ROACTEMRA 200mg perfusive solution concentrate medication leaflet

RoActemra 20 mg/mL concentrate for solution for infusion

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 produced in Chinese hamster ovary (CHO) cells byrecombinant DNA technology.

Each 80 mg vial contains 0.10 mmol (2.21 mg) sodium and 2 mg (0.5 mg/mL) polysorbate 80.

Each 200 mg vial contains 0.20 mmol (4.43 mg) sodium and 5 mg (0.5 mg/mL) polysorbate 80.

Each 400 mg vial contains 0.39 mmol (8.85 mg) sodium and 10 mg (0.5 mg/mL) polysorbate 80.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear to opalescent, colourless to pale yellow solution with a pH of 6.3-6.7 and an osmolality of172-229 mOsm/kg.

Rheumatoid arthritis (RA)

RoActemra, in combination with methotrexate (MTX), is indicated for:

* the treatment of severe, active and progressive RA in adults not previously treated with MTX.

* the treatment of moderate to severe active RA in adult patients who have either respondedinadequately 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 wherecontinued treatment with MTX is inappropriate.

RoActemra has been shown to reduce the rate of progression of joint damage as measured by X-rayand to improve physical function when given in combination with MTX.

Coronavirus disease 2019 (COVID-19)

RoActemra is indicated for the treatment of COVID-19 in adults who are receiving systemiccorticosteroids and require supplemental oxygen or mechanical ventilation.

Systemic juvenile idiopathic arthritis (sJIA)

RoActemra is indicated for the treatment of active sJIA in patients 2 years of age and older, who haveresponded inadequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) andsystemic corticosteroids. RoActemra can be given as monotherapy (in case of intolerance to MTX orwhere treatment with MTX is inappropriate) or in combination with MTX.

RoActemra in combination with MTX is indicated for the treatment of pJIA (rheumatoid factorpositive or negative and extended oligoarthritis) in patients 2 years of age and older, who haveresponded inadequately to previous therapy with MTX. RoActemra can be given as monotherapy incase 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 orlife-threatening CRS in adults and paediatric patients 2 years of age and older.

Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatmentof RA, COVID-19, sJIA, pJIA or CRS.

All patients treated with RoActemra must be given the Patient Card.

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 notrecommended (see section 5.2).

Doses above 1.2 g have not been evaluated in clinical trials (see section 5.1).

Dose adjustments due to laboratory abnormalities (see section 4.4)

* Liver enzyme abnormalities

Laboratory value Action> 1 to 3 × Upper Modify the dose of the concomitant MTX if appropriate.

Limit of Normal(ULN) For persistent increases in this range, reduce tocilizumab dose to 4 mg/kg orinterrupt treatment until alanine aminotransferase (ALT) or aspartateaminotransferase (AST) have normalised.

Restart with 4 mg/kg or 8 mg/kg, as clinically appropriate.

> 3 to 5 × ULN Interrupt tocilizumab dosing until < 3 × ULN and follow recommendationsabove for > 1 to 3 × ULN.

(confirmed byrepeat testing, see For persistent increases > 3 × ULN, discontinue treatment.section 4.4).

> 5 × ULN Discontinue treatment.

* Low absolute neutrophil count (ANC)

In patients not previously treated with tocilizumab, initiation is not recommended in patients with anabsolute neutrophil count (ANC) below 2 × 109/L.

Laboratory Value Action(cells × 109/L)

ANC > 1 Maintain dose.

ANC 0.5 to 1 Interrupt tocilizumab dosing.

When ANC increases > 1 × 109/ L resume treatment at 4 mg/kg and increase to8 mg/kg as clinically appropriate.

ANC < 0.5 Discontinue treatment.

* Low platelet count

Laboratory Value Action(cells × 103/µL)50 to 100 Interrupt tocilizumab dosing.

When platelet count > 100 × 103/µL resume treatment at 4 mg/kg and increaseto 8 mg/kg as clinically appropriate.

< 50 Discontinue treatment.

COVID-19 patients

The recommended posology for treatment of COVID-19 is a single 60-minute intravenous infusion of8 mg/kg body weight in patients who are receiving systemic corticosteroids and require supplementaloxygen or mechanical ventilation, see section 5.1. If clinical signs or symptoms worsen or do notimprove after the first dose, one additional infusion of tocilizumab 8 mg/kg may be administered. Theinterval between the two infusions must be at least 8 hours.

For individuals whose body weight is more than 100 kg, doses exceeding 800 mg per infusion are notrecommended (see section 5.2).

Administration of tocilizumab is not recommended in patients with COVID-19 who have any of thefollowing laboratory abnormalities:

Laboratory test type Laboratory value Action

Liver enzyme > 10 × ULN Administration of tocilizumab

Absolute neutrophil count < 1 × 109/L is not recommended

Platelet count < 50 × 103/µL

Cytokine Release Syndrome (CRS) (adults and paediatrics)

The recommended posology for treatment of CRS given as a 60-minute intravenous infusion is8 mg/kg in patients weighing greater than or equal to 30 kg or 12 mg/kg in patients weighing less than30 kg. Tocilizumab can be given alone or in combination with corticosteroids.

If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, up to3 additional doses of tocilizumab may be administered. The interval between consecutive doses mustbe 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 dueto the underlying malignancy, preceding lymphodepleting chemotherapy or the CRS.

No dose adjustment is required in elderly patients > 65 years of age.

No dose adjustment is required in patients with mild renal impairment. Tocilizumab has not beenstudied in patients with moderate to severe renal impairment (see section 5.2). Renal function must bemonitored closely in these patients.

Tocilizumab has not been studied in patients with hepatic impairment. Therefore, no doserecommendations can be made.

Paediatric populationsJIA patients

The recommended posology in patients above 2 years of age is 8 mg/kg once every 2 weeks inpatients weighing greater than or equal to 30 kg or 12 mg/kg once every 2 weeks in patients weighingless than 30 kg. The dose must be calculated based on the patient’s body weight at eachadministration. A change in dose should only be based on a consistent change in the patient’s bodyweight over time.

The safety and efficacy of intravenous tocilizumab in children below 2 years of age has not beenestablished. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendationon a posology can be made.

Dose interruptions of tocilizumab for the following laboratory abnormalities are recommended in sJIApatients in the tables below. If appropriate, the dose of concomitant MTX and/or other medicinalproducts should be modified or dosing stopped and tocilizumab dosing interrupted until the clinicalsituation has been evaluated. As there are many co-morbid conditions that may affect laboratoryvalues in sJIA, the decision to discontinue tocilizumab for a laboratory abnormality should be basedupon the medical assessment of the individual patient.

* Liver enzyme abnormalities

Laboratory Value Action> 1 to 3 × ULN Modify the dose of the concomitant MTX if appropriate.

For persistent increases in this range, interrupt tocilizumab until ALT/ASThave normalised.

> 3 × ULN to Modify the dose of the concomitant MTX if appropriate.5 × ULN

Interrupt tocilizumab dosing until < 3 × ULN and follow recommendationsabove for > 1 to 3 × ULN.

> 5 × ULN Discontinue tocilizumab.

The decision to discontinue treatment in sJIA for a laboratory abnormality mustbe based on the medical assessment of the individual patient.

* Low absolute neutrophil count (ANC)

Laboratory Value Action(cells × 109/L)

ANC > 1 Maintain dose.

ANC 0.5 to 1 Interrupt tocilizumab dosing.

When ANC increases to > 1 × 109/L resume treatment.

ANC < 0.5 Discontinue tocilizumab.

The decision to discontinue treatment in sJIA for a laboratory abnormality mustbe based on the medical assessment of the individual patient.

* Low platelet count

Laboratory Value Action(cells × 103/µL)50 to 100 Modify the dose of the concomitant MTX if appropriate.

Interrupt tocilizumab dosing.

When platelet count is > 100 × 103/µL resume treatment.

< 50 Discontinue tocilizumab.

The decision to discontinue treatment in sJIA for a laboratory abnormalitymust be based on the medical assessment of the individual patient.

There are insufficient clinical data to assess the impact of a tocilizumab dose reduction in sJIA patientswho have experienced laboratory abnormalities.

Available data suggest that clinical improvement is observed within 6 weeks of initiation of treatmentwith tocilizumab. Continued therapy must be carefully reconsidered in a patient exhibiting noimprovement within this timeframe.

pJIA patients

The recommended posology in patients above 2 years of age is 8 mg/kg once every 4 weeks inpatients weighing greater than or equal to 30 kg or 10 mg/kg once every 4 weeks in patients weighingless than 30 kg. The dose must be calculated based on the patient’s body weight at eachadministration. A change in dose should only be based on a consistent change in the patient’s bodyweight over time.

The safety and efficacy of intravenous tocilizumab in children below 2 years of age has not beenestablished. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendationon a posology can be made.

