039831 
 

United Kingdom 
Roche Products Ltd. 
Tel: +44 (0) 1707 366000  
or 
Chugai Pharma UK Ltd. 
Tel: +44 (0) 208 987 5600 
 

Lietuva 
UAB “Roche Lietuva” 
Tel: +370 5 2546799 
 

 

 
This leaflet was last revised  
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu/.  
  

http://www.ema.europa.eu/


142 

The following information is intended for healthcare professionals only: 
 
Instructions for dilution prior to administration 
Parenteral medicinal products should be inspected visually for particulate matter or discoloration prior 
to administration. Only solutions which are clear to opalescent, colourless to pale yellow and free of 
visible particles should be diluted. 
 
RA and CRS adult patients (≥ 30 kg) 
Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) solution for injection 
from a 100 mL infusion bag, equal to the volume of RoActemra concentrate required for the patients 
dose, under aseptic conditions. The required amount of RoActemra concentrate (0.4 mL/kg) should be 
withdrawn from the vial and placed in the 100 mL infusion bag. This should be a final volume of 
100 mL. To mix the solution, gently invert the infusion bag to avoid foaming. 
 
Use in the paediatric population 
 
sJIA, pJIA and CRS patients ≥ 30 kg 
Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) solution for injection 
from a 100 mL infusion bag, equal to the volume of RoActemra concentrate required for the patients 
dose, under aseptic conditions. The required amount of RoActemra concentrate (0.4 mL/kg) should be 
withdrawn from the vial and placed in the 100 mL infusion bag. This should be a final volume of 
100 mL. To mix the solution, gently invert the infusion bag to avoid foaming. 
 
sJIA and CRS patients < 30 kg 
Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) solution for injection 
from a 50 mL infusion bag, equal to the volume of RoActemra concentrate required for the patients 
dose, under aseptic conditions. The required amount of RoActemra concentrate (0.6 mL/kg) should be 
withdrawn from the vial and placed in the 50 mL infusion bag. This should be a final volume of 
50 mL. To mix the solution, gently invert the infusion bag to avoid foaming. 
 
pJIA patients < 30 kg 
Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) solution for injection 
from a 50 mL infusion bag, equal to the volume of RoActemra concentrate required for the patients 
dose, under aseptic conditions. The required amount of RoActemra concentrate (0.5 mL/kg) should be 
withdrawn from the vial and placed in the 50 mL infusion bag. This should be a final volume of 
50 mL. To mix the solution, gently invert the infusion bag to avoid foaming. 
 
RoActemra is for single-use only. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 

  



143 

Package leaflet: Information for the user 
 

RoActemra 162 mg solution for injection in pre-filled syringe 
Tocilizumab 

 
Read all of this leaflet carefully before you start using this medicine because it contains  
important information for you. 
 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor, pharmacist or nurse. 
• This medicine has been prescribed for you only. Do not pass it onto others. It may harm them 

even if their signs of illness are the same as yours. 
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
In addition to this leaflet, you will be given a Patient Alert Card, which contains important safety 
information that you need to be aware of before and during treatment with RoActemra. 
 
What is in this leaflet:  
1. What RoActemra is and what it is used for 
2. What you need to know before you use RoActemra 
3. How to use RoActemra 
4. Possible side effects 
5. How to store RoActemra 
6. Contents of the pack and other information 
 
 
1. What RoActemra is and what it is used for 
 
RoActemra contains the active substance tocilizumab, which is a protein made from specific immune 
cells (monoclonal antibody), that blocks the action of a specific protein (cytokine) called interleukin-6. 
This protein is involved in inflammatory processes of the body, and blocking it can reduce the 
inflammation in your body. RoActemra is used to treat: 
 
• adults with moderate to severe active rheumatoid arthritis (RA), an autoimmune disease, if 

previous therapies did not work well enough.  
 
• adults with severe, active and progressive rheumatoid arthritis (RA), who have not had 

previous treatment with methotrexate. 
 
RoActemra helps to reduce RA symptoms such as pain and swelling in your joints, and can also 
improve your performance of daily tasks. RoActemra has been shown to slow the damage to the 
cartilage and bone of the joints caused by the disease and to improve your ability to do normal 
daily activities. 
 
RoActemra is usually given in combination with another medicine for RA called methotrexate. 
However, RoActemra can be given alone if your doctor determines that methotrexate is 
inappropriate. 
 

• adults with a disease of the arteries called giant cell arteritis (GCA), caused by 
inflammation of the body’s largest arteries, especially those that supply blood to the head and 
neck. Symptoms include headache, fatigue and jaw pain. Effects can include strokes and 
blindness.  
 



144 

RoActemra can reduce pain and swelling in the arteries and veins in your head, neck and arms.  
 
GCA is often treated with medicines called steroids. They are usually effective, but can have 
side effects if used at high doses for a long time. Reducing the steroid dose can also lead to a 
flare-up of the GCA. Adding RoActemra to the treatment means that steroids can be used for a 
shorter time, while still controlling GCA. 
 

• children and adolescents, aged 1 year and over, with active systemic juvenile idiopathic 
arthritis (sJIA), an inflammatory disease that causes pain and swelling in one or more joints as 
well as fever and rash.  
 
RoActemra is used to improve the symptoms of sJIA. It can be given in combination with 
methotrexate or alone.   
 

• children and adolescents, aged 2 years and over, with active polyarticular juvenile 
idiopathic arthritis (pJIA). This is an inflammatory disease that causes pain and swelling in one 
or more joints.  
 
RoActemra is used to improve the symptoms of pJIA. It can be given in combination with 
methotrexate or alone.  

 
 
2. What you need to know before you use RoActemra 
 
Do not use RoActemra 
• if you or a child patient you look after are allergic to tocilizumab or any of the other ingredients 

of this medicine (listed in section 6). 
• if you or a child patient you look after have an active, severe infection. 
 
If either of these applies to you, tell a doctor. Do not use RoActemra. 
 
Warnings and precautions  
 
Talk to your doctor, pharmacist or nurse before using RoActemra. 
 
• If you experience allergic reactions such as chest tightness, wheezing, severe dizziness or light-

headedness, swelling of the lips, tongue, face or skin itching, hives or rash during or after the 
injection, then tell your doctor immediately.  

 
• Do not take the next dose until you have informed your doctor AND your doctor has told you to 

take the next dose if you have experienced any allergic reaction symptoms after RoActemra 
administration. 

• If you have any kind of infection, short- or long-term, or if you often get infections. Tell your 
doctor immediately if you feel unwell. RoActemra can reduce your body’s ability to respond to 
infections and may make an existing infection worse or increase the chance of getting a new 
infection. 

 
• If you have had tuberculosis, tell your doctor. Your doctor will check for signs and symptoms 

of tuberculosis before starting RoActemra. If symptoms of tuberculosis (persistent cough, 
weight loss, listlessness, mild fever) or any other infection appear during or after therapy tell 
your doctor immediately. 

 
• If you have had intestinal ulcers or diverticulitis, tell your doctor. Symptoms would include 

abdominal pain and unexplained changes in bowel habits with a fever. 
 