Dose interruptions of tocilizumab for the following laboratory abnormalities are recommended in pJIApatients in the tables below. If appropriate, the dose of concomitant MTX and/or other medicinalproducts should be modified or dosing stopped and tocilizumab dosing interrupted until the clinicalsituation has been evaluated. As there are many co-morbid conditions that may effect laboratoryvalues in pJIA, the decision to discontinue tocilizumab for a laboratory abnormality should be basedupon the medical assessment of the individual patient.

* Liver enzyme abnormalities

Laboratory Value Action> 1 to 3 × ULN Modify the dose of the concomitant MTX if appropriate.

For persistent increases in this range, interrupt tocilizumab until ALT/ASThave normalised.

> 3 × ULN to Modify the dose of the concomitant MTX if appropriate.5 × ULN

Interrupt tocilizumab dosing until < 3 × ULN and follow recommendationsabove for > 1 to 3 × ULN.

> 5 × ULN Discontinue tocilizumab.

The decision to discontinue treatment in pJIA for a laboratory abnormalitymust be based on the medical assessment of the individual patient.

* Low absolute neutrophil count (ANC)

Laboratory Value Action(cells × 109/L)

ANC > 1 Maintain dose.

ANC 0.5 to 1 Interrupt tocilizumab dosing.

When ANC increases to > 1 × 109/L resume treatment.

ANC < 0.5 Discontinue tocilizumab.

The decision to discontinue treatment in pJIA for a laboratory abnormalitymust be based on the medical assessment of the individual patient.

* Low platelet count

Laboratory Value Action(cells × 103/µL)50 to 100 Modify the dose of the concomitant MTX if appropriate.

Interrupt tocilizumab dosing.

When platelet count is > 100 × 103/µL resume treatment.

< 50 Discontinue tocilizumab.

The decision to discontinue treatment in pJIA for a laboratory abnormalitymust 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 treatmentwith tocilizumab. Continued therapy must be carefully reconsidered in a patient exhibiting noimprovement within this timeframe.

CRS

Tocilizumab may be used in paediatric patients (2 years of age and older) at the same posology as inadults in CRS. See section 4.2 Posology and method of administration, Cytokine Release Syndrome(CRS) (adults and paediatrics) subsection.

After dilution, this medicinal product should be administered as an intravenous infusion over 1 hour. Ifsigns and symptoms of an infusion-related reaction occur, the infusion needs to be slowed or stoppedand appropriate medicinal product/supportive care must be administered immediately (see section 4.4).

RA, sJIA, pJIA, CRS and COVID-19 patients ≥ 30 kg

This medicinal product needs to be diluted to a final volume of 100 mL with sterile, non-pyrogenicsodium 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

This medicinal product needs to be diluted to a final volume of 50 mL with sterile, non-pyrogenicsodium 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.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Active, severe infections with the exception of COVID-19 (see section 4.4).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

RA, pJIA and sJIA patients

Serious and sometimes fatal infections have been reported in patients receiving immunosuppressiveagents including tocilizumab (see section 4.8). Treatment must not be initiated in patients with activeinfections (see section 4.3). Administration of tocilizumab must be interrupted if a patient develops aserious infection until the infection is controlled (see section 4.8). Healthcare professionals shouldexercise caution when considering the use of this medicinal product in patients with a history ofrecurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes andinterstitial lung disease) which may predispose patients to infections.

Vigilance for the timely detection of serious infection is recommended for patients receivingbiological treatments as signs and symptoms of acute inflammation may be lessened, associated withsuppression of the acute phase reaction. The effects of tocilizumab on C-reactive protein (CRP),neutrophils and signs and symptoms of infection must be considered when evaluating a patient for apotential infection. Patients (which includes younger children with sJIA or pJIA who may be less ableto communicate their symptoms) and parents/guardians of sJIA or pJIA patients should be instructedto contact their healthcare professional immediately when any symptoms suggesting infection appear,in order to assure rapid evaluation and appropriate treatment.

Tuberculosis (TB)

As recommended for other biological treatments, RA, pJIA and sJIA patients should be screened forlatent TB infection prior to starting tocilizumab therapy. Patients with latent TB must be treated withstandard anti-mycobacterial therapy before initiating treatment. Prescribers are reminded of the risk offalse negative tuberculin skin and interferon-gamma TB blood test results, especially in patients whoare 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 aftertherapy with this medicinal product.

Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinicaltrials with tocilizumab, patients who screened positive for hepatitis were excluded.

Complications of diverticulitis

Events of diverticular perforations as complications of diverticulitis have been reported uncommonlywith tocilizumab in RA patients (see section 4.8). This medicinal product should be used with cautionin patients with previous history of intestinal ulceration or diverticulitis. Patients presenting withsymptoms potentially indicative of complicated diverticulitis, such as abdominal pain, haemorrhageand/or unexplained change in bowel habits with fever must be evaluated promptly for earlyidentification of diverticulitis, which can be associated with gastrointestinal perforation.

Serious hypersensitivity reactions have been reported in association with infusion of tocilizumab (seesection 4.8). Such reactions may be more severe, and potentially fatal in patients who haveexperienced hypersensitivity reactions during previous infusions even if they have receivedpremedication with steroids and antihistamines. Appropriate treatment should be available forimmediate use in the event of an anaphylactic reaction during treatment. If an anaphylactic reaction orother serious hypersensitivity/serious infusion-related reaction occurs, administration of tocilizumabmust be stopped immediately and treatment should be permanently discontinued.

Active hepatic disease and hepatic impairment

Treatment with tocilizumab, particularly when administered concomitantly with MTX, may beassociated with elevations in hepatic transaminases, therefore, caution should be exercised whenconsidering treatment of patients with active hepatic disease or hepatic impairment (see sections 4.2and 4.8).

Transient or intermittent mild and moderate elevations of hepatic transaminases have been reportedcommonly with tocilizumab treatment (see section 4.8). An increased frequency of these elevationswas observed when potentially hepatotoxic medicinal products (e.g. MTX) were used in combinationwith tocilizumab. When clinically indicated, other liver function tests including bilirubin should beconsidered.

Serious drug-induced liver injury, including acute liver failure, hepatitis and jaundice, have beenobserved with tocilizumab (see section 4.8). Serious hepatic injury occurred between 2 weeks to morethan 5 years after initiation of treatment. Cases of liver failure resulting in liver transplantation havebeen reported. Patients must be advised to immediately seek medical help if they experience signs andsymptoms of hepatic injury.

Caution should be exercised when considering initiation of treatment in patients with elevated ALT or

AST > 1.5 × ULN. In RA, pJIA and sJIA patients with baseline ALT or AST > 5 × ULN, treatment isnot recommended.

In RA, pJIA and sJIA patients, ALT/AST should be monitored every 4 to 8 weeks for the first6 months of treatment followed by every 12 weeks thereafter. For recommended modifications,including tocilizumab discontinuation, based on transaminases levels see section 4.2. For ALT or ASTelevations > 3-5 × ULN, confirmed by repeat testing, treatment must be interrupted.

Decreases in neutrophil and platelet counts have occurred following treatment with tocilizumab8 mg/kg in combination with MTX (see section 4.8). There may be an increased risk of neutropenia inpatients who have previously been treated with a TNF antagonist.

In patients not previously treated with tocilizumab, initiation is not recommended in patients with an(ANC) below 2 × 109/L. Caution should be exercised when considering initiation of treatment inpatients with a low platelet count (i.e. platelet count below 100 × 103/ µL). In RA, pJIA and sJIApatients who develop an ANC < 0.5 × 109/ l or a platelet count < 50 × 103/µL, continued treatment isnot recommended.

Severe neutropenia may be associated with an increased risk of serious infections, although there hasbeen no clear association between decreases in neutrophils and the occurrence of serious infections inclinical trials with tocilizumab to date.

In RA patients, neutrophils and platelets should be monitored 4 to 8 weeks after start of therapy andthereafter according to standard clinical practice. For recommended dose modifications based on ANCand platelet counts, see section 4.2.

In pJIA and sJIA patients, neutrophils and platelets should be monitored at the time of second infusionand thereafter according to good clinical practice, see section 4.2.

Lipid parameters

Elevations in lipid parameters including total cholesterol, low-density lipoprotein (LDL), high-densitylipoprotein (HDL) and triglycerides were observed in patients treated with tocilizumab (seesection 4.8). In the majority of patients, there was no increase in atherogenic indices, and elevations intotal cholesterol responded to treatment with lipid lowering agents.

In RA, pJIA andsJIA patients, assessment of lipid parameters should be performed 4 to 8 weeksfollowing initiation of therapy. Patients should be managed according to local clinical guidelines formanagement of hyperlipidaemia.

Neurological disorders

Physicians should be vigilant for symptoms potentially indicative of new-onset central demyelinatingdisorders. The potential for central demyelination with tocilizumab is currently unknown.

The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products mayincrease the risk of malignancy. The clinical data are insufficient to assess the potential incidence ofmalignancy following exposure to tocilizumab. Long-term safety evaluations are ongoing.

Live and live attenuated vaccines should not be given concurrently with this medicinal product asclinical safety has not been established. In a randomised open-label study, adult RA patients treatedwith tocilizumab and MTX were able to mount an effective response to both the 23-valentpneumococcal polysaccharide and tetanus toxoid vaccines which was comparable to the response seenin patients on MTX only. It is recommended that all patients, particularly pJIA and sJIA patients, bebrought up to date with all immunisations in agreement with current immunisation guidelines prior toinitiating therapy. The interval between live vaccinations and initiation of therapy should be inaccordance with current vaccination guidelines regarding immunosuppressive agents.

RA patients have an increased risk for cardiovascular disorders and must have risk factors(e.g. hypertension, hyperlipidaemia) managed as part of usual standard of care.

Combination with TNF antagonists

There is no experience with the use of tocilizumab with TNF antagonists or other biological treatmentsfor RA, pJIA or sJIA patients. This medicinal product is not recommended for use with otherbiological agents.

After dilution with 0.9% sodium chloride solution, this medicinal product contains 230.6 mg sodiumper maximum dose of 800 mg, equivalent to 11.5% of the WHO recommended maximum daily intakeof 2 g sodium for an adult.

Polysorbate

This medicine contains 2 mg of polysorbate 80 in each 80 mg vial, 5 mg of polysorbate 80 in each200 mg vial and 10 mg polysorbate 80 in each 400 mg vial, which is equivalent to 0.5 mg/mL.

Polysorbates may cause allergic reactions. Patients' known allergies shall be taken into consideration.

COVID-19 patients

* The efficacy of this medicinal product has not been established in the treatment of COVID-19patients who do not have elevated CRP levels, see section 5.1.

* This medicinal product must not be administered to COVID-19 patients who are not receivingsystemic corticosteroids as an increase in mortality cannot be excluded in this subgroup, seesection 5.1.

In COVID-19 patients, this medicinal product should not be administered if they have any otherconcurrent severe active infection. Healthcare professionals should exercise caution when consideringthe use of tocilizumab in patients with a history of recurring or chronic infections or with underlyingconditions (e.g. diverticulitis, diabetes, and interstitial lung disease) which may predispose patients toinfections.

Patients hospitalised with COVID-19 may have elevated ALT or AST levels. Multi-organ failure withinvolvement of the liver is recognised as a complication of severe COVID-19. The decision toadminister tocilizumab should balance the potential benefit of treating COVID-19 against the potentialrisks of acute treatment with tocilizumab. In COVID-19 patients with elevated ALT or AST above10 × ULN, administration of tocilizumab treatment is not recommended. In COVID-19 patients, ALT/AST should be monitored according to current standard clinical practices.

In COVID-19 patients who develop an ANC < 1 × 109/L or a platelet count < 50 × 103/µL,administration of treatment is not recommended. Neutrophil and platelet counts should be monitoredaccording to current standard clinical practices, see section 4.2.

Paediatric populationsJIA Patients

Macrophage activation syndrome (MAS) is a serious life-threatening disorder that may develop insJIA patients. In clinical trials, tocilizumab has not been studied in patients during an episode of active

MAS.

Interaction studies have only been performed in adults.

Concomitant administration of a single dose of 10 mg/kg tocilizumab with 10-25 mg MTX onceweekly had no clinically significant effect on MTX exposure.

Population pharmacokinetic analyses did not detect any effect of MTX, NSAIDs or corticosteroids ontocilizumab clearance.

The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL-6, that stimulatechronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitorytherapy, such as tocilizumab, is introduced.

In vitro trials with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2,

CYP2C9, CYP2C19 and CYP3A4 enzyme expression. Tocilizumab normalises expression of theseenzymes.

In a study in RA patients, levels of simvastatin (CYP3A4) were decreased by 57% one week followinga single dose of tocilizumab, to the level similar to, or slightly higher than, those observed in healthysubjects.

When starting or stopping therapy with tocilizumab, patients taking medicinal products which areindividually 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, orbenzodiazepines) must be monitored as doses may need to be increased to maintain therapeutic effect.

Given its long elimination half-life (t1/2), the effect of tocilizumab on CYP450 enzyme activity maypersist for several weeks after stopping therapy.

Women of childbearing potential have to use effective contraception during and up to 3 months aftertreatment.

There are no adequate data from the use of tocilizumab in pregnant women. A study in animals hasshown 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.

It is unknown whether tocilizumab is excreted in human milk. The excretion of tocilizumab in milkhas not been studied in animals. A decision must be made whether to discontinue breast-feeding or todiscontinue/abstain from RoActemra therapy taking into account the benefit of breast-feeding for thechild and the benefit of therapy for the woman.

Available non-clinical data do not suggest an effect on fertility under tocilizumab treatment.

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

RA, sJIA, pJIA and CRS

The most commonly reported adverse reactions are upper respiratory tract infections, nasopharyngitis,headache, hypertension and increased ALT.

The most serious adverse reactions are serious infections, complications of diverticulitis, andhypersensitivity reactions.

COVID-19

The most commonly reported adverse reactions are hepatic transaminases increased, constipation,and urinary tract infection.

Adverse reactions from clinical trials and/or post-marketing experience with tocilizumab based onspontaneous case reports, literature cases and cases from non-interventional study programs are listedin Table 1 and in Table 2 by MedDRA system organ class (SOC). The corresponding frequencycategory for each adverse reaction is based on the following convention: very common ( ≥ 1/10);common ( ≥ 1/100 to < 1/10), uncommon ( ≥ 1/1 000 to < 1/100), rare ( ≥ 1/10 000 to < 1/1 000), veryrare ( < 1/10 000), and frequency not known (cannot be estimated from the available data). Withineach frequency grouping, adverse reactions are presented in order of decreasing seriousness.

RA patients

Table 1. List of adverse reactions occurring in patients with RA receiving tocilizumab as monotherapyor in combination with MTX or other DMARDs in the double-blind controlled period or duringpost-marketing experience

MedDRA Frequency categories with preferred terms

SOC

Very Common Uncommon Rare Very rarecommon

Infections Upper Cellulitis, Diverticulitisand respiratory Pneumonia,infestations tract Oral herpesinfections simplex,

Herpes zoster

Blood and Leukopenia,lymphatic Neutropenia,system Hypofibrino-disorders genaemia

Immune Anaphylaxissystem (fatal)1, 2 ,3disorders

Endocrine Hypothy-disorders roidism

Metabolism Hypercholeste Hypertri-and rolaemia* glyceridaemianutritiondisorders

Nervous Headache,system Dizzinessdisorders

Eye Conjunctivitisdisorders

Vascular Hypertensiondisorders

Respiratory Cough,, thoracic Dyspnoeaandmediastinaldisorders

MedDRA Frequency categories with preferred terms

SOC

Very Common Uncommon Rare Very rarecommon

Gastroin- Abdominal Stomatitis,testinal pain, Mouth Gastric ulcerdisorders ulceration,

Gastritis

Hepatobi- Drug-induced Hepatic failureliary liver injury,disorders Hepatitis,

Jaundice,:

Skin and Rash, Stevens-subcutane- Pruritus, Johnson-ous tissue Urticaria Syndrome3disorders

Renal and Nephroli-urinary thiasisdisorders

General Peripheraldisorders oedema,and Hypersensitivadministra- ity reactionstion siteconditions

Investiga- Hepatictions transaminasesincreased,

Weightincreased,

Total bilirubinincreased*

* Includes elevations collected as part of routine laboratory monitoring (see text below)1 See section 4.32 See section 4.43 This adverse reaction was identified through post-marketing surveillance but not observed in controlled clinical trials. Thefrequency category was estimated as the upper limit of the 95% confidence interval calculated on the basis of the totalnumber of patients exposed to tocilizumab in clinical trials.

Patients with COVID-19

The safety evaluation of this medicinal product in COVID-19 was based on 3 randomised,double-blind, placebo-controlled trials (studies ML42528, WA42380, and WA42511). A total of974 patients were exposed to tocilizumab in these studies. Collection of safety data from the

RECOVERY trial was limited and is not presented here.

The following adverse reactions, listed by MedDRA SOC in Table 2, have been adjudicated fromevents which occurred in at least 3% of tocilizumab treated patients and more commonly than that inpatients on placebo in the pooled safety-evaluable population from clinical trials ML42528,

WA42380, and WA42511.

Table 2. List of adverse reactions1 identified from the pooled safety-evaluable population fromtocilizumab clinical trials in COVID-19 patients2

MedDRA SOC Class Preferred Terms and frequency

Common

Infections and infestations Urinary tract infection

Metabolism and nutrition Hypokalaemiadisorders

Psychiatric disorders Anxiety, Insomnia

Vascular disorders Hypertension

Gastrointestinal disorders Constipation, Diarrhoea, Nausea

Hepatobiliary disorders Hepatic transaminases increased1 Patients are counted once for each category regardless of the number of reactions2 Includes adjudicated reactions reported in studies WA42511, WA42380 and ML42528

Patients with sJIA or pJIA

Adverse reactions in the sJIA and pJIA patients treated with tocilizumab are listed in the Table 3 andpresented by MedDRA SOC. The corresponding frequency category for each adverse reaction is basedon the following convention: very common ( ≥ 1/10); common ( ≥ 1/100 to < 1/10) or uncommon( ≥ 1/1 000 to < 1/100).