145 

• If you have liver disease, tell your doctor. Before you use RoActemra, your doctor may do a 
blood test to measure your liver function. 

 
• If any patient has recently been vaccinated, or is planning a vaccination, tell your doctor. All 

patients should be up-to-date with all their vaccinations before they start treatment with 
RoActemra. Certain types of vaccines should not be given while receiving RoActemra. 

 
• If you have cancer, tell your doctor. Your doctor will have to decide if you can still be given 

RoActemra. 
 
• If you have cardiovascular risk factors such as raised blood pressure and raised cholesterol 

levels, tell your doctor. These factors need to be monitored while receiving RoActemra. 
 
• If you have moderate to severe kidney function problems, your doctor will monitor you. 
 
• If you have persistent headaches. 
 
Your doctor will perform a blood test before you receive RoActemra, to determine if you have a low 
white blood cell count, low platelet count or high liver enzymes. 
 
Children and adolescents 
RoActemra subcutaneous injection is not recommended for use in children under 1 year of age. 
RoActemra must not be given to children with sJIA weighing less than 10 kg.  
 
If a child has a history of macrophage activation syndrome (activation and uncontrolled proliferation 
of specific blood cells), tell your doctor. Your doctor will have to decide if they can still be given 
RoActemra. 
 
Other medicines and RoActemra 
Tell your doctor if you are taking any other medicines, or have recently taken any. RoActemra can 
affect the way some medicines work, and the dose of these may require adjustment. If you are using 
medicines containing any of the following active substances, tell your doctor: 
• methylprednisolone, dexamethasone, used to reduce inflammation 
• simvastatin or atorvastatin, used to reduce cholesterol levels 
• calcium channel blockers (e.g. amlodipine), used to treat raised blood pressure 
• theophylline, used to treat asthma 
• warfarin or phenprocoumon, used as a blood thinning agents 
• phenytoin, used to treat convulsions 
• ciclosporin, used to suppress your immune system during organ transplants 
• benzodiazepines (e.g. temazepam), used to relieve anxiety 
 
Due to lack of clinical experience, RoActemra is not recommended for use with other biological 
medicines for the treatment of RA, sJIA, pJIA or GCA. 
 
Pregnancy, breast-feeding and fertility 
 
RoActemra is not to be used in pregnancy unless clearly necessary. Talk to your doctor if you are 
pregnant, may be pregnant, or intend to become pregnant.  
 
Women of childbearing potential must use effective contraception during and up to 3 months after 
treatment. 
 
Stop breast-feeding if you are to be given RoActemra, and talk to your doctor. Leave a gap of at 
least 3 months after your last treatment before you start breast-feeding. It is not known whether 
RoActemra is passed into breast milk. 
 



146 

Driving and using machines 
This medicine can cause dizziness. If you feel dizzy, do not drive or use machines.  
 
 
3. How to use RoActemra 
 
Always use this medicine exactly as your doctor, pharmacist or nurse has told you. You should check 
with your doctor, pharmacist or nurse if you are not sure. 
 
The treatment will be prescribed and started by healthcare professionals experienced in the diagnosis 
and treatment of RA, sJIA, pJIA or GCA. 
 
The recommended dose  
The dose for RA and GCA adults is 162 mg (the content of 1 pre-filled syringe) given once a week. 
 
Children and adolescents with sJIA (aged 1 year and over) 
The usual dose of RoActemra depends on the patient’s weight.  
• If the patient weighs less than 30 kg: the dose is 162 mg (the content of 1 pre-filled syringe) once 

every 2 weeks  
• If the patient weighs 30 kg or more: the dose is 162 mg (the content of 1 pre-filled syringe) once 

every week 
 
Children and adolescents with pJIA (aged 2 and over) 
The usual dose of RoActemra depends on the patient’s weight. 
• If the patient weighs less than 30 kg: the dose is 162 mg (the content of 1 pre-filled syringe), once 

every 3 weeks  
• If the patient weighs 30 kg or more: the dose is 162 mg (the content of 1 pre-filled syringe), once 

every 2 weeks. 
 
RoActemra is given by injection under the skin (subcutaneously). At the start, your doctor or nurse 
may inject RoActemra. However, your doctor may decide that you may inject RoActemra yourself. In 
this case you will get training on how to inject RoActemra yourself. Parents and carers will get 
training on how to inject RoActemra for patients who cannot inject themselves, such as children. 
 
Talk to your doctor if you have any questions about giving yourself or a child patient you look after an 
injection. You will find detailed “Instructions for administration” at the end of this leaflet.  
 
If you use more RoActemra than you should 
Because RoActemra is given in one pre-filled syringe, it is unlikely that you will receive too much. 
However, if you are worried, talk to your doctor, pharmacist or nurse.  
 
If an adult with RA or GCA or a child or adolescent with sJIA misses or forgets a dose 
It is very important to use RoActemra exactly as prescribed by your doctor. Keep track of your next  
dose.  
• If you miss your weekly dose within 7 days, take your dose on the next scheduled day.  
• If you miss your once every 2 weeks dose within 7 days, inject a dose as soon as you remember 

and take your next dose at your regular scheduled time.  
• If you miss your dose by more than 7 days, or you are not sure when to inject RoActemra, call 

your doctor or pharmacist.  
 
If a child or adolescent with pJIA misses or forgets a dose 
It is very important to use RoActemra exactly as prescribed by the doctor. Keep track of the next 
dose.  
• If a dose is missed within 7 days, inject a dose as soon as you remember and give the next dose 

at the regular scheduled time.  



147 

• If a dose is missed by more than 7 days, or you are not sure when to inject RoActemra, call the 
doctor or pharmacist. 

 
If you stop using RoActemra 
You should not stop using RoActemra without discussing with your doctor first. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, RoActemra can cause side effects, although not everybody gets them.  
Side effects could occur 3 months or more after your last dose of RoActemra. 
 
Possible serious side effects: tell a doctor straight away.  
These are common: they may affect up to 1 in every 10 users 
 
Allergic reactions during or after injection: 
• difficulty with breathing, chest tightness or light-headedness 
• rash, itching, hives, swelling of the lips, tongue or face 
If you notice any of these, tell your doctor immediately. 
 
Signs of serious infections: 
• fever and chills  
• mouth or skin blisters  
• stomach ache 
 
Signs and symptoms of liver toxicity 
These may affect up to 1 in every 1000 users 
• tiredness,  
• abdominal pain,  
• jaundice (yellow discoloration of skin or eyes) 
 
If you notice any of these, tell your doctor as soon as possible. 
 
Very common side effects:  
These may affect 1 in 10 patients or more 
• upper respiratory tract infections with typical symptoms such as cough, blocked nose, runny 

nose, sore throat and headache, 
• high blood fat (cholesterol) levels 
• injection site reactions. 
 