Table 3. List of adverse reactions occurring in clinical trial patients with sJIA or pJIA receivingtocilizumab as monotherapy or in combination with MTX.

MedDRA SOC Preferrred term (PT) Frequency

Infections and Infestations Very Common Common Uncommon

Upper Respiratory pJIA, sJIA

Tract Infections

Nasopharyngitis pJIA, sJIA

Headache pJIA sJIA

Gastrointestinal Disorders

Nausea pJIA

Diarrhoea pJIA, sJIA

General disorders and administration siteconditions

Infusion related pJIA1, sJIA2reactions

Hepatic transaminases pJIAincreased

Decrease in neutrophil sJIA pJIAcount

Platelet count sJIA pJIAdecreased

Cholesterol increased sJIA pJIA1. Infusion-related reaction events in pJIA patients included but were not limited to headache, nausea and hypotension2. Infusion-related reaction events in sJIA patients included but were not limited to rash, urticaria, diarrhoea, epigastricdiscomfort, arthralgia and headache

RA patients

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 yearsin the placebo plus DMARD group. In the long-term exposure population, the overall rate of infectionswith tocilizumab was 108 events per 100 patient years exposure.

In 6-month controlled clinical trials, the rate of serious infections with tocilizumab 8 mg/kg plus

DMARDs was 5.3 events per 100 patient years exposure compared to 3.9 events per 100 patient yearsexposure in the placebo plus DMARD group. In the monotherapy study, the rate of serious infectionswas 3.6 events per 100 patient years of exposure in the tocilizumab group and 1.5 events per100 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, includedactive tuberculosis, which may present with intrapulmonary or extrapulmonary disease, invasivepulmonary infections, including candidiasis, aspergillosis, coccidioidomycosis and pneumocystisjirovecii, pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterialarthritis. Cases of opportunistic infections have been reported.

Impaired lung function may increase the risk for developing infections. There have beenpost-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, was0.26 events per 100 patient years with tocilizumab therapy. In the long-term exposure population theoverall rate of gastrointestinal perforation was 0.28 events per 100 patient years. Reports ofgastrointestinal perforation on treatment were primarily reported as complications of diverticulitisincluding generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess.

In the 6-month controlled trials adverse events associated with infusion (selected events occurringduring or within 24 hours of infusion) were reported by 6.9% of patients in the tocilizumab 8 mg/kgplus DMARD group and 5.1% of patients in the placebo plus DMARD group. Events reported duringthe infusion were primarily episodes of hypertension; events reported within 24 hours of finishing aninfusion 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 foldhigher with the 4 mg/kg dose, compared to the 8 mg/kg dose. Clinically significant hypersensitivityreactions associated with tocilizumab and requiring treatment discontinuation were reported in a totalof 56 out of 4 009 patients (1.4%) treated during the controlled and open label clinical trials. Thesereactions 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).

A total of 2 876 patients have been tested for anti-tocilizumab antibodies in the 6-month controlledclinical trials. Of the 46 patients (1.6%) who developed anti-tocilizumab antibodies, 6 had anassociated medically significant hypersensitivity reaction, of which 5 led to permanent discontinuationof treatment. Thirty patients (1.1%) developed neutralising antibodies.

In the 6-month controlled trials decreases in neutrophil counts below 1 × 109/ L occurred in 3.4% ofpatients on tocilizumab 8 mg/kg plus DMARDs compared to < 0.1% of patients on placebo plus

DMARDs. Approximately half of the patients who developed an ANC < 1 × 109/ L did so within8 weeks after starting therapy. Decreases below 0.5 × 109/ L were reported in 0.3% patients receivingtocilizumab 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 ofdecreases in neutrophil counts remained consistent with what was seen in the 6-month controlledclinical trials.

Platelets

In the 6-month controlled trials decreases in platelet counts below 100 × 103/µL occurred in 1.7% ofpatients on tocilizumab 8 mg/kg plus DMARDs compared to < 1% on placebo plus DMARDs. Thesedecreases occurred without associated bleeding events.

During the double-blind controlled period and with long-term exposure, the pattern and incidence ofdecreases in platelet counts remained consistent with what was seen in the 6-month controlled clinicaltrials.

Very rare reports of pancytopenia have occurred in the post-marketing setting.

Hepatic transaminase elevations

During the 6-month controlled trials transient elevations in ALT/AST > 3 × ULN were observed in2.1% of patients on tocilizumab 8 mg/kg compared to 4.9% of patients on MTX and in 6.5% ofpatients who received 8 mg/kg tocilizumab plus DMARDs compared to 1.5% of patients on placeboplus DMARDs.

The addition of potentially hepatotoxic medicinal products (e.g. MTX) to tocilizumab monotherapyresulted in increased frequency of these elevations. Elevations of ALT/AST > 5 × ULN were observedin 0.7% of tocilizumab monotherapy patients and 1.4% of tocilizumab plus DMARD patients, themajority of whom were discontinued permanently from tocilizumab treatment. During thedouble-blind controlled period, the incidence of indirect bilirubin greater than the upper limit ofnormal, collected as a routine laboratory parameter, is 6.2% in patients treated with 8 mg/kgtocilizumab + DMARD. A total of 5.8% of patients experienced an elevation of indirect bilirubinof > 1 to 2 × ULN and 0.4% had an elevation of > 2 × ULN.

During the double-blind controlled period and with long-term exposure, the pattern and incidence ofelevation in ALT/AST remained consistent with what was seen in the 6-month controlled clinicaltrials.

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 routinelaboratory monitoring it was seen that approximately 24% of patients receiving tocilizumab in clinicaltrials experienced sustained elevations in total cholesterol ≥ 6.2 mmol/ L with 15% experiencing asustained increase in LDL to ≥ 4.1 mmol/ L. Elevations in lipid parameters responded to treatmentwith lipid-lowering agents.

During the double-blind controlled period and with long-term exposure, the pattern and incidence ofelevations in lipid parameters remained consistent with what was seen in the 6-month controlled trials.

Rare reports of Stevens-Johnson Syndrome have occurred in the post-marketing setting.

COVID-19 patients

In the pooled safety-evaluable population from trials ML42528, WA42380, and WA42511, the ratesof infection/serious infection events were balanced between COVID-19 patients receiving tocilizumab(30.3%/18.6%, n=974) versus placebo (32.1%/22.8%, n=483).

The safety profile observed in the baseline systemic corticosteroids treatment group was consistentwith the safety profile of tocilizumab from the overall population presented in Table 2. In thissubgroup, infections and serious infections occurred in 27.8% and 18.1% of patients treated withintravenous tocilizumab and in 30.5% and 22.9% of patients treated with placebo, respectively.

The incidence of laboratory abnormalities was generally similar between patients with COVID-19who received one or two doses of tocilizumab-intravenous compared with those who received placeboin the randomised, double-blind, placebo-controlled trials with few exceptions. Decreases in plateletsand neutrophils and elevations of ALT and AST were more frequent among patients receivingtocilizumab-intravenous versus placebo (see section 4.2 and 4.4).

In general, the adverse reactions in pJIA and sJIA patients were similar in type to those seen in RApatients, see section 4.8.

Description of selected adverse reactions in pJIA patients

The safety profile of intravenous tocilizumab in pJIA has been studied in 188 patients from 2 to17 years of age. The total patient exposure was 184.4 patient years. The frequency of adverse reactionsin pJIA patients can be found in Table 3. The types of adverse reactions in pJIA patients were similarto those seen in RA and sJIA patients. When compared to the adult RA population, events ofnasopharyngitis, headache, nausea, and decreased neutrophil count were more frequently reported inthe pJIA population. Events of cholesterol increased were less frequently reported in the pJIApopulation than in the adult RA population.

The rate of infections in the tocilizumab all exposure population was 163.7 per 100 patient years. Themost common events observed were nasopharyngitis and upper respiratory tract infections. The rate ofserious infections was numerically higher in patients weighing < 30 kg treated with 10 mg/kgtocilizumab (12.2 per 100 patient years) compared to patients weighing ≥ 30 kg, treated with 8 mg/kgtocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions wasalso 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%).

In pJIA patients, infusion-related reactions are defined as all events occurring during or within24 hours of an infusion. In the tocilizumab all exposure population, 11 patients (5.9%) experiencedinfusion-related reactions during the infusion and 38 patients (20.2%) experienced an event within24 hours of an infusion. The most common events occurring during infusion were headache, nauseaand hypotension and within 24 hours of infusion were dizziness and hypotension. In general, theadverse reactions observed during or within 24 hours of an infusion were similar in nature to thoseseen in RA and sJIA patients, see section 4.8.

No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatmentdiscontinuation were reported.

One patient in the 10 mg/kg < 30 kg group developed positive anti-tocilizumab antibodies withoutdeveloping a hypersensitivity reaction and subsequently withdrew from the study.

During routine laboratory monitoring in the tocilizumab all exposure population, a decrease inneutrophil 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 adecrease in platelet count to≤ 50 × 103/µL without associated bleeding events.

Hepatic transaminase elevations

During routine laboratory monitoring in the tocilizumab all exposure population, elevation in ALT or

AST ≥ 3 × ULN occurred in 3.7% and < 1% of patients, respectively.

Lipid parameters

During routine laboratory monitoring in the intravenous tocilizumab study WA19977 3.4% and 10.4%of patients experienced a post-baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL andtotal cholesterol value to ≥ 200 mg/dL at any time during the study treatment, respectively.

Description of selected adverse reactions in sJIA patients

The safety profile of intravenous tocilizumab in sJIA has been studied in 112 patients from 2 to17 years of age. In the 12 week double-blind, controlled phase, 75 patients received treatment withtocilizumab (8 mg/kg or 12 mg/kg based upon body weight). After 12 weeks or at the time ofswitching from placebo to tocilizumab, due to disease worsening, patients were treated in the openlabel extension phase.

In general, the adverse reactions in sJIA patients were similar in type to those seen in RA patients. Thefrequency of adverse reactions in sJIA patients can be found in Table 3. When compared to the adult

RA population, patients with sJIA experienced a higher frequency of nasopharyngitis, decrease inneutrophil counts, hepatic transaminases increased, and diarrhoea. Events of cholesterol increasedwere less frequently reported in the sJIA population than in the adult RA population.

In the 12 week controlled phase, the rate of all infections in the intravenous tocilizumab group was344.7 per 100 patient years and 287.0 per 100 patient years in the placebo group. In the open labelextension phase (Part II), the overall rate of infections remained similar at 306.6 per 100 patient years.

In the 12 week controlled phase, the rate of serious infections in the intravenous tocilizumab groupwas 11.5 per 100 patient years. At one year in the open label extension phase the overall rate of seriousinfections remained stable at 11.3 per 100 patient years. Reported serious infections were similar tothose seen in RA patients with the addition of varicella and otitis media.

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 eventsoccurring during infusion. One event (angioedema) was considered serious and life-threatening, andthe 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 theplacebo group experienced an event within 24 hours of infusion. In the tocilizumab group, the eventsincluded, but were not limited to rash, urticaria, diarrhoea, epigastric discomfort, arthralgia andheadache. One of these events, urticaria, was considered serious.

Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatmentdiscontinuation, were reported in 1 out of 112 patients ( < 1%) treated with tocilizumab during thecontrolled and up to and including the open label clinical trial.

All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developedpositive anti-tocilizumab antibodies with one of these patients having a hypersensitivity reactionleading to withdrawal. The incidence of anti-tocilizumab antibody formation might be underestimatedbecause of interference of tocilizumab with the assay and higher tocilizumab concentration observedin children compared to adults.

During routine laboratory monitoring in the 12 week controlled phase, a decrease in neutrophil countsbelow 1 × 109/L occurred in 7% of patients in the tocilizumab group, and no decreases in the placebogroup.

In the open label extension phase, decreases in neutrophil counts below 1 × 109/L, occurred in 15% ofthe tocilizumab group.

Platelets

During routine laboratory monitoring in the 12 week controlled phase, 3% of patients in the placebogroup and 1% in the tocilizumab group had a decrease in platelet count to ≤ 100 × 103/µL.

In the open label extension phase, decreases in platelet counts below 100 × 103/µL, occurred in 3% ofpatients in the tocilizumab group, without associated bleeding events.

Hepatic transaminase elevations

During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or

AST ≥ 3 × ULN occurred in 5% and 3% of patients, respectively, in the tocilizumab group, and 0% inthe placebo group.

In the open label extension phase, elevation in ALT or AST ≥ 3 × ULN occurred in 12% and 4% ofpatients, respectively, in the tocilizumab group.

Immunoglobulin G

IgG levels decrease during therapy. A decrease to the lower limit of normal occurred in 15 patients atsome point in the study.

Lipid parameters

During routine laboratory monitoring in the 12 week controlled phase (study WA18221), 13.4% and33.3% of patients experienced a post-baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dLand 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 valueto ≥ 200 mg/dL at any time during study treatment, respectively.

CRS patients

The safety of tocilizumab in CRS has been evaluated in a retrospective analysis of data from clinicaltrials, where 51 patients were treated with intravenous tocilizumab 8 mg/kg (12 mg/kg for patients lessthan 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There are limited data available on overdose with tocilizumab. One case of accidental overdose wasreported in which a patient with multiple myeloma received a single dose of 40 mg/kg. No adversereactions were observed.

No serious adverse reactions were observed in healthy volunteers who received a single dose up to28 mg/kg, although dose limiting neutropenia was observed.

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

Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R andmIL-6R). Tocilizumab has been shown to inhibit sIL-6R and mIL-6R-mediated signalling. IL-6 is apleiotropic 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-cellactivation, induction of immunoglobulin secretion, induction of hepatic acute phase protein synthesisand stimulation of haemopoiesis. IL-6 has been implicated in the pathogenesis of diseases includinginflammatory diseases, osteoporosis and neoplasia.

In clinical trials with RA patients treated with tocilizumab, rapid decreases in CRP, erythrocytesedimentation rate (ESR), serum amyloid A (SAA) and fibrinogen were observed. Consistent with theeffect on acute phase reactants, treatment with tocilizumab was associated with reduction in plateletcount within the normal range. Increases in haemoglobin levels were observed, through tocilizumabdecreasing the IL-6 driven effects on hepcidin production to increase iron availability. In treatedpatients, decreases in the levels of CRP to within normal ranges were seen as early as week 2, withdecreases maintained while on treatment.

In healthy subjects administered tocilizumab in doses from 2 to 28 mg/kg, absolute neutrophil countsdecreased to their lowest 3 to 5 days following administration. Thereafter, neutrophils recoveredtowards baseline in a dose dependent manner. Rheumatoid arthritis patients demonstrated a similarpattern of absolute neutrophil counts following tocilizumab administration (see section 4.8).

In COVID-19 patients with one dose of tocilizumab 8 mg/kg administered intravenously, decreases inthe levels of CRP to within normal ranges were seen as early as day 7.

RA patients

The efficacy of tocilizumab in alleviating the signs and symptoms of RA was assessed in fiverandomised, double-blind, multi-centre trials. Trials I-V enrolled patients ≥ 18 years of age with active

RA diagnosed according to the American College of Rheumatology (ACR) criteria and who had atleast eight tender and six swollen joints at baseline.

In Study I, tocilizumab was administered intravenously every four weeks as monotherapy. In Trials II,

III and V, tocilizumab was administered intravenously every four weeks in combination with MTX vs.placebo and MTX. In Study IV, tocilizumab was administered intravenously every 4 weeks incombination with other DMARDs vs. placebo and other DMARDs. The primary endpoint for each ofthe five trials 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 torandomisation and who had not discontinued previous MTX treatment as a result of clinicallyimportant toxic effects or lack of response. The majority (67%) of patients were MTX-naïve. Doses of8 mg/kg of tocilizumab were given every four weeks as monotherapy. The comparator group wasweekly 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, evaluated1,196 patients who had an inadequate clinical response to MTX. Doses of 4 or 8 mg/kg of tocilizumabor 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 withtocilizumab 8 mg/kg. Of the patients who completed the study who were originally randomised toplacebo + MTX, 86% received open-label tocilizumab 8 mg/kg in year 2. The primary endpoint atweek 24 was the proportion of patients who achieved an ACR 20 response. At week 52 and week 104the 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 or8 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 rheumatologictherapy, including one or more DMARDs. Doses of 8 mg/kg tocilizumab or placebo were given everyfour weeks in combination with stable DMARDs.

Study V evaluated 499 patients who had an inadequate clinical response or were intolerant to one ormore 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).

In all trials, patients treated with tocilizumab 8 mg/kg had statistically significant higher ACR 20, 50,70 response rates at 6 months compared to control (Table 4). In study I, superiority of tocilizumab8 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 themagnitude of response continued to improve with duration of treatment. Continued durable responseswere seen for over 3 years in the open label extension trials I-V.

In patients treated with tocilizumab 8 mg/kg, significant improvements were noted on all individualcomponents of the ACR response including: tender and swollen joint counts; patients and physicianglobal assessment; disability index scores; pain assessment and CRP compared to patients receivingplacebo plus MTX or other DMARDs in all trials.

Patients in trials I - V had a mean Disease Activity Score (DAS28) of 6.5-6.8 at baseline. Significantreduction 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 DAS28clinical 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 trials II, III and IV, the proportion of patients achieving an ACR 20, 50 and 70response was significantly higher (59% vs. 50%, 37% vs. 27%, 18% vs. 11%, respectively) in thetocilizumab 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 significantlyhigher (31% vs. 16% respectively) in patients receiving tocilizumab 8 mg/kg plus DMARD than inpatients receiving tocilizumab 4 mg/kg plus DMARD (p < 0.0001).