Common side effects:  
These may affect up to 1 in 10 patients 
• lung infection (pneumonia) 
• shingles (herpes zoster) 
• cold sores (oral herpes simplex), blisters 
• skin infection (cellulitis) sometimes with fever and chills  
• rash and itching, hives 
• allergic (hypersensitivity) reactions  
• eye infection (conjunctivitis) 
• headache, dizziness, high blood pressure 
• mouth ulceration, stomach pain 
• fluid retention (oedema) in the lower legs, weight increase 
• cough, shortness of breath 



148 

• low white blood cell counts shown by blood tests (neutropenia, leucopenia) 
• abnormal liver function tests (increased transaminases)  
• increased bilirubin shown by blood tests 
• low fibrinogen levels in the blood (a protein involved in blood clotting). 
 
Uncommon side effects:  
These may affect up to 1 in every 100 patients 
• diverticulitis (fever, nausea, diarrhoea, constipation, stomach pain) 
• red swollen areas in the mouth 
• high blood fat (triglycerides) 
• stomach ulcer 
• kidney stones  
• underactive thyroid. 
 
Rare side effects: 
These may affect up to1in every 1,000 patients 
• Stevens-Johnson syndrome (skin rash, which may lead to severe blistering and peeling of the 

skin) 
• Fatal Allergic Reactions (Anaphylaxis [fatal]) 
• inflammation of the liver (hepatitis), jaundice   
 
Very rare side effects: 
These may affect up to 1 in every 10,000 patients 
• low counts for white blood cells, red blood cells and platelets in blood tests. 
• liver failure 
 
Side effects in children and adolescents with sJIA or pJIA  
Side effects in children and adolescents with sJIA or pJIA are generally similar to those in adults. 
Some side effects are seen more often in children and adolescents: inflamed nose and throat, headache, 
feeling sick (nausea) and lower white blood cell counts. 
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store RoActemra 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the pre-filled syringe label and carton 
(EXP). The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C - 8°C). Do not freeze.  
 
Keep the pre-filled syringes in the outer carton in order to protect from light and moisture. 
 
Once removed from the refrigerator, RoActemra must be administered within 8 hours and should not 
be kept above 30°C. 
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


149 

Do not use if the medicine is cloudy or contains particles, is any colour besides colourless to 
yellowish, or any part of the pre-filled syringe appears to be damaged. 
 
The syringe should not be shaken. After removing the cap the injection must be started within 5 
minutes to prevent the medicine from drying out and blocking the needle. If the pre-filled syringe is 
not used within 5 minutes of cap removal, you must dispose of it in a puncture resistant container and 
use a new pre-filled syringe. 
 
If following insertion of the needle, you cannot depress the plunger, you must dispose of the pre-filled 
syringe in a puncture resistant container and use a new pre-filled syringe. 
 
 
6. Contents of the pack and other information 
 
What RoActemra contains 
• The active substance is tocilizumab.  
 Each pre-filled syringe contains 162 mg tocilizumab in 0.9 mL. 
 
• The other ingredients are L-Histidine, L-Histidine monohydrochloride monohydrate, , L-

Arginine hydrochloride, L-Methionine, Polysorbate 80 and Water for injections. 
 
What RoActemra looks like and contents of the pack 
RoActemra is a solution for injection. The solution is colourless to slightly yellowish. 
 
RoActemra is supplied as a 0.9 mL pre-filled syringe containing 162 mg tocilizumab solution for 
injection. 
 
Each pack contains 4 pre-filled syringes with multipacks containing 12 (3 packs of 4) pre-filled 
syringes. Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
Manufacturer 
Roche Pharma AG 
Emil-Barell-Str. 1 
D-79639 Grenzach-Wyhlen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
N.V. Roche S.A. 
Tél/Tel: +32 (0) 2 525 82 11 
 

Luxembourg/Luxemburg 
(Voir/siehe Belgique/Belgien) 
 

България 
Рош България ЕООД 
Тел: +359 2 818 44 44 
 

Magyarország 
Roche (Magyarország) Kft. 
Tel: +36 - 23 446 800 
 

Česká republika 
Roche s. r. o. 
Tel: +420 - 2 20382111 

Malta  
(See Ireland)  
 



150 

Danmark 
Roche a/s 
Tlf: +45 - 36 39 99 99 
 

Nederland 
Roche Nederland B.V. 
Tel: +31 (0) 348 438050 
 

Deutschland 
Roche Pharma AG 
Tel: +49 (0) 7624 140  
oder 
Chugai Pharma Europe 
Zweigniederlassung Deutschland 
Tel: +49 (0) 69 663000 0 
 

Norge 
Roche Norge AS 
Tlf: +47 - 22 78 90 00 
 

Eesti 
Roche Eesti OÜ 
Tel: + 372 - 6 177 380 
 

Österreich 
Roche Austria GmbH 
Tel: +43 (0) 1 27739 
 

Ελλάδα 
Roche (Hellas) A.E.  
Τηλ: +30 210 61 66 100 
 

Polska 
Roche Polska Sp.z o.o. 
Tel: +48 - 22 345 18 88 
 

España 
Roche Farma S.A. 
Tel: +34 - 91 324 81 00 
 

Portugal 
Roche Farmacêutica Química, Lda 
Tel: +351 - 21 425 70 00 
 

France 
Roche 
Tél: +33 (0) 1 47 61 40 00 
ou 
Chugai Pharma France 
Tél: +33 (0) 1 56 37 05 20 
 

România 
Roche România S.R.L. 
Tel: +40 21 206 47 01 
 

Hrvatska 
Roche d.o.o. 
Tel: +385 1 47 22 333 
 
Ireland 
Roche Products (Ireland) Ltd. 
Tel: +353 (0) 1 469 0700 
 

 
 
 
 
Slovenija 
Roche farmacevtska družba d.o.o. 
Tel: +386 - 1 360 26 00 
 

Ísland  
Roche a/s 
c/o Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika  
Roche Slovensko, s.r.o. 
Tel: +421 - 2 52638201 
 

Italia 
Roche S.p.A. 
Tel: +39 - 039 2471 

Suomi/Finland 
Roche Oy  
Puh/Tel: +358 (0) 10 554 500 
 

Kύπρος  
Γ.Α.Σταμάτης & Σια Λτδ. 
Τηλ: +357 - 22 76 62 76 
 

Sverige 
Roche AB 
Tel: +46 (0) 8 726 1200 
 



151 

Latvija 
Roche Latvija SIA 
Tel: +371 - 6 7039831 
 

United Kingdom 
Roche Products Ltd. 
Tel: +44 (0) 1707 366000  
or 
Chugai Pharma UK Ltd. 
Tel: +44 (0) 208 987 5600 
 

Lietuva 
UAB “Roche Lietuva” 
Tel: +370 5 2546799 
 

 

 
This leaflet was last revised 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu/.  

http://www.ema.europa.eu/


152 

What do I need to know to use my RoActemra pre-filled syringe safely? 
 
It is important to read, understand and follow these instructions so that you or your caregiver uses the 
RoActemra syringe correctly. These instructions do not replace training from your healthcare provider. 
Your healthcare provider should show you how to prepare and inject properly before you use the 
RoActemra syringe for the first time. Ask your healthcare provider any questions you may have. Do 
not attempt to administer an injection until you are sure that you understand how to use the 
RoActemra syringe.  
 