Table 4. ACR responses in placebo-/MTX-/DMARDs-controlled trials (% patients)

Study I Study II Study III Study IV Study V

AMBITION LITHE OPTION TOWARD RADIATEweek TCZ MT TCZ PBO TCZ PBO TCZ PBO + TCZ PBO +8 mg/k X 8 mg/k + MT 8 mg/k + MT 8 mg/kg DMAR 8 mg/k MTXg g X g X + D g+ MT + MT DMAR + MT

X X D X

N = N = N = N = N = N = N = N = N = N =286 284 398 393 205 204 803 413 170 158

ACR 2024 70%** 52% 56%** 27% 59%** 26% 61%*** 24% 50%** 10%

* * * *52 56%** 25%

*

ACR 5024 44%** 33% 32%** 10% 44%** 11% 38%*** 9% 29%** 4%

* * *52 36%** 10%

*

ACR 7024 28%** 15% 13%** 2% 22%** 2% 21%*** 3% 12%** 1%

* *52 20%** 4%

*

ACR - American College of Rheumatology (ACR) criteria

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 clinicalresponse (maintenance of an ACR 70 response for 24 weeks or more).

In Study II, in patients with an inadequate response to MTX, inhibition of structural joint damage wasassessed radiographically and expressed as change in modified Sharp score and its components, theerosion score and joint space narrowing score. Inhibition of joint structural damage was shown withsignificantly less radiographic progression in patients receiving tocilizumab compared to control(Table 5).

In the open-label extension of Study II the inhibition of progression of structural joint damage intocilizumab plus MTX-treated patients was maintained in the second year of treatment. The meanchange from baseline at week 104 in total Sharp-Genant score was significantly lower for patientsrandomised to tocilizumab 8 mg/kg plus MTX (p < 0.0001) compared with patients who wererandomised to placebo plus MTX.

Table 5. Radiographic mean changes over 52 weeks in Study II

PBO + MTX TCZ 8 mg/kg + MTX(+ TCZ from week 24)

N = 393 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 noprogression 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 remainedconsistent following 2 years of treatment (83%; n=353). Ninety three percent (93%; n=271) of patientshad 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 wereobserved in patients treated with tocilizumab compared with patients treated with DMARDs. Duringthe open-label period of Study II, the improvement in physical function has been maintained for up to2 years. At week 52, the mean change in HAQ-DI was -0.58 in the tocilizumab 8 mg/kg plus MTXgroup compared with -0.39 in the placebo + MTX group. The mean change in HAQ-DI wasmaintained 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 tocilizumabcompared with DMARDs (p < 0.0001) at week 24. Mean haemoglobin levels increased by week 2 andremained 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 withadalimumab monotherapy, evaluated 326 patients with RA who were intolerant of MTX or wherecontinued treatment with MTX was considered inappropriate (including MTX inadequate responders).

Patients in the tocilizumab arm received an intravenous infusion of tocilizumab (8 mg/kg) every4 weeks (q4w) and a subcutaneous placebo injection every 2 weeks (q2w). Patients in the adalimumabarm received an adalimumab subcutaneous injection (40 mg) q2w plus an intravenous placeboinfusion q4w. A statistically significant superior treatment effect was seen in favour of tocilizumabover adalimumab in control of disease activity from baseline to week 24 for the primary endpoint ofchange in DAS28 and for all secondary endpoints (Table 6).

Table 6. Efficacy results for Study VI (WA19924)

ADA + Placebo TCZ + Placebo(IV) (SC)

N = 162 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

ACR 20 response, n (%) 80 (49.4) 106 (65.0) 0.0038

ACR 50 response, n (%) 45 (27.8) 77 (47.2) 0.0002

ACR 70 response, n (%) 29 (17.9) 53 (32.5) 0.0023a p-value is adjusted for region and duration of RA for all endpoints and additionally baseline value for all continuousendpoints.b Non-responder Imputation used for missing data. Multiplicity controlled using Bonferroni-Holm Procedure

IV = intravenous

SC = subcutaneous

TCZ = tocilizumab

ADA = adalimumab

The overall clinical adverse event profile was similar between tocilizumab and adalimumab. Theproportion of patients with serious adverse events was balanced between the treatment groups(tocilizumab 11.7% vs. adalimumab 9.9%). The types of adverse reactions in the tocilizumab armwere consistent with the known safety profile of tocilizumab and adverse reactions were reported at asimilar frequency compared with Table 1. A higher incidence of infections and infestations wasreported in the tocilizumab arm (48% vs. 42%), with no difference in the incidence of seriousinfections (3.1%). Both study treatments induced the same pattern of changes in laboratory safetyparameters (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 tocilizumabcompared with adalimumab. Four (2.5%) patients in the tocilizumab arm and two (1.2%) patients inthe adalimumab arm experienced CTC grade 3 or 4 neutrophil count decreases. Eleven (6.8%) patientsin 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) forpatients in the tocilizumab arm and 0.19 mmol/L (7 mg/dL) for patients in the adalimumab arm. Thesafety observed in the tocilizumab arm was consistent with the known safety profile of tocilizumaband no new or unexpected adverse 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 evaluated1162 MTX-naïve adult patients with moderate to severe, active early RA (mean diseaseduration ≤ 6 months). Approximately 20% of patients had received prior treatment with DMARDsother than MTX. This study evaluated the efficacy of intravenous tocilizumab 4 or 8 mg/kg every4 weeks/MTX combination therapy, intravenous tocilizumab 8 mg/kg monotherapy and MTXmonotherapy in reducing the signs and symptoms and rate of progression of joint damage for104 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 tocilizumab8 mg/kg + MTX and tocilizumab monotherapy groups met the primary endpoint compared with MTXalone. The tocilizumab 8 mg/kg + MTX group also showed statistically significant results across thekey secondary endpoints. Numerically greater responses compared with MTX alone were observed inthe tocilizumab 8 mg/kg monotherapy group in all secondary endpoints, including radiographicendpoints. 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 resultsfrom study VII are shown in Table 7.

Table 7. Efficacy Results for Study VII (WA19926) on MTX-naïve, early RA patients

TCZ4 mg/kg

TCZ 8 mg/kg TCZ 8 mg/kg + Placebo ++ MTX + placebo MTX MTX

N=290 N=292 N=288 N=287

Primary endpoint

DAS28 Remissionweek 24 n (%) 130 (44.8)*** 113 (38.7)*** 92 (31.9) 43 (15.0)

Key secondary endpoints

DAS 28 remissionweek 52 n (%) 142 (49.0)*** 115 (39.4) 98 (34.0) 56 (19.5)

ACRweek 24 ACR 20, n (%) 216 (74.5)* 205 (70.2) 212 187 (65.2)(73.6)

ACR 50, n (%) 165 (56.9)** 139 (47.6) 138 124 (43.2)(47.9)

ACR 70, n (%) 112 (38.6)** 88 (30.1) 100 73 (25.4)(34.7)week 52 ACR 20, n (%) 195 (67.2)* 184 (63.0) 181 164 (57.1)(62.8)

ACR 50, n (%) 162 (55.9)** 144 (49.3) 151 117 (40.8)(52.4)

ACR 70, n (%) 125 (43.1)** 105 (36.0) 107 83 (28.9)(37.2)

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 226 (83)‡ 226 (82)‡ 211 (79) 194 (73)from baseline in mTSS of ≤ 0)

Exploratory endpointsweek 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

TCZ - tocilizumab

MTX - methotrexate

ACR - American College of Rheumatology (ACR) criteria

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 hastherefore not been controlled for multiplicity)

COVID-19

RECOVERY (randomised evaluation of COVID-19 therapy) collaborative group study in hospitalisedadults diagnosed with COVID-19

RECOVERY was a large, randomised, controlled, open-label, multi-centre platform study conductedin the United Kingdom to evaluate the efficacy and safety of potential treatments in hospitalised adultpatients with severe COVID-19. All eligible patients received usual care and underwent an initial(main) randomisation. Eligible patients for the trial had clinically suspected or laboratory-confirmed

SARS-CoV-2 infection and no medical contraindications to any of the treatments. Patients withclinical evidence of progressive COVID-19 (defined as oxygen saturation < 92% on room air orreceiving oxygen therapy, and CRP ≥ 75 mg/L) qualified for a second randomisation to receive eitherintravenous tocilizumab or usual care alone.

Efficacy analyses were performed in the intent-to-treat (ITT) population comprising 4116 patients whowere randomised with 2022 patients in the tocilizumab + usual care arm and 2094 patients in the usualcare alone arm. The baseline demographic and disease characteristics of the ITT population were wellbalanced across treatment arms. The mean age of participants was 63.6 years (standard deviation [SD]13.6 years). The majority of patients were male (67%) and White (76%). The median (range) level of

CRP was 143 mg/L (75-982).

At baseline, 0.2% (n=9) of patients were not on supplemental oxygen, 45% of patients required lowflow oxygen, 41% of patients required non-invasive ventilation or high-flow oxygen and 14% ofpatients required invasive mechanical ventilation; 82% were reported receiving systemiccorticosteroids (defined as patients who initiated treatment with systemic corticosteroids either prior toor at the time of randomisation). The most common comorbidities were diabetes (28.4%), heartdisease (22.6%) and chronic lung disease (23.3%).

The primary outcome was time to death through Day 28. The hazard ratio comparing thetocilizumab + usual care arm to the usual care alone arm was 0.85 (95% CI: 0.76 to 0.94), astatistically significant result (p=0.0028). The probabilities of dying by Day 28 were estimated to be30.7% and 34.9% in the tocilizumab and usual care arms, respectively. The risk difference wasestimated to be -4.1% (95% CI: -7.0% to -1.3%), consistent with the primary analysis. The hazardratio among the pre-specified subgroup of patients receiving systemic corticosteroids at baseline was0.79 (95% CI: 0.70 to 0.89), and for the pre-specified subgroup not receiving systemic corticosteroidsat baseline was 1.16 (95% CI: 0.91 to 1.48).

The median time to hospital discharge was 19 days in the tocilizumab+ usual care arm and > 28 daysin the usual care arm (hazard ratio [95% CI]=1.22 [1.12 to 1.33]).

Among patients not requiring invasive mechanical ventilation at baseline, the proportion of patientswho required mechanical ventilation or died by Day 28 was 35% (619/1754) in thetocilizumab + usual care arm and 42% (754/1800) in the usual care alone arm (risk ratio [95% CI] =0.84, [0.77 to 0.92] p < 0.0001).

Paediatric population with sJIA

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 atotal disease duration of at least 6 months and active disease but were not experiencing an acute flarerequiring corticosteroid doses of more than 0.5 mg/kg prednisone equivalent. Efficacy for thetreatment of macrophage activation syndrome (MAS) has not been investigated.

Patients (treated with or without MTX) were randomised (tocilizumab:placebo = 2:1) to one of twotreatment groups, 75 patients received tocilizumab infusions every two weeks, either 8 mg/kg forpatients ≥ 30 kg or 12 mg/kg for patients < 30 kg and 37 patients were assigned to receiving placeboinfusions every two weeks. Corticosteroid tapering was permitted from week six for patients whoachieved a JIA ACR 70 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.

The primary endpoint was the proportion of patients with at least 30% improvement in the JIA ACRcore set (JIA ACR 30 response) at week 12 and absence of fever (no temperature recording ≥ 37.5 °Cin 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 significantlydifferent (p < 0.0001).

The percent of patients achieving JIA ACR 30, 50, 70 and 90 responses are shown in Table 8.

Table 8. JIA ACR response rates at week 12 (% patients)

Response rate Tocilizumab Placebo

N = 75 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

In the tocilizumab treated patients, 85% who had fever due to sJIA at baseline were free of fever (notemperature 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 of41 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 ACR 70 response were permitted corticosteroid dose reduction. Seventeen(24%) tocilizumab treated patients versus 1 (3%) placebo patient were able to reduce their dose ofcorticosteroid by at least 20% without experiencing a subsequent JIA ACR 30 flare or occurrence ofsystemic symptoms to week 12 (p=0.028). Reductions in corticosteroids continued, with 44 patientsoff 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 importantimprovement in the Childhood Health Assessment Questionnaire - Disability Index (defined as anindividual total score decrease of ≥ 0.13) was significantly higher than in placebo treated patients, 77%versus 19% (p < 0.0001).

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 atweek 12, in comparison to 2 out of 29 (7%) of placebo treated patients with haemoglobin < LLN atbaseline (p < 0.0001).

Paediatric population with pJIA

The efficacy of tocilizumab was assessed in a three-part study WA19977 including an open-labelextension in children with active pJIA. Part I consisted of a 16-week active tocilizumab treatmentlead-in period (n=188) followed by Part II, a 24-week randomised double-blind placebo-controlledwithdrawal period (n=163), followed by Part III, a 64-week open-label period. In Part 1, eligiblepatients ≥ 30 kg received tocilizumab at 8 mg/kg intravenous every 4 weeks for 4 doses.

Patients < 30 kg were randomised 1:1 to receive either tocilizumab 8 mg/kg or 10 mg/kg intravenousevery 4 weeks for 4 doses. Patients who completed Part I of the study and achieved at least a JIA

ACR 30 response at week 16 compared to baseline were eligible to enter the blinded withdrawalperiod (Part II) of the study. In Part II, patients were randomised 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 ACR 30flare criteria (relative to week 16) and qualified for escape to tocilizumab therapy (same dose receivedin Part I).

The primary endpoint was the proportion of patients with a JIA ACR 30 flare at week 40 relative toweek 16. Forty eight percent (48.1%, 39/81) of the patients treated with placebo flared compared with25.6% (21/82) of tocilizumab treated patients. These proportions were statistically significantlydifferent (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 70responses at week 40 relative to baseline are shown in Table 9. In this statistical analysis, patients whoflared (and escaped to tocilizumab) 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 offlare status, showed that by week 40, 95.1% of patients who had received continuous tocilizumabtherapy, had achieved JIA ACR 30 or higher.

Table 9. JIA ACR response rates at week 40 relative to baseline (percentage of patients)

Response rate Tocilizumab Placebo

N=82 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 receivingtocilizumab compared to placebo (adjusted mean changes of -14.3 vs -11.4, p=0.0435). Thephysician’s global assessment of disease activity, as measured on a 0-100 mm scale, showed a greaterreduction in disease activity for tocilizumab compared to placebo (adjusted mean changes of -45.2 mmvs -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 a0-100 mm scale compared to a reduction of 22.3 mm for placebo patients (highly statisticallysignificant; p=0.0076).

The ACR response rates were numerically lower for patients with prior biologic treatment as shown in

Table 10 below.

Table 10. Number and proportion of patients with a JIA ACR 30 flare and proportion of patients with

JIA ACR 30/50/70/90 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 ACR 30 Flare 18 (78.3) 21 (36.2) 12 (44.4) 9 (16.4)

JIA ACR 30 Response 6 (26.1) 38 (65.5) 15 (55.6) 46 (83.6)

JIA ACR 50 Response 5 (21.7) 37 (63.8) 14 (51.9) 46 (83.6)

JIA ACR 70 Response 2 (8.7) 32 (55.2) 13 (48.1) 40 (72.7)

JIA ACR 90 Response 2 (8.7) 17 (29.3) 5 (18.5) 32 (58.2)

TCZ = tocilizumab

Patients randomised to tocilizumab had fewer ACR 30 flares and higher overall ACR responses thanpatients receiving placebo regardless of a history of prior biologic use.

CRS

The efficacy of tocilizumab for the treatment of CRS was assessed in a retrospective analysis of datafrom clinical trials of CAR T-cell therapies (tisagenlecleucel and axicabtagene ciloleucel) forhaematological 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 orlife-threatening CRS; only the first episode of CRS was included in the analysis. The efficacypopulation for the tisagenlecleucel cohort included 28 males and 23 females (total 51 patients) ofmedian age 17 years (range, 3-68 years). The median time from start of CRS to first dose oftocilizumab was 3 days (range, 0-18 days). Resolution of CRS was defined as lack of fever and offvasopressors for at least 24 hours. Patients were considered responders if CRS resolved within 14 daysof the first dose of tocilizumab, if no more than 2 doses were needed, and no medicinal products otherthan tocilizumab 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 withtocilizumab in all subsets of the paediatric population in treatment of cytokine release syndromeassociated with CAR T-cell therapy.

COVID-19

The European Medicines Agency has deferred the obligation to submit the results of studies withtocilizumab in one or more subsets of the paediatric population in the treatment of COVID-19.

RA patients

The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis ona database composed of 3552 RA patients treated with a one-hour infusion of 4 or 8 mg/kgtocilizumab every 4 weeks for 24 weeks or with 162 mg tocilizumab given subcutaneously either oncea week or every other week for 24 weeks.

The following parameters (predicted mean ± SD) were estimated for a dose of 8 mg/kg tocilizumabgiven every 4 weeks: steady-state area under curve (AUC) = 38 000 ± 13 000 h µg/mL, troughconcentration (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. Theaccumulation ratio was higher for Cmin (2.49), which was expected based on the non-linear clearancecontribution 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 Cmaxincreased 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 patientpopulation (i.e. all body weights) reported above. The dose-response curve for tocilizumab flattens athigher exposure, resulting in smaller efficacy gains for each incremental increase in tocilizumabconcentration such that clinically meaningful increases in efficacy were not demonstrated in patientstreated with > 800 mg of tocilizumab. Therefore, tocilizumab doses exceeding 800 mg per infusion arenot recommended (see section 4.2).