Please also read the Patient Leaflet that comes with the RoActemra syringe for the most important 
information you need to know about the medicine. It is important to remain under your healthcare 
provider's care while using RoActemra. 
 
Important Information: 
 

• Do not use the syringe if it appears to be damaged 
• Do not use if medicine is cloudy, hazy, discolored or contains particles 
• Do not try to take apart the syringe at any time 
• Do not remove the needle-cap until you are ready to inject 
• Do not inject through clothing covering the skin 
• Never re-use the same syringe 
• Do not touch the syringe trigger fingers as this may damage the syringe 

 
Storage 
 
Keep the RoActemra syringe and all medicines out of the sight and reach of children. Always store the 
syringe in a refrigerator at a temperature of 2°C - 8°C. Protect the syringe from freezing and from 
light. Keep the pre-filled syringes in the outer carton to protect it from light and keep them dry. 
 
Pre-filled Syringe parts 

 
 
You will need the following to give your injection: 
Included in the box: 

• Pre-filled Syringe 
 

Not included in the box: 
• Alcohol pad 
• Sterile cotton ball or gauze 
• Puncture-resistant container or sharps container for safe disposal of needle-cap and used syringe 
 



153 

A place to prepare your supplies:  
• Find a well-lit, clean, flat surface such as a table 

 
Step 1. Visually check the syringe 
 

• Take the box containing the syringe out of the refrigerator and open the box. Do not touch the 
trigger fingers on the syringe as this may damage the syringe. 

• Remove the syringe from the box and visually examine the syringe, as well as the medicine in 
the syringe. This is important to ensure that the syringe and medicine are safe to use. 

• Check the expiration date on the box and syringe (See Fig. A) to make sure that it has not passed 
(expired). Do not use the syringe if the expiration date has passed. This is important to ensure 
that the syringe and medicine are safe to use. 

 

 
 

Dispose of the syringe and do not use if: 
• the medicine is cloudy 
• the medicine contains particles 
• the medicine is any color besides colorless to yellowish 
• any part of the syringe appears to be damaged 
 

Step 2. Allow the syringe to adjust to room temperature 
• Do not remove the needle-cap on your syringe until Step 5. Early removal of the needle-cap can 
cause the medication to dry out and block the needle. 
 
• Place the syringe on a clean flat surface and allow the syringe to come to room temperature 

(18°C – 28°C) for about 25-30 minutes to warm up. Not allowing the syringe to come to room 
temperature could result in an uncomfortable injection and it may be difficult to depress the 
plunger. 

• Do not warm up the syringe in any other way. 
 
Step 3. Clean your hands 
 

• Wash your hands with soap and water. 
 

Step 4. Choose and prepare an injection site 
 

• The recommended injection sites are the front and middle of your thighs and the lower part of 
the abdomen below the navel (belly button) except for the five centimeter area directly around 
the navel. (See Fig. B) 

• If a caregiver is giving the injection, the outer area of the upper arms may also be used. (See Fig. 
B) 

 



154 

 
 

• You should use a different place each time you give yourself an injection, at least three 
centimeters from the area you used for your previous injection. 

• Do not inject into areas that could be bothered by a belt or waistband. Do not inject into moles, 
scars, bruises, or areas where the skin is tender, red, hard or not intact. 

• Clean the chosen injection site area using the alcohol pad (See Fig. C), to reduce the risk of 
infection. 

 

 
 

• Let the skin dry for approximately 10 seconds. 
• Be sure not to touch the cleaned area prior to the injection. Do not fan or blow on the clean area. 

 
Step 5. Remove needle-cap 
 

• Do not hold the syringe by the plunger while removing the needle-cap. 
• Hold the needle-shield of the syringe firmly with one hand and pull off the needle-cap with the 

other hand. (See Fig. D) If you cannot remove the needle cap you should request the help of a 
caregiver or contact your healthcare provider. 

 

 
 



155 

• Do not touch the needle or let it touch any surface. 
• You may see a drop of liquid at the end of the needle. This is normal. 
• Throw away the needle-cap in the puncture resistant container or sharps container. 
 
NOTE: Once the needle-cap is removed, the syringe must be used immediately. 
 
•  If it is not used within 5 minutes of cap removal, the syringe must be disposed of in the 

puncture resistant container or sharps container and a new syringe must be used. If the needle 
cap is removed for more than 5 minutes, it may be more difficult to perform an injection as the 
medicine can dry out and block the needle. 

 
• Never reattach the needle-cap after removal. 

 
Step 6. Give the injection 
 

• Hold the syringe comfortably in your hand. 
• To be sure the needle can be inserted correctly under the skin, pinch a fold of loose skin at the 

clean injection site with your free hand. Pinching the skin is important to ensure that you inject 
under the skin (into fatty tissue) but not any deeper (into muscle). Injection into muscle could 
result in an uncomfortable injection. 

• Do not hold or push on the plunger while inserting the needle into the skin. 
• Insert the needle all the way into the pinched skin at an angle between 45° to 90° with a quick, 

firm action. (See Fig. E). 
 

 
 

It is important to choose the correct angle to ensure the medication is delivered under the skin (into 
fatty tissue), otherwise the injection could be painful and the medication may not work. 
 

• Then keep the syringe in position and let go of the pinch of skin. 
• Slowly inject all of the medicine by gently pushing the plunger all the way down. (See Fig. F). 

You must press the plunger all the way down to ensure that you get the full dose of medication 
and to ensure the trigger fingers are completely pushed to the side. If the plunger is not fully 
depressed the needle shield will not extend to cover the needle when it is removed. If the needle 
is not covered proceed carefully, and place the syringe into the puncture resistant container to 
avoid injury with the needle. 

 



156 

 
• Once the plunger is pushed all the way down, keep pressing down on the plunger to be sure all 

of the medicine is injected before taking the needle out of the skin. 
• Keep pressing down on the plunger while you take the needle out of the skin at the same angle 

as inserted. (See Fig. G) 
• If following insertion of the needle, you cannot press down the plunger, you must dispose of the 

pre-filled syringe in a puncture resistant container and use a new pre-filled syringe (starting 
again at Step 2). If you still experience difficulty, you should consult your healthcare provider. 

 

 
 

• Once the needle is removed completely from the skin, you can release the plunger, allowing the 
needle-shield to protect the needle. (See Fig. H) 

 

 
• If you see drops of blood at the injection site, you can press a sterile cotton ball or gauze over the 

injection site for approximately 10 seconds. 
• Do not rub the injection site. 

 



157 

Step 7. Dispose of the syringe 
 

• Do not try to re-cap your syringe. 
• Throw away used syringes in a puncture-resistant container or sharps container. Ask your 

healthcare provider or pharmacist for information about where you can get a "sharps" container 
or what other types of puncture-resistant containers you can use to safely dispose of your used 
syringes, if you do not have one. (See Fig. I) 

 

 
 

Check with your healthcare provider for instructions about the right way to throw away used syringes. 
There may be local or state laws about how to throw away used syringes. 