COVID-19 patients

The pharmacokinetics of tocilizumab was characterised using a population pharmacokinetic analysisof a database composed of 380 adult COVID-19 patients in Study WA42380 (COVACTA) and Study

CA42481 (MARIPOSA) that treated with a single infusion of 8 mg/kg tocilizumab or two infusionsseparated by at least 8 hours. The following parameters (predicted mean ± SD) were estimated for adose of 8 mg/kg tocilizumab: area under curve over 28 days (AUC0-28) = 18312 (5184) hour*µg/mL,concentration at Day 28 (Cday28) = 0.934 (1.93) µg/mL and maximum concentration (Cmax) = 154(34.9) µg/mL. The AUC0-28, Cday28 and Cmax, following two doses of 8 mg/kg tocilizumab separated by8 hours, were also estimated (predicted mean ± SD): 42240 (11520) hour*µg/mL and 8.94(8.5) µg/mL, and 296 (64.7) µg/mL respectively.

In RA patients the central volume of distribution was 3.72 L, the peripheral volume of distribution was3.35 L resulting in a volume of distribution at steady-state of 7.07 L.

In COVID-19 adult patients, the central volume of distribution was 4.52 L, the peripheral volume ofdistribution was 4.23 L, resulting in a volume of distribution of 8.75 L.

Following intravenous administration, tocilizumab undergoes a dual elimination from the circulation,one following a linear clearance and one following a concentration-dependent non-linear clearance. In

RA patients, the linear clearance was 9.5 mL/h. In COVID-19 adult patients, the linear clearance was17.6 mL/h in patients with baseline ordinal scale category 3 (OS 3, patients requiring supplementaloxygen), 22.5 mL/h in patients with baseline OS 4 (patients requiring high-flow oxygen or non-invasive ventilation), 29 mL/h in patients with baseline OS 5 (patients requiring mechanicalventilation), and 35.4 mL/h in patients with baseline OS 6 (patients requiring extracorporealmembrane oxygenation (ECMO) or mechanical ventilation and additional organ support). Theconcentration-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 ismainly determined by the linear clearance.

In RA patients, the t1/2 of tocilizumab was concentration-dependent. At steady-state following a doseof 8 mg/kg every 4 weeks, the effective t1/2 decreased with decreasing concentrations within a dosinginterval from 18 days to 6 days.

In COVID-19 patients, serum concentrations were below the limit of quantification after 35 days onaverage following one infusion of tocilizumab intravenous 8 mg/kg.

Pharmacokinetic parameters of tocilizumab did not change with time. A more than dose-proportionalincrease in the AUC and Cmin was observed for doses of 4 and 8 mg/kg every 4 weeks. Cmax increaseddose-proportionally. At steady-state, predicted AUC and Cmin were 3.2 and 30 fold higher at 8 mg/kgas compared to 4 mg/kg, respectively.

No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab has beenconducted. Most of the patients in the population pharmacokinetic analysis had normal renal functionor 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.

No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab has beenconducted.

Age, gender and ethnicity

Population pharmacokinetic analyses in RA and COVID-19 patients, showed that age, gender andethnic origin did not affect the pharmacokinetics of tocilizumab.

Results of the population PK analysis for COVID-19 patients confirmed that body weight and diseaseseverity are both covariates which have an appreciable impact on the linear clearance of tocilizumab.

sJIA Patients

The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis ona database composed of 140 sJIA patients treated with 8 mg/kg intravenous every 2 weeks (patientswith a body weight ≥ 30 kg) 12 mg/kg intravenous every 2 weeks (patients with a bodyweight < 30 kg), 162 mg subcutaneous every week (patients weighing ≥ 30 kg), 162 mg subcutaneousevery 10 days or every 2 weeks (patients weighing below 30 kg).

Table 11. Predicted mean ± SD PK parameters at steady-state after intravenous dosing in sJIA

Tocilizumab 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 2.01 1.95

AUCτ*

*τ = 2 weeks for intravenous regimens

After intravenous dosing, approximately 90% of the steady-state was reached by week 8 for both the12 mg/kg (body weight < 30 kg) and 8 mg/kg Q2W (body weight ≥ 30 kg) regimens.

In sJIA patients, the central volume of distribution was 1.87 L and the peripheral volume ofdistribution was 2.14 L resulting in a volume of distribution at a steady-state of 4.01 L. The linearclearance 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 characterised by a populationpharmacokinetic analysis which included 237 patients who were treated with 8 mg/kg intravenousevery 4 weeks (patients weighing ≥ 30 kg), 10 mg/kg intravenous every 4 weeks (patients weighingbelow 30 kg), 162 mg subcutaneous every 2 weeks (patients weighing ≥ 30 kg), or 162 mgsubcutaneous every 3 weeks (patients weighing below 30 kg).

Table 12. Predicted mean ± SD PK parameters at steady-state after intravenous dosing in pJIA

Tocilizumab 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 1.16 1.05

AUCτ*

*τ = 4 weeks for intravenous regimens

After intravenous dosing, approximately 90% of the steady-state was reached by week 12 for the10 mg/kg (body weight < 30 kg), and by week 16 for the 8 mg/kg (body weight ≥ 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 atsteady-state.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity and genotoxicity.

Carcinogenicity studies were not performed because IgG1 monoclonal antibodies are not deemed tohave intrinsic carcinogenic potential.

Available non-clinical data demonstrated the effect of IL-6 on malignant progression and apoptosisresistance to various cancer types. This data does not suggest a relevant risk for cancer initiation andprogression under tocilizumab treatment. Additionally, proliferative lesions were not observed in a6-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 onendocrine active and reproductive system organs were not observed in a chronic cynomolgus monkeytoxicity study and reproductive performance was not affected in IL-6 deficient mice. Tocilizumabadministered to cynomolgus monkeys during early gestation, was observed to have no direct orindirect harmful effect on pregnancy or embryonal-foetal development. However, a slight increase inabortion/embryonal-foetal death was observed with high systemic exposure (> 100 × human exposure)in the 50 mg/kg/day high-dose group compared to placebo and other low-dose groups. Although IL-6does not seem to be a critical cytokine for foetal growth or the immunological control of thematernal/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 noimpairment of skeletal growth, immune function and sexual maturation.

Sucrose

Polysorbate 80 (E 433)

Disodium phosphate dodecahydrate (for pH-adjustment)

Sodium dihydrogen phosphate dihydrate (for pH-adjustment)

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial3 years

Diluted product

After dilution, the prepared solution for infusion is physically and chemically stable in sodiumchloride 9 mg/mL (0.9%) solution for injection. It can be stored for 24 hours at 30 ºC and for up to2 weeks in a refrigerator at 2 °C - 8 °C.

From a microbiological point of view, the prepared solution for infusion must be used immediately. Ifnot used immediately, in use storage times and conditions prior to use are the responsibility of the userand would normally not be longer than 24 hours at 2 °C - 8 °C, unless dilution has taken place incontrolled and validated aseptic conditions.

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 after dilution of the medicinal product see section 6.3.

RoActemra is supplied in a vial (type I glass) with a stopper (butyl rubber) containing 4 mL, 10 mL or20 mL concentrate. Pack sizes of 1 and 4 vials.

Not all pack sizes may be marketed.

Instructions for dilution prior to administration

Parenteral medicinal products must be inspected visually for particulate matter or discolouration priorto administration. Only solutions which are clear to opalescent, colourless to pale yellow and free ofvisible particles should be diluted. Use a sterile needle and syringe to prepare the product.

Adult RA, CRS ( ≥ 30 kg) and COVID-19 patients

Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) solution for injectionfrom a 100 mL infusion bag, equal to the volume of concentrate required for the patients dose, underaseptic conditions. The required amount of concentrate (0.4 mL/kg) should be withdrawn from the vialand 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.

Paediatric populationsJIA, pJIA and CRS patients ≥ 30 kg

Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) solution for injectionfrom a 100 mL infusion bag, equal to the volume of concentrate required for the patients dose, underaseptic conditions. The required amount of concentrate (0.4 mL/kg) should be withdrawn from thevial and placed in the 100 mL infusion bag. This should be a final volume of 100 mL. To mix thesolution, 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 injectionfrom a 50 mL infusion bag, equal to the volume of concentrate required for the patients dose, underaseptic conditions. The required amount of concentrate (0.6 mL/kg) should be withdrawn from thevial and placed in the 50 mL infusion bag. This should be a final volume of 50 mL. To mix thesolution, 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 injectionfrom a 50 mL infusion bag, equal to the volume of concentrate required for the patients dose, underaseptic conditions. The required amount of concentrate (0.5 mL/kg) should be withdrawn from thevial and placed in the 50 mL infusion bag. This should be a final volume of 50 mL. To mix thesolution, gently invert the infusion bag to avoid foaming.

When diluted with sodium chloride 9 mg/mL (0.9%) solution for injection, RoActemra is compatiblewith intravenous infusion bags composed of polyvinyl chloride (PVC), polyethylene (PE),polypropylene (PP).

RoActemra is for single-use only.

Any unused product or waste material should be disposed of in accordance with local requirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

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

Date of first authorisation: 16 January 2009

Date of last renewal: 25 September 2013

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.