 
Do not throw away used syringes or the puncture resistant container in household trash and do not 
recycle them.  
 

• Dispose of the full container as instructed by your healthcare provider or pharmacist. 
• Always keep the puncture-resistant container out of the sight and reach of children. 

 
Patient advice regarding hypersensitivity reactions (also known as anaphylaxis, if severe) 
 
If you develop symptoms such as, but not limited to skin rash, itching, chills, swelling of face, lips, 
tongue or throat, chest pain, wheezing, difficulty breathing or swallowing or feeling dizzy or faint at 
any time while not at the clinic during or following an RoACTEMRA injection you should seek 
emergency care immediately. 
 
Patient advice regarding early recognition and treatment to limit risk of a serious infection  
 
Be alert for the first signs of infection such as: 
 
• body aches, fever, chills 
• cough, chest discomfort/tightness, shortness of breath 
• redness, heat, unusual swelling of skin or joint 
• abdominal pain/tenderness and/or change in bowel function 
 
Call your doctor and seek medical attention without delay if you think you might be developing an 
infection.  
 
If you have any concerns or questions about your syringe, contact your healthcare provider or 
pharmacist for assistance. 



158 

Package leaflet: Information for the user 
 

RoActemra 162 mg solution for injection in pre-filled pen (ACTPen®) 
Tocilizumab 

 
Read all of this leaflet carefully before you start using this medicine because it contains  
important information for you. 
 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor, pharmacist or nurse. 
• This medicine has been prescribed for you only. Do not pass it onto others. It may harm them 

even if their signs of illness are the same as yours.  
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
In addition to this leaflet, you will be given a Patient Alert Card, which contains important safety 
information that you need to be aware of before and during treatment with RoActemra. 
 
What is in this leaflet:  
1. What RoActemra is and what it is used for 
2. What you need to know before you use RoActemra 
3. How to use RoActemra 
4. Possible side effects 
5. How to store RoActemra 
6. Contents of the pack and other information 
 
 
1. What RoActemra is and what it is used for 
 
RoActemra contains the active substance tocilizumab, which is a protein made from specific immune 
cells (monoclonal antibody), that blocks the action of a specific protein (cytokine) called interleukin-6. 
This protein is involved in inflammatory processes of the body, and blocking it can reduce the 
inflammation in your body. RoActemra is used to treat: 
 
• adults with moderate to severe active rheumatoid arthritis (RA), an autoimmune disease, if 

previous therapies did not work well enough.  
 

• adults with severe, active and progressive rheumatoid arthritis (RA), who have not had 
previous treatment with methotrexate..  

 
RoActemra helps to reduce symptoms such as pain and swelling in your joints and can also 
improve your performance of daily tasks. RoActemra has been shown to slow the damage to the 
cartilage and bone of the joints caused by the disease and to improve your ability to do normal 
daily activities. 

 
RoActemra is usually given in combination with another medicine for RA called methotrexate. 
However, RoActemra can be given alone if your doctor determines that methotrexate is 
inappropriate. 

 
• adults with a disease of the arteries called giant cell arteritis (GCA), caused by inflammation 

of the body’s largest arteries, especially those that supply blood to the head and neck. Symptoms 
include headache, fatigue and jaw pain. Effects can include strokes and blindness.  

 



159 

RoActemra can reduce pain and swelling in the arteries and veins in your head, neck and arms.  
 

GCA is often treated with medicines called steroids. They are usually effective, but can have side 
effects if used at high doses for a long time. Reducing the steroid dose can also lead to a flare-up 
of the GCA. Adding RoActemra to the treatment means that steroids can be used for a shorter 
time, while still controlling GCA. 

 
• children and adolescents, aged 12 years and over, with active systemic juvenile idiopathic 

arthritis (sJIA), an inflammatory disease that causes pain and swelling in one or more joints as 
well as fever and rash.  
 
RoActemra is used to improve the symptoms of sJIA. It can be given in combination with 
methotrexate or alone.   

 
• children and adolescents, aged 12 years and over, with active polyarticular juvenile idiopathic 

arthritis (pJIA). This is an inflammatory disease that causes pain and swelling in one or more 
joints.  

 
RoActemra is used to improve the symptoms of pJIA. It can be given in combination with 
methotrexate or alone.  
 

 
2. What you need to know before you use RoActemra 
 
Do not use RoActemra 
• if you or a child patient you look after are allergic to tocilizumab or any of the other ingredients 

of this medicine (listed in section 6). 
• if you or a child patient you look after have an active, severe infection. 
 
If either of these applies to you, tell a doctor. Do not use RoActemra. 
 
Warnings and precautions  
 
Talk to your doctor, pharmacist or nurse before using RoActemra. 
 
• If you experience allergic reactions such as chest tightness, wheezing, severe dizziness or light-

headedness, swelling of the lips, tongue, face or skin itching, hives or rash during or after the 
injection, then tell your doctor immediately.  

 
• Do not take the next dose until you have informed your doctor AND your doctor has told you to 
 take the next dose if you have experienced any allergic reaction symptoms after RoActemra 
 administration. 
 
• If you have any kind of infection, short- or long-term, or if you often get infections. Tell your 

doctor immediately if you feel unwell. RoActemra can reduce your body’s ability to respond to 
infections and may make an existing infection worse or increase the chance of getting a new 
infection. 

 
• If you have had tuberculosis, tell your doctor. Your doctor will check for signs and 
 symptoms of tuberculosis before starting RoActemra. If symptoms of tuberculosis (persistent 
 cough, weight loss, listlessness, mild fever) or any other infection appear during or after therapy 
 tell your doctor immediately. 
 
• If you have had intestinal ulcers or diverticulitis, tell your doctor. Symptoms would include 

abdominal pain and unexplained changes in bowel habits with a fever. 
 



160 

• If you have liver disease, tell your doctor. Before you use RoActemra, your doctor may do a 
blood test to measure your liver function. 

 
• If any patient has recently been vaccinated, or is planning a vaccination, tell your doctor. All 

patients should be up-to-date with all their vaccinations before they start treatment with 
RoActemra. Certain types of vaccines should not be given while receiving RoActemra. 

 
• If you have cancer, tell your doctor. Your doctor will have to decide if you can still be given 

RoActemra. 
 
• If you have cardiovascular risk factors such as raised blood pressure and raised cholesterol 

levels, tell your doctor. These factors need to be monitored while receiving RoActemra. 
 
• If you have moderate to severe kidney function problems, your doctor will monitor you. 
 
• If you have persistent headaches. 
 
Your doctor will perform a blood test before you receive RoActemra, to determine if you have a low 
white blood cell count, low platelet count or high liver enzymes. 
 
Children and adolescents 
RoActemra pre-filled pen (ACTPen®) is not recommended for use in children under 12 years of age. 
RoActemra must not be given to children with sJIA weighing less than 10 kg.  
 
If a child has a history of macrophage activation syndrome (activation and uncontrolled proliferation 
of specific blood cells), tell your doctor. Your doctor will have to decide if they can still be given 
RoActemra. 
 
Other medicines and RoActemra 
Tell your doctor if you are taking any other medicines, or have recently taken any. RoActemra can 
affect the way some medicines work, and the dose of these may require adjustment. If you are using 
medicines containing any of the following active substances, tell your doctor: 
• methylprednisolone, dexamethasone, used to reduce inflammation 
• simvastatin or atorvastatin, used to reduce cholesterol levels 
• calcium channel blockers (e.g. amlodipine), used to treat raised blood pressure 
• theophylline, used to treat asthma 
• warfarin or phenprocoumon, used as a blood thinning agents 
• phenytoin, used to treat convulsions 
• ciclosporin, used to suppress your immune system during organ transplants 
• benzodiazepines (e.g. temazepam), used to relieve anxiety 
 
Due to lack of clinical experience, RoActemra is not recommended for use with other biological 
medicines for the treatment of RA, sJIA, pJIA, or GCA. 
 
Pregnancy, breast-feeding and fertility 
 
RoActemra is not to be used in pregnancy unless clearly necessary. Talk to your doctor if you are 
pregnant, may be pregnant, or intend to become pregnant.  
 
Women of childbearing potential must use effective contraception during and up to 3 months after 
treatment. 
 
Stop breast-feeding if you are to be given RoActemra, and talk to your doctor. Leave a gap of at 
least 3 months after your last treatment before you start breast-feeding. It is not known whether 
RoActemra is passed into breast milk. 
 



161 

Driving and using machines 
This medicine can cause dizziness. If you feel dizzy, do not drive or use machines.  
 
 
3. How to use RoActemra 
 
Always use this medicine exactly as your doctor, pharmacist or nurse has told you. You should check 
with your doctor, pharmacist or nurse if you are not sure. 
 
The treatment will be prescribed and started by healthcare professionals experienced in the diagnosis 
and treatment of RA, sJIA, pJIA or GCA. 
 
The recommended dose  
The dose with RA or GCA for all adults is 162 mg (the content of 1 pre-filled pen) given once a week. 
 
Adolescents with sJIA (aged 12 years and over) 
The usual dose of RoActemra depends on the patient’s weight.  
• If the patient weighs less than 30 kg: the dose is 162 mg (the content of 1 pre-filled pen) once 

every 2 weeks  
• If the patient weighs 30 kg or more: the dose is 162 mg (the content of 1 pre-filled pen) once every 

week 
 
The pre-filled pen should not be used to treat children less than 12 years of age. 
 
Adolescents with pJIA (aged 12 years and over) 
The usual dose of RoActemra depends on the patient’s weight. 
• If the patient weighs less than 30 kg: the dose is 162 mg (the content of 1 pre-filled pen), once 

every 3 weeks  
• If the patient weighs 30 kg or more: the dose is 162 mg (the content of 1 pre-filled pen), once 

every 2 weeks. 
 
The pre-filled pen should not be used to treat children less than 12 years of age. 
 
RoActemra is given by injection under the skin (subcutaneously). At the start, your doctor or nurse 
may inject RoActemra (ACTPen®). However, your doctor may decide that you may inject RoActemra 
yourself. In this case you will get training on how to inject RoActemra yourself.  Parents and carers 
will get training on how to inject RoActemra for patients who cannot inject themselves. 
 
Talk to your doctor if you have any questions about giving yourself or an adolescent patient you look 
after an injection. You will find detailed “Instructions for administration” at the end of this leaflet.  
 
If you use more RoActemra than you should 
Because RoActemra is given in one pre-filled pen, it is unlikely that you will receive too much. 
However, if you are worried, talk to your doctor, pharmacist or nurse.  
 
If an adult with RA or GCA or an adolescent with sJIA misses or forgets a dose 
It is very important to use RoActemra exactly as prescribed by your doctor. Keep track of your next  
dose.  

• If you miss your weekly dose within 7 days, take your dose on the next scheduled day.  
• If you miss your once every other week dose within 7 days, inject a dose as soon as you 

remember and take your next dose at your regular scheduled time.  
• If you miss your weekly or once every other week dose by more than 7 days, or you are not 

sure when to inject RoActemra, call your doctor or pharmacist. 
 



162 

If an adolescent with pJIA misses or forgets a dose 
It is very important to use RoActemra exactly as prescribed by the doctor. Keep track of the next 
dose.  
• If a dose is missed within 7 days, inject a dose as soon as you remember and give the next dose 

at the regular scheduled time.  
• If a dose is missed by more than 7 days, or you are not sure when to inject RoActemra, call the 

doctor or pharmacist. 
 
If you stop using RoActemra 
You should not stop using RoActemra without discussing with your doctor first. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, RoActemra can cause side effects, although not everybody gets them.  
Side effects could occur 3 months or more after your last dose of RoActemra. 
 
Possible serious side effects: tell a doctor straight away.  
These are common: they may affect up to 1 in every 10 users 
 
Allergic reactions during or after injection: 
• difficulty with breathing, chest tightness or light-headedness 
• rash, itching, hives, swelling of the lips, tongue or face 
If you notice any of these, tell your doctor immediately. 
 
Signs of serious infections: 
• fever and chills  
• mouth or skin blisters  
• stomach ache 
 
Signs and symptoms of liver toxicity 
These may affect up to 1 in every 1000 users 
• tiredness,  
• abdominal pain,  
• jaundice (yellow discoloration of skin or eyes) 
 
If you notice any of these, tell your doctor as soon as possible. 
 
Very common side effects:  
These may affect 1 in 10 patients or more 
• upper respiratory tract infections with typical symptoms such as cough, blocked nose, runny 

nose, sore throat and headache 
• high blood fat (cholesterol) levels. 
• injection site reactions. 
 
Common side effects:  
These may affect up to 1 in 10 patients 
• lung infection (pneumonia) 
• shingles (herpes zoster) 
• cold sores (oral herpes simplex), blisters 
• skin infection (cellulitis) sometimes with fever and chills  
• rash and itching, hives 
• allergic (hypersensitivity) reactions  
• eye infection (conjunctivitis) 



163 

• headache, dizziness, high blood pressure 
• mouth ulceration, stomach pain 
• fluid retention (oedema) in the lower legs, weight increase 
• cough, shortness of breath 
• low white blood cell counts shown by blood tests (neutropenia, leucopenia) 
• abnormal liver function tests (increased transaminases)  
• increased bilirubin shown by blood tests 
• low fibrinogen levels in the blood (a protein involved in blood clotting). 
 
Uncommon side effects:  
These may affect up to 1 in every 100 patients 
• diverticulitis (fever, nausea, diarrhoea, constipation, stomach pain) 
• red swollen areas in the mouth 
• high blood fat (triglycerides) 
• stomach ulcer 
• kidney stones  
• underactive thyroid. 
 
Rare side effects: 
These may affect up to1in every 1,000 patients 
• Stevens-Johnson Syndrome (skin rash, which may lead to severe blistering and peeling of the 

skin) 
• Fatal Allergic Reactions (Anaphylaxis [fatal]) 
• inflammation of the liver (hepatitis), jaundice   
 
Very rare side effects: 
These may affect up to 1 in every 10,000 patients 
• low counts for white blood cells, red blood cells and platelets in blood tests. 
• liver failure 

 
Side effects in children and adolescents with sJIA or pJIA  
Side effects in children and adolescents with sJIA or pJIA are generally similar to those in adults. 
Some side effects are seen more often in children and adolescents: inflamed nose and throat, headache, 
feeling sick (nausea) and lower white blood cell counts. 

 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store RoActemra 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the pre-filled pen label and carton 
(EXP). The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C - 8°C). Do not freeze.  
 
Keep the pre-filled pens in the outer carton in order to protect from light and moisture. 
 
Once removed from the refrigerator, RoActemra must be administered within 8 hours and should not 
be kept above 30°C. 
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


164 

Do not use if the medicine is cloudy or contains particles, is any colour besides colourless to 
yellowish, or any part of the pre-filled pen appears to be damaged. 
 
The pen should not be shaken. After removing the cap the injection must be started within 3 minutes 
to prevent the medicine from drying out and blocking the needle. If the pre-filled pen is not used 
within 3 minutes of cap removal, you must dispose of it in a puncture resistant container and use a new 
pre-filled pen. 
 
If following pressing the activation button the purple indicator does not move, you must dispose of the 
pre-filled pen in a puncture resistant container. Do not try to re-use the pre-filled pen. Do not repeat 
the injection with another pre-filled pen. Call your healthcare provider for help. 
 
 
6. Contents of the pack and other information 
 
What RoActemra contains 
• The active substance is tocilizumab.  
 Each pre-filled pen contains 162 mg tocilizumab in 0.9 mL. 
 
• The other ingredients are L-Histidine, L-Histidine monohydrochloride monohydrate, L-

Arginine hydrochloride, L-Methionine, Polysorbate 80 and Water for injections. 
 
What RoActemra looks like and contents of the pack 
RoActemra is a solution for injection. The solution is colourless to slightly yellowish. 
 
RoActemra is supplied as a 0.9 mL pre-filled pen containing 162 mg tocilizumab solution for  
injection. 
 
Each pack contains 4 pre-filled pens with multipacks containing 12 (3 packs of 4) pre-filled pens. 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
Manufacturer 
Roche Pharma AG 
Emil-Barell-Str. 1 
D-79639 Grenzach-Wyhlen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
N.V. Roche S.A. 
Tél/Tel: +32 (0) 2 525 82 11 
 

Luxembourg/Luxemburg 
(Voir/siehe Belgique/Belgien) 
 

България 
Рош България ЕООД 
Тел: +359 2 818 44 44 
 

Magyarország 
Roche (Magyarország) Kft. 
Tel: +36 - 23 446 800 
 

Česká republika 
Roche s. r. o. 
Tel: +420 - 2 20382111 

Malta  
(See Ireland) 
 



165 

Danmark 
Roche a/s 
Tlf: +45 - 36 39 99 99 
 

Nederland 
Roche Nederland B.V. 
Tel: +31 (0) 348 438050 
 

Deutschland 
Roche Pharma AG 
Tel: +49 (0) 7624 140  
 

Norge 
Roche Norge AS 
Tlf: +47 - 22 78 90 00 
 

Eesti 
Roche Eesti OÜ 
Tel: + 372 - 6 177 380 
 

Österreich 
Roche Austria GmbH 
Tel: +43 (0) 1 27739 
 

Ελλάδα 
Roche (Hellas) A.E.  
Τηλ: +30 210 61 66 100 
 

Polska 
Roche Polska Sp.z o.o. 
Tel: +48 - 22 345 18 88 
 

España 
Roche Farma S.A. 
Tel: +34 - 91 324 81 00 
 

Portugal 
Roche Farmacêutica Química, Lda 
Tel: +351 - 21 425 70 00 
 

France 
Roche 
Tél: +33 (0) 1 47 61 40 00 
 

România 
Roche România S.R.L. 
Tel: +40 21 206 47 01 
 

Hrvatska 
Roche d.o.o. 
Tel: +385 1 47 22 333 
 
Ireland 
Roche Products (Ireland) Ltd. 
Tel: +353 (0) 1 469 0700 
 

 
 
 
 
Slovenija 
Roche farmacevtska družba d.o.o. 
Tel: +386 - 1 360 26 00 
 

Ísland  
Roche a/s 
c/o Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika  
Roche Slovensko, s.r.o. 
Tel: +421 - 2 52638201 
 

Italia 
Roche S.p.A. 
Tel: +39 - 039 2471 

Suomi/Finland 
Roche Oy  
Puh/Tel: +358 (0) 10 554 500 
 

Kύπρος  
Γ.Α.Σταμάτης & Σια Λτδ. 
Τηλ: +357 - 22 76 62 76 
 

Sverige 
Roche AB 
Tel: +46 (0) 8 726 1200 
 

Latvija 
Roche Latvija SIA 
Tel: +371 - 6 7039831 
 

United Kingdom 
Roche Products Ltd. 
Tel: +44 (0) 1707 366000  
 

Lietuva 
UAB “Roche Lietuva” 
Tel: +370 5 2546799 
 

 

 



166 

This leaflet was last revised 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu/.  
 

http://www.ema.europa.eu/


167 

What you need to know to use your RoActemra pre-filled pen (ACTPen) safely. 

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

Important:  Keep your unused pre-filled pens in the original carton and keep in the refrigerator at 2˚C 
to 8˚C (36˚F to 46˚F).  Do not freeze. 

• Do not remove the pre-filled pen cap until you are ready to inject RoACTEMRA. 

• Do not try to take apart the pre-filled pen at any time. 

• Do not reuse the same pre-filled pen.  

• Do not use the pre-filled pen through clothing.   

• Do not leave the pre-filled pen unattended.  

• Keep out of the reach of children. 

Parts of your RoACTEMRA pre-filled pen (See Figure A). 

   

 
Figure A 



168 

 
Supplies needed for an injection using your RoACTEMRA pre-filled pen (See Figure B): 

• 1 RoACTEMRA pre-filled pen 
• 1 Alcohol pad 
• 1 Sterile cotton ball or gauze 
• 1 Puncture-resistant container or sharps container for safe disposal of pre-filled pen cap and 

used pre-filled pen (see Step 4 “Dispose of the pre-filled pen”) 
 

 
Figure B 

 
Step 1. Preparing for a RoACTEMRA Injection 
Find a comfortable space with a clean, flat, working surface. 

• Take the box containing the pre-filled pen out of the refrigerator. 
• If you are opening the box for the first time, check to make sure that it is properly sealed. Do 

not use the pre-filled pen if the box looks like it has already been opened. 
• Check that the pre-filled pen box is not damaged. Do not use RoActemra pre-filled pen if the 

box looks damaged.  
• Check the expiration date on the pre-filled pen box. Do not use the pre-filled pen if the 

expiration date has passed because it may not be safe to use.   
• Open the box, and remove 1 single-use RoACTEMRA pre-filled pen from the box.  
• Return any remaining pre-filled pens in the box to the refrigerator. 
• Check the expiration date on the RoACTEMRA pre-filled pen (See Figure A).  Do not 

use it if the expiration date has passed because it may not be safe to use.  If the expiration date 
has passed, safely dispose of the pre-filled pen in a sharps container and get a new one. 

• Check the pre-filled pen to make sure it is not damaged.  Do not use the pre-filled pen if it 
appears to be damaged or if you have accidentally dropped the pre-filled pen. 

• Place the pre-filled pen on a clean, flat surface and let the pre-filled pen warm up for 45 
minutes to allow it to reach room temperature. If the pre-filled pen does not reach room 
temperature, this could cause your injection to feel uncomfortable and it could take longer to 
inject. 



169 

• Do not speed up the warming process in any way, such as using the microwave or placing 
the pre-filled pen in warm water. 

• Do not leave the pre-filled pen to warm up in direct sunlight. 
Do not remove the green cap while allowing your RoACTEMRA pre-filled pen to reach 
room temperature. 
• Hold your RoACTEMRA pre-filled pen with the green cap pointing down (See Figure C). 

 

 
Figure C  

 
• Look in the clear Window area. Check the liquid in the RoACTEMRA pre-filled pen (See 

Figure C).  It should be clear and colorless to pale yellow.  Do not inject RoACTEMRA if the 
liquid is cloudy, discolored, or has lumps or particles in it because it may not be safe to use.  
Safely dispose of the pre-filled pen in a sharps container and get a new one.    

• Wash your hands well with soap and water. 

Step 2. Choose and Prepare an Injection Site 
Choose an Injection Site 

• The front of your thigh or your abdomen except for the 2-inch (5cm) area around your navel 
are the recommended injection sites (See Figure D). 

• The outer area of the upper arms may also be used only if the injection is being given by a 
caregiver.  Do not attempt to use the upper arm area by yourself (See Figure D). 

Rotate Injection Site   
• Choose a different injection site for each new injection at least 1 inch (2.5cm) from the last 

area you injected. 
• Do not inject into moles, scars, bruises, or areas where the skin is tender, red, hard or not 

intact. 
 



170 

 
Figure D 

 
Prepare the Injection Site 

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

• Do not fan or blow on the clean area. 
Step 3. Inject RoACTEMRA 

• Hold the RoACTEMRA pre-filled pen firmly with one hand. Twist and pull off the green 
cap with the other hand (See Figure E). The green cap contains a loose fitting metal tube.  

• If you cannot remove the green cap you should ask a caregiver for help or contact your 
healthcare provider.  

 
 

 
Figure E 

Important: Do not touch the needle shield which is located at the tip of the pre-filled pen 
below the Window area (see Figure A), to avoid accidental needle stick injury. 

• Throw away the green cap in a sharps container. 
• After you remove the green cap, the pre-filled pen is ready for use. If the pre-filled pen is not 

used within 3 minutes of the cap removal, the pre-filled pen should be disposed of in the 
sharps container and a new pre-filled pen should be used. 

• Never reattach the green cap after removal. 



171 

• Hold the pre-filled pen comfortably in 1 hand by the upper part, so that you can see the 
Window area of the pre-filled pen (See Figure F).   

 

 
Figure F 

 
• Use your other hand to gently pinch the area of skin you cleaned, to prepare a firm injection 

site (See Figure G). The pre-filled pen requires a firm injection site to properly activate. 

• Pinching the skin is important to make sure that you inject under the skin (into fatty tissue) but 
not any deeper (into muscle).  Injection into muscle could cause the injection to feel 
uncomfortable. 

 

 
Figure G 

 

• Do not press the green activation button yet.  
• Place the needle-shield of the pre-filled pen against your pinched skin at a 90° angle (See 

Figure H).  
• It is important to use the correct angle to make sure the medicine is delivered under the skin 

(into fatty tissue), or the injection could be painful and the medicine may not work. 
 



172 

 
Figure H 

 
• To use the pre-filled pen, you first have to unlock the green Activation button. 
• To unlock it, press the pre-filled pen firmly against your pinched skin until the needle-shield is  
completely pushed in (See Figure I).  
 

 
Figure I 

 
• Continue to keep the needle-shield pushed in.  
• If you don’t keep the needle-shield completely pushed against the skin, the green Activation 

button will not work. 
• Continue to pinch the skin while you keep the pre-filled pen in place. 

• Press the green Activation button to start the injection. A “click” sound indicates the start of 
the injection. Keep the green button pressed in and continue holding the pre-filled pen pressed 
firmly against your skin (See Figure J). If you cannot start the injection you should ask for 
help from a caregiver or contact your healthcare provider. 



173 

 
Figure J 

 
• The purple indicator will move along the Window area during the injection  

(See Figure K). 
• Watch the purple indicator until it stops moving to be sure the full dose of medication is 

injected. 

  
Figure K 

 
• The injection may take up to 10 seconds. 
• You may hear a second “click” during the injection but you should continue to hold the pre-

filled pen firmly against your skin until the purple indicator stops moving.  
• When the purple indicator has stopped moving, release the green button. Lift the pre-filled pen 

straight off of the injection site at a 90° angle to remove the needle from the skin.  The needle-
shield will then move out and lock into place covering the needle (See Figure L). 

 
Figure L 

 



174 

• Check the Window area to see that it is filled with the purple indicator (See Figure L). 
• If the Window area is not filled by the purple indicator then: 

• The needle-shield may not have locked. Do not touch the needle-shield of the pre-
filled pen, because you may stick yourself with the needle. If the needle is not 
covered, carefully place the pre-filled pen into the sharps container to avoid any injury 
with the needle. 

• You may not have received your full dose of RoACTEMRA. Do not try to re-use the 
pre-filled pen. Do not repeat the injection with another pre-filled pen. Call your 
healthcare provider for help. 

After the Injection 
• There may be a little bleeding at the injection site.  You can press a cotton ball or gauze over 

the injection site.  
• Do not rub the injection site. 
• If needed, you may cover the injection site with a small bandage. 

Step 4.  Dispose of the pre-filled pen 
• The RoACTEMRA pre-filled pen should not be reused. 
• Put the used pre-filled pen into your sharps container (see “How do I dispose of used pre-filled 

pens?”) 
• Do not put the cap back on the pre-filled pen. 
• If your injection is given by another person, this person must also be careful when 

removing the pre-filled pen and disposing of it to prevent accidental needle stick injury 
and passing infection. 

How do I dispose of used pre-filled pens? 
• Put your used RoACTEMRA pre-filled pen and green cap in a sharps disposal container right 

away after use (See Figure M).    
• Do not throw away (dispose of) the pre-filled pen and the green cap in your household 

trash and do not recycle them. 
 

 
Figure M 

 
• Dispose of the full container as instructed by your healthcare provider or pharmacist. 
• Always keep the puncture-resistant container out of the sight and reach of children. 

 



175 

Keep the RoACTEMRA pre-filled pen and disposal container out of the reach of children. 
Record your Injection 

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

If you have any questions or concerns about your RoACTEMRA pre-filled pen, talk to your 
healthcare provider familiar with RoACTEMRA. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER  RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET