ROACTEMRA 162mg injection solution in pre-filled syringe medication leaflet

RoActemra 162 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 162 mg of tocilizumab in 0.9 mL.

Tocilizumab is a recombinant humanised, anti-human monoclonal antibody of the immunoglobulin G1(IgG1) sub-class.

Excipient with known effects

Each 162 mg/0.9 mL syringe contains 0.18 mg (0.2 mg/mL) polysorbate 80.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

A colourless to slightly yellowish solution with a pH of 5.5-6.5 and an osmolality of200-372 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 methotrexate.

Systemic juvenile idiopathic arthritis (sJIA)

RoActemra is indicated for the treatment of active sJIA in patients 1 year 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.

Giant cell arteritis (GCA)

RoActemra is indicated for the treatment of GCA in adult patients.

Tocilizumab subcutaneous formulation is administered with a single-use PFS+NSD (pre-filled syringeand needle safety device). Treatment should be initiated by healthcare professionals experienced in thediagnosis and treatment of RA, sJIA, pJIA and/or GCA. The first injection must be performed underthe supervision of a qualified health care professional. A patient or parent/guardian can self-inject thismedicinal product only if the physician determines that it is appropriate and the patient orparent/guardian agrees to medical follow-up as necessary and has been trained in proper injectiontechnique.

Patients who transition from tocilizumab intravenous therapy to subcutaneous administration shouldadminister the first subcutaneous dose at the time of the next scheduled intravenous dose under thesupervision of a qualified health care professional.

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

Suitability of the patient or parent/guardian for subcutaneous home use should be assessed and patientsor parent/guardian instructed to inform a healthcare professional before administering the next dose ifthey experience symptoms of an allergic reaction. Patients should seek immediate medical attention ifdeveloping symptoms of serious allergic reactions (see section 4.4).

RA

The recommended posology is subcutaneous 162 mg once every week.

Limited information is available regarding switching patients from tocilizumab intravenousformulation to tocilizumab subcutaneous fixed dose formulation. The once every week dosing intervalshould be followed.

Patients transitioning from intravenous to subcutaneous formulation should administer their firstsubcutaneous dose instead of the next scheduled intravenous dose under the supervision of a qualifiedhealthcare professional.

GCA

The recommended posology is subcutaneous 162 mg once every week in combination with a taperingcourse of glucocorticoids. This medicinal product can be used alone following discontinuation ofglucocorticoids.

Tocilizumab monotherapy should not be used for the treatment of acute relapses (see section 4.4).

Based upon the chronic nature of GCA, treatment beyond 52 weeks should be guided by diseaseactivity, physician discretion, and patient choice.

RA and GCA patients

Dose adjustments due to laboratory abnormalities (see section 4.4).

* Liver enzyme abnormalities

Laboratory Value Action> 1 to 3 × Upper Dose modify concomitant DMARDs (RA) or immunomodulatory agents

Limit of Normal (GCA) if appropriate.(ULN) For persistent increases in this range, reduce tocilizumab dose frequency toevery other week injection or interrupt treatment until alanine aminotransferase(ALT) or aspartate aminotransferase (AST) have normalised.

Restart with weekly or every other week injection, as clinically appropriate.

> 3 to 5 × ULN Interrupt treatment dosing until < 3 × ULN and follow recommendations abovefor > 1 to 3 × ULN.

For persistent increases > 3 × ULN (confirmed by repeat testing, seesection 4.4.), discontinue treatment.

> 5 × ULN Discontinue treatment.

* Low absolute neutrophil count (ANC)

In patients not previously treated with tocilizumab, initiation is not recommended in patients with an

ANC below 2 × 109/L

Laboratory Value Action(cells × 109/L)

ANC > 1 Maintain dose.

ANC 0.5 to 1 Interrupt tocilizumab dosing.

When ANC increases > 1 × 109/L resume treatment dosing every other weekand increase to every week injection, 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 dosing every other weekand increase to every week injection as clinically appropriate.

< 50 Discontinue treatment.

RA and GCA

If a patient misses a subcutaneous weekly injection of tocilizumab within 7 days of the scheduleddose, he/she should be instructed to take the missed dose on the next scheduled day. If a patient missesa subcutaneous once every other week injection of tocilizumab within 7 days of the scheduled dose,he/she should be instructed to take the missed dose immediately and the next dose on the nextscheduled day.

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

No dose adjustment is required in patients with mild or moderate renal impairment. Tocilizumab hasnot been studied in patients with 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.

The safety and efficacy of tocilizumab subcutaneous formulation in children from birth to less than1 year have not been established. No data are available.

A change in dose should only be based on a consistent change in the patient’s body weight over time.

Tocilizumab can be used alone or in combination with MTX.

sJIA patients

The recommended posology in patients above 1 year of age is subcutaneous 162 mg once every weekin patients weighing greater than or equal to 30 kg or subcutaneous 162 mg once every 2 weeks inpatients weighing less than 30 kg.

Patients must have a minimum body weight of 10 kg when receiving tocilizumab subcutaneously.

pJIA patients

The recommended posology in patients above 2 years of age is subcutaneous 162 mg once every2 weeks in patients weighing greater than or equal to 30 kg or subcutaneous 162 mg once every3 weeks in patients weighing less than 30 kg.

sJIA and pJIA patients

Dose adjustments due to laboratory abnormalities

If appropriate, the dose of concomitant MTX and/or other medicinal products should be modified ordosing stopped and tocilizumab dosing interrupted until the clinical situation has been evaluated. Asthere are many co-morbid conditions that may effect laboratory values in sJIA or pJIA, the decision todiscontinue tocilizumab for a laboratory abnormality should be based upon the medical assessment ofthe individual patient.

* Liver enzyme abnormalities

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

For persistent increases in this range, interrupt tocilizumab until ALT/AST havenormalised.

> 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 or pJIA for a laboratoryabnormality must 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 sJIA or pJIA for a laboratoryabnormality must 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 sJIA or pJIA for a laboratoryabnormality must be based on the medical assessment of the individual patient.

Reduction of tocilizumab dosing frequency due to laboratory abnormalities has not been studied insJIA or pJIA patients.

The safety and efficacy of tocilizumab subcutaneous formulation in children with conditions otherthan sJIA or pJIA have not been established.

Available data with the intravenous formulation suggest that clinical improvement is observed within12 weeks of initiation of treatment with tocilizumab. Continued therapy must be carefullyreconsidered in a patient exhibiting no improvement within this timeframe.

If a sJIA patient misses a subcutaneous weekly injection of tocilizumab within 7 days of the scheduleddose, he/she should be instructed to take the missed dose on the next scheduled day. If a patient missesa subcutaneous once every 2 week injection of tocilizumab within 7 days of the scheduled dose, he/sheshould be instructed to take the missed dose immediately and the next dose on the next scheduled day.

If a pJIA patient misses a subcutaneous injection of tocilizumab within 7 days of the scheduled dose,he/she should take the missed dose as soon as they remember and take the next dose at the regularscheduled time. If a patient misses a subcutaneous injection of tocilizumab by more than 7 days of thescheduled dose or is unsure when to inject it, call the doctor or pharmacist.

This medicinal product is for subcutaneous use.

After proper training in injection technique, patients may self-inject with this medicinal product if theirphysician determines that it is appropriate. The total content (0.9 mL) of the pre-filled syringe shouldbe administered as a subcutaneous injection. The recommended injection sites (abdomen, thigh andupper arm) should be rotated and injections should never be given into moles, scars, or areas where theskin is tender, bruised, red, hard, or not intact.

The pre-filled syringe should not be shaken.

Comprehensive instructions for the administration of RoActemra in a pre-filled syringe are given inthe package leaflet, see section 6.6.

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

Active, severe infections (see section 4.4).

RoActemra subcutaneous formulation is not intended for intravenous administration.

RoActemra subcutaneous formulation is not intended to be given to children with sJIA weighing lessthan 10 kg.

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

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 receivingimmunosuppressive agents such as tocilizumab as signs and symptoms of acute inflammation may belessened, due to suppression of the acute phase reactants. The effects of tocilizumab on C-reactiveprotein (CRP), neutrophils and signs and symptoms of infection must be considered when evaluating apatient for a potential infection. Patients (which includes younger children with sJIA or pJIA who maybe less able to communicate their symptoms) and parents/guardians of sJIA or pJIA patients, should beinstructed to contact their healthcare professional immediately when any symptoms suggestinginfection appear, in order to assure rapid evaluation and appropriate treatment.

As recommended for other biological treatments, all patients should be screened for latent tuberculosis(TB) infection prior to starting tocilizumab therapy. Patients with latent TB must be treated 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 and parents/guardians of sJIA or pJIA patients should be advised to seek medical advice ifsigns/symptoms (e.g., persistent cough, wasting/weight loss, low grade fever) suggestive of atuberculosis infection occur during or after therapy 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 uncommonlyin patients treated with tocilizumab (see section 4.8). This medicinal product should be used withcaution in patients with previous history of intestinal ulceration or diverticulitis. Patients presentingwith symptoms potentially indicative of complicated diverticulitis, such as abdominal pain,haemorrhage and/or unexplained change in bowel habits with fever must be evaluated promptly forearly identification of diverticulitis which can be associated with gastrointestinal perforation.

Serious hypersensitivity reactions, including anaphylaxis have been reported in association withtocilizumab (see section 4.8). Such reactions may be more severe, and potentially fatal in patients whohave experienced hypersensitivity reactions during previous treatment with tocilizumab even if theyhave received premedication with steroids and antihistamines. If an anaphylactic reaction or otherserious hypersensitivity reaction occurs, administration of tocilizumab must be stopped immediately,appropriate therapy initiated and treatment should be permanently discontinued.

Active hepatic disease and hepatic impairment

Treatment with tocilizumab, particularly when administered concomitantly with MTX, may 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 patients with baseline ALT or AST > 5 × ULN, treatment is not recommended.

In RA, GCA, pJIA and sJIA patients, ALT/AST should be monitored every 4 to 8 weeks for the 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, treatment should 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 patients who develop an

ANC < 0.5 × 109/L or a platelet count < 50 × 103/µL, continued treatment is not recommended.

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

In RA and GCA patients, neutrophils and platelets should be monitored 4 to 8 weeks after start oftherapy and thereafter according to standard clinical practice. For recommended dose modificationsbased on ANC and platelet counts, see section 4.2.

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

Lipid parameters

Elevations in lipid parameters including total cholesterol, low-density lipoprotein (LDL), high-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 all patients, assessment of lipid parameters should be performed 4 to 8 weeks following initiation oftherapy. Patients should be managed according to local clinical guidelines for management ofhyperlipidaemia.

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 paediatric or elderly patients,be brought up to date with all immunisations in agreement with current immunisation guidelines priorto initiating 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 patients. This medicinal product is not recommended for use with other biological agents.

Polysorbate

This medicine contains 0.18 mg of polysorbate 80 in each 162 mg/0.9 mL syringe which is equivalentto 0.2 mg/mL. Polysorbates may cause allergic reactions. Patients' known allergies shall be taken intoconsideration.

GCA

Tocilizumab monotherapy should not be used for the treatment of acute relapses as efficacy in thissetting has not been established. Glucocorticoids should be given according to medical judgement andpractice guidelines.

sJIA

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 in RA patients. In GCA patients, no effect of cumulative corticosteroid dose ontocilizumab exposure was observed.

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

The safety profile comes from 4510 patients exposed to tocilizumab in clinical trials; the majority ofthese patients were participating in adult RA trials (n=4009), while the remaining experience comesfrom GCA (n=149), pJIA (n=240) and sJIA (n=112) trials. The safety profile of tocilizumab acrossthese indications remains similar and undifferentiated.

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

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

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 are presented by MedDRA system organ class. The corresponding frequency categoryfor each AR is based on the following convention: very common ( ≥ 1/10); common ( ≥ 1/100to < 1/10), uncommon ( ≥ 1/1 000 to < 1/100) rare, ( ≥ 1/10 000 to < 1/1 000), very rare ( < 1/10 000),and frequency not known (cannot be estimated from the available data). Within each frequencygrouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. List of adverse reactions occurring in patients treated with tocilizumab

MedDRA Frequency categories with preferred terms

SOC Very common Common Uncommon Rare Very rare

Infections and Upper Cellulitis, Pneumonia, Diverticulitisinfestations respiratory tract Oral herpes simplex,infections Herpes zoster

Blood and Leukopenia,lymphatic Neutropenia,system Hypofibrinogenaemiadisorders

Immune Anaphylaxissystem (fatal)1, 2 ,3disorders

Endocrine Hypothyroididisorders sm

Metabolism Hypercholestero Hypertriglycand nutrition laemia* eridaemiadisorders

Nervous Headache, Dizzinesssystemdisorders

Eye disorders Conjunctivitis

Vascular Hypertensiondisorders

Respiratory, Cough, Dyspnoeathoracic andmediastinaldisorders

Gastrointestin Abdominal pain, Stomatitis,al disorders Mouth ulceration, Gastric ulcer

Gastritis

Hepatobiliary Drug-induced Hepatic failuredisorders liver injury,

Hepatitis,

Jaundice

Skin and Rash, Pruritus, Stevens-subcutaneous Urticaria Johnson-tissue Syndrome3disorders

Renal and Nephrolithiasurinary isdisorders

General Injection site Peripheral oedemadisorders and reaction Hypersensitivityadministration reaction,site conditions

MedDRA Frequency categories with preferred terms

SOC Very common Common Uncommon Rare Very rare

Investigations Hepatic transaminasesincreased, Weightincreased, Totalbilirubin increased*

* 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.

Description of selected adverse reactions (subcutaneous use)

RA patients

The safety of subcutaneous tocilizumab in RA includes a double-blind, controlled, multi-centre study,

SC-I. SC-I was a non-inferiority study that compared the efficacy and safety of 162 mg administeredevery week versus 8 mg/kg intravenous in 1262 patients with RA. All patients received backgroundnon-biologic DMARD(s). The safety and immunogenicity observed for tocilizumab administeredsubcutaneous was consistent with the known safety profile of intravenous tocilizumab and no new orunexpected adverse reactions were observed (see Table 1). A higher frequency of injection sitereactions was observed in the subcutaneous arms compared with placebo subcutaneous injections inthe intravenous arms.

During the 6-month controlled period, in SC-I, the frequency of injection site reactions was 10.1%(64/631) and 2.4% (15/631) for the subcutaneous tocilizumab and the subcutaneous placebo(intravenous group) weekly injections, respectively. These injection site reactions (including erythema,pruritus, pain and haematoma) were mild to moderate in severity. The majority was resolved withoutany treatment and none necessitated treatment discontinuation.

In SC-I, a total of 625 patients treated with tocilizumab 162 mg weekly were tested for anti-tocilizumab antibodies in the 6-month controlled period. Five patients (0.8%) developed positive anti-tocilizumab antibodies; of these, all developed neutralising anti-tocilizumab antibodies. One patientwas tested positive for IgE isotype (0.2%).

In SC-II, a total of 434 patients treated with tocilizumab 162 mg every other week were tested for anti-tocilizumab antibodies in the 6 month controlled period. Seven patients (1.6%) developed positiveanti-tocilizumab antibodies; of these, six (1.4%) developed neutralising anti-tocilizumab antibodies.

Four patients were tested positive for IgE isotype (0.9%).

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

During routine laboratory monitoring in the tocilizumab 6 month controlled clinical trial SC-I, adecrease in neutrophil count below 1 × 109/L occurred in 2.9% of patients on the subcutaneous weeklydose.

There was no clear relationship between decreases in neutrophils below 1 × 109/L and the occurrenceof serious infections.

Platelets

During routine laboratory monitoring in the tocilizumab 6 month clinical trial SC-I, none of thepatients on the subcutaneous weekly dose had a decrease in platelet count to ≤ 50 × 103/µL.

Hepatic transaminase elevations

During routine laboratory monitoring in the tocilizumab 6-month controlled clinical trial SC-I,elevation in ALT or AST ≥ 3 × ULN occurred in 6.5% and 1.4% of patients, respectively on thesubcutaneous weekly dose.

Lipid parameters

During routine laboratory monitoring in the tocilizumab 6 month controlled clinical trial SC-I, 19% ofpatients experienced sustained elevations in total cholesterol > 6.2 mmol/L (240 mg/dL), with 9%experiencing a sustained increase in LDL to ≥ 4.1 mmol/L (160 mg/dL) on the subcutaneous weeklydose.

sJIA patients

The safety profile of subcutaneous tocilizumab was evaluated in 51 paediatric patients (1 to 17 yearsof age) with sJIA. In general, the adverse reactions in patients with sJIA were similar in type to thoseseen in RA patients (see Undesirable Effects section above).

The rate of infection in sJIA patients treated with subcutaneous tocilizumab was comparable to sJIApatients treated with intravenous tocilizumab.

Injection Site Reactions (ISRs)

In the subcutaneous study (WA28118), a total of 41.2% (21/51) sJIA patients experienced ISRs totocilizumab subcutaneous. The most common ISRs were erythema, pruritus, pain, and swelling at theinjection site. The majority of ISRs reported were Grade 1 events and all ISRs reported were non-serious and none required patient withdrawal from treatment or dose interruption.

In the subcutaneous study (WA28118), 46 of the 51 (90.2%) patients tested for anti-tocilizumabantibodies at baseline had at least one post-baseline screening assay result. No patient developedpositive anti-tocilizumab antibodies post baseline.

Laboratory Abnormalities

In the 52-week open-label subcutaneous study (WA28118), neutrophil count decrease to below1 × 109/L occurred in 23.5% of patients treated with tocilizumab subcutaneous. Decreases in plateletcounts to below 100 × 103/µL occurred in 2% of the patients treated with tocilizumab subcutaneous.

An elevation in ALT or AST to ≥ 3 × ULN occurred in 9.8% and 4.0% patients treated withtocilizumab subcutaneous, respectively.

Lipid parameters

In the 52-week open-label subcutaneous study (WA28118), 23.4% and 35.4% of patients experienceda 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.

pJIA patients

The safety profile of subcutaneous tocilizumab was also evaluated in 52 paediatric patients with pJIA.

The total patient exposure to tocilizumab in the pJIA all exposure population was 184.4 patient yearsfor intravenous and 50.4 patient years for subcutaneous tocilizumab. In general, the safety profileobserved in patients with pJIA was consistent with the known safety profile of tocilizumab with theexception of ISRs (see Table 1). A higher frequency of pJIA patients experienced ISRs followingsubcutaneous injections compared to adult RA.

In the subcutaneous tocilizumab study, the rate of infection in pJIA patients treated with subcutaneoustreatment was comparable with pJIA patients treated with intravenous treatment.

Injection Site Reactions

A total of 28.8% (15/52) pJIA patients experienced ISRs to tocilizumab subcutaneous. These ISRsoccurred in a 44% of patients ≥ 30 kg compared to 14.8% of patients below 30 kg. The most common

ISRs were injection site erythema, swelling, haematoma, pain and pruritis. All ISRs reported werenon-serious Grade 1 events, and none of the ISRs required patient withdrawal from treatment or doseinterruption.

In the subcutaneous study 5.8% [3/52] developed positive neutralising anti-tocilizumab antibodieswithout developing a serious or clinically significant hypersensitivity reaction. Of these 3 patients, 1subsequently withdrew from the study. No correlation between antibody development and clinicalresponse or adverse events was observed

During routine laboratory monitoring in the tocilizumab all exposure population, a decrease inneutrophil count below 1 × 109/L occurred in 15.4% of patients treated with subcutaneous tocilizumab.

An elevation in ALT or AST ≥ 3 × ULN occurred in 9.6% and 3.8% patients treated with tocilizumabsubcutaneous, respectively. No patients treated with subcutaneous tocilizumab experienced a decreasein platelet count to ≤50 × 103 /µL.

Lipid parameters

In the subcutaneous study, 14.3% and 12.8% of patients experienced a post-baseline elevation of their

LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time duringstudy treatment, respectively.

GCA patients

The safety of subcutaneous tocilizumab has been studied in one Phase III study (WA28119) with 251

GCA patients. The total patient years duration in the tocilizumab all exposure population was138.5 patient years during the 12 month double-blind, placebo-controlled phase of the study. Theoverall safety profile observed in the treatment groups was consistent with the known safety profile oftocilizumab (see Table 1).

The rate of infection/serious infection events was balanced between the tocilizumab weekly group(200.2/9.7 events per 100 patient years) vs. placebo plus 26 weeks prednisone taper (156.0/4.2 eventsper 100 patient years) and placebo plus 52 weeks taper (210.2/12.5 events per 100 patient years)groups.

In the tocilizumab subcutaneous weekly group, a total of 6% (6/100) patients reported an adversereaction occurring at the site of a subcutaneous injection. No injection site reaction was reported as aserious adverse event or required treatment discontinuation.

In the tocilizumab subcutaneous weekly group, one patient (1.1%, 1/95) developed positiveneutralising anti-tocilizumab antibodies, though not of the IgE isotype. This patient did not develop ahypersensitivity reaction or injection site reaction.

During routine laboratory monitoring in the tocilizumab 12 month controlled clinical trial, a decreasein neutrophil count below 1 × 109/L occurred in 4% of patients in the tocilizumab subcutaneousweekly group. This was not observed in either of the placebo plus prednisone taper groups.

Platelets

During routine laboratory monitoring in the tocilizumab 12 month controlled clinical trial, one patient(1%, 1/100) in the tocilizumab subcutaneous weekly group had a single transient occurence ofdecrease in platelet count to < 100 × 103/µL without associated bleeding events. A decrease in plateletcount below 100 × 103/µL was not observed in either of the placebo plus prednisone taper groups.

Hepatic transaminase elevations

During routine laboratory monitoring in the tocilizumab 12 month controlled clinical trial, elevation in

ALT ≥ 3 × ULN occurred in 3% of patients in the tocilizumab subcutaneous weekly group comparedto 2% in the placebo plus 52 week prednisone taper group and none in the placebo plus 26 weekprednisone taper group. An elevation in AST > 3 ULN occurred in 1% of patients in the tocilizumabsubcutaneous weekly group, compared to no patients in either of the placebo plus prednisone tapergroups.

Lipid parameters

During routine laboratory monitoring in the tocilizumab 12 month controlled clinical trial, 34%of patients experienced sustained elevations in total cholesterol > 6.2 mmol/L (240 mg/dL),with 15% experiencing a sustained increase in LDL to ≥ 4.1 mmol/L (160 mg/dL) in thetocilizumab subcutaneous weekly group.

Description of selected adverse reactions (intravenous use)

RA patients

The safety of tocilizumab has been studied in 5 Phase III, double-blind controlled trials and theirextension periods.

The all control population includes all patients from the double-blind phases of each core study fromrandomisation until either the first change in the treatment regimen, or two years is reached. Thecontrol period in 4 of the trials was 6 months and in 1 study was up to 2 years. In the double-blindcontrolled trials 774 patients received tocilizumab 4 mg/kg in combination with MTX, 1870 patientsreceived tocilizumab 8 mg/kg in combination with MTX/other DMARDs and 288 patients receivedtocilizumab 8 mg/kg monotherapy.

The all exposure population includes all patients who received at least one dose of tocilizumab eitherin the double-blind control period or open label extension phase in trials. Of the 4009 patients in thispopulation, 3577 received treatment for at least 6 months, 3296 for at least one year; 2806 receivedtreatment for at least 2 years and 1222 for 3 years.

In the 6-month controlled trials the rate of all infections reported with tocilizumab 8 mg/kg plus

DMARD treatment was 127 events per 100 patient years compared to 112 events per 100 patient 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 all exposure population the overall rate of serious infections was 4.7 events per 100 patientyears. Reported serious infections, some with fatal outcome, included pneumonia, cellulitis, herpeszoster, gastroenteritis, diverticulitis, sepsis, bacterial arthritis. Cases of opportunistic infections havealso 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 6/3778 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 13 out of 3778 patients (0.3%) 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 intravenoustocilizumab (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% of patientsreceiving tocilizumab 8 mg/kg plus DMARDs. Infections with neutropenia have been reported.

During the double-blind controlled period and with long-term exposure, the pattern and incidence 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 treatment withlipid-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.

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 administeredintravenously. No adverse reactions 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 tocilizumab, rapid decreases in CRP, erythrocyte sedimentation rate (ESR),serum amyloid A (SAA) and fibrinogen were observed. Consistent with the effect on acute phasereactants, treatment with tocilizumab was associated with reduction in platelet count within the normalrange. Increases in haemoglobin levels were observed, through tocilizumab decreasing the IL-6 driveneffects on hepcidin production to increase iron availability. In treated patients, decreases in the levelsof CRP to within normal ranges were seen as early as week 2, with decreases maintained while ontreatment.

In GCA clinical study WA28119, similar rapid decreases in CRP and ESR were observed along withslight increases in mean corpuscular haemoglobin concentration. In healthy subjects administeredtocilizumab in doses from 2 to 28 mg/kg intravenously and 81 to 162 mg subcutaneously, absoluteneutrophil counts decreased to their lowest 2 to 5 days following administration. Thereafter,neutrophils recovered towards baseline in a dose dependent manner.

Patients demonstrate a comparable (to healthy subjects) decrease of absolute neutrophil countsfollowing tocilizumab administration (see section 4.8).

RA (Subcutaneous use)

The efficacy of subcutaneous administered tocilizumab in alleviating the signs and symptoms of RAand radiographic response, was assessed in two randomised, double-blind, controlled, multi-centretrials. For study I (SC-I), patients were required to be > 18 years of age with moderate to severe active

RA diagnosed according to ACR criteria who had at least 4 tender and 4 swollen joints at baseline. Allpatients received background non-biologic DMARD(s). For study II (SC-II), patients were required tobe > 18 years of age with moderate to severe active RA diagnosed according to ACR criteria who hadat least 8 tender and 6 swollen joints at baseline.

Switching from 8 mg/kg intravenous once every 4 weeks to 162 mg subcutaneous once every week,will alter exposure in the patient. The extent varies with the patient’s body weight (increased in lightbody weight patients and decreased in heavy body weight patients) but clinical outcome is consistentwith that observed in intravenous treated patients.

Study SC-I evaluated patients with moderate to severe active RA who had an inadequate clinicalresponse to their existing rheumatologic therapy, including one or more DMARD(s) whereapproximately 20% had a history of inadequate response to at least one TNF inhibitor. In SC-I,1262 patients were randomised 1:1 to receive tocilizumab subcutaneous 162 mg every week ortocilizumab intravenous 8 mg/kg every four weeks in combination with non-biologic DMARD(s). Theprimary endpoint in the study was the difference in the proportion of patients who achieved an

ACR 20 response at week 24. The results from study SC-I is shown in Table 2.

Table 2. ACR responses in study SC-I (% patients) at week 24

SC-Ia

TCZ SC 162 mg every week TCZ IV 8 mg/kg+ DMARD + DMARD

N=558

N=537

ACR 20 week 24 69.4% 73.4%

Weighted difference (95% CI) -4.0 (-9.2, 1.2)

ACR 50 week 24 47.0% 48.6%

Weighted difference (95% CI) -1.8 (-7.5, 4.0)

ACR 70 week 24 24.0% 27.9%

Weighted difference (95% CI) -3.8 (-9.0, 1.3)

DMARD = disease-modifying anti-rheumatic drugs

TCZ = tocilizumab

IV = intravenous

SC = subcutaneousa = Per Protocol Population

Patients in study SC-I had a mean Disease Activity Score (DAS28) at baseline of 6.6 and 6.7 on thesubcutaneous and intravenous arms, respectively. At week 24, a significant reduction in DAS28 frombaseline (mean improvement) of 3.5 was observed on both treatment arms, and a comparableproportion of patients had achieved DAS28 clinical remission (DAS28 < 2.6) on the subcutaneous(38.4%) and intravenous (36.9%) arms.

The radiographic response of subcutaneous administered tocilizumab was assessed in a double-blind,controlled, multi-centre study in patients with active RA (SC-II). Study SC-II evaluated patients withmoderate to severe active RA who had an inadequate clinical response to their existing rheumatologictherapy, including one or more DMARD(s) where approximately 20% had a history of inadequateresponse to at least one TNF inhibitor. Patients were required to be > 18 years of age with active RAdiagnosed according to ACR criteria who had at least 8 tender and 6 swollen joints at baseline. In SC-

II, 656 patients were randomised 2:1 to tocilizumab subcutaneous 162 mg every other week orplacebo, in combination with non-biologic DMARD(s).

In study SC-II, inhibition of structural joint damage was assessed radiographically and expressed as achange from baseline in the van der Heijde modified mean total Sharp score (mTSS). At week 24,inhibition of structural damage was shown, with significantly less radiographic progression in patientsreceiving tocilizumab subcutaneous compared to placebo (mean mTSS of 0.62 vs. 1.23, p=0.0149 (van

Elteren). These results are consistent with those observed in patients treated with intravenoustocilizumab.

In study SC-II, at week 24 there was ACR 20 of 60.9%, ACR 50 of 39.8% and ACR 70 of 19.7% forpatients treated with tocilizumab subcutaneous every other week versus placebo ACR 20 of 31.5%,

ACR 50 of 12.3% and ACR 70 of 5.0%. Patients had mean DAS28 at baseline of 6.7 on subcutaneousand 6.6 on placebo arms. At week 24, a significant reduction in DAS28 from baseline of 3.1 wasobserved on subcutaneous and 1.7 on placebo arm, and for DAS28 < 2.6, 32.0% was observed onsubcutaneous and 4.0% on placebo arm.

Health-related and quality of life outcomes

In study SC-I, the mean decrease in HAQ-DI from baseline to week 24 was 0.6 on both thesubcutaneous and intravenous arms. The proportion of patients achieving a clinically relevantimprovement in HAQ-DI at week 24 (change from baseline of ≥ 0.3 units) was also comparable on thesubcutaneous (65.2%) versus intravenous (67.4%) arms, with a weighted difference in proportions of -2.3% (95% CI - 8.1, 3.4). For SF-36, the mean change from baseline at week 24 in the mentalcomponent score was 6.22 for the subcutaneous arm and 6.54 for the intravenous arm, and for thephysical component score was also similar with 9.49 for the subcutaneous arm and 9.65 for theintravenous arm.

In study SC-II, mean decrease in HAQ-DI from baseline to week 24 was significantly greater forpatients treated with tocilizumab subcutaneous every other week (0.4) versus placebo (0.3). Proportionof patients achieving a clinically relevant improvement in HAQ-DI at week 24 (change from baselineof ≥ 0.3 units) was higher for subcutaneous treatment every other week (58%) versus placebo (46.8%).

SF-36 (mean change in mental and physical component scores) was significantly greater withtocilizumab subcutaneous group (6.5 and 5.3) versus placebo (3.8 and 2.9).

sJIA (subcutaneous)

A 52-week, open-label, multi-centre, PK/PD and safety study (WA28118) was conducted in paediatricpatients with sJIA, aged 1 to 17 years, to determine the appropriate subcutaneous dose of tocilizumabthat achieved comparable PK/PD and safety profiles to the intravenous regimen.

Eligible patients received treatment dosed according to body weight, with patients weighing ≥ 30 kg(n=26) dosed with 162 mg of tocilizumab every week (QW) and patients weighing below 30 kg(n=25) dosed with 162 mg of tocilizumab every 10 days (Q10D; n=8) or every 2 weeks (Q2W; n=17)for 52 weeks. Of these 51 patients, 26 (51%) were naive to treatment and 25 (49%) had been receivingtocilizumab intravenous and switched to tocilizumab subcutaneous at baseline.

Exploratory efficacy results showed that tocilizumab subcutaneous improved all exploratory efficacyparameters including Juvenile Arthritis Disease Activity Score (JADAS)-71, for TCZ naïve patientsand maintained all exploratory efficacy parameters for patients who switched from intravenous tosubcutaneous treatment over the entire course of the study for patients in both body weight groups(below 30 kg and ≥ 30 kg).

pJIA (subcutaneous)

A 52-week, open-label, multi-centre, PK-PD and safety study was conducted in paediatric patientswith pJIA, aged 1 to 17 years old, to determine the appropriate subcutaneous dose of tocilizumab thatachieved comparable PK/PD and safety profiles to the intravenous regimen.

Eligible patients received tocilizumab dosed according to body weight, with patients weighing ≥ 30 kg(n=25) dosed with 162 mg of tocilizumab every 2 weeks (Q2W) and patients weighing below 30 kg(n=27) dosed with 162 mg of tocilizumab every 3 weeks (Q3W) for 52 weeks. Of these 52 patients, 37(71%) were naive to treatment and 15 (29%) had been receiving tocilizumab intravenous and switchedto tocilizumab subcutaneous at baseline.

The tocilizumab subcutaneous regimens of 162 mg Q3W for patients weighing below 30 kg and of162 mg Q2W for patients weighing ≥ 30 kg respectively provide PK exposure and PD responses tosupport efficacy and safety outcomes similar to those achieved with the approved tocilizumabintravenous regimens for pJIA.

Exploratory efficacy results showed that tocilizumab subcutaneous improved median Juvenile

Arthritis Disease Activity Score (JADAS)-71 for treatment naïve patients and maintained the median

JADAS-71 for patients who switched from intravenous to subcutaneous treatment over the entirecourse of the study for patients in both body weight groups (below 30 kg and ≥30 kg).

GCA (subcutaneous)

Study WA28119 was a randomised, multi-centre, double-blind placebo-controlled Phase IIIsuperiority study conducted to assess the efficacy and safety of tocilizumab in patients with GCA.

Two hundred and fifty one (251) patients with new-onset or relapsing GCA were enrolled andassigned to one of four treatment arms. The study consisted of a 52-week blinded period (Part 1),followed by a 104-week open-label extension (Part 2). The purpose of Part 2 was to describe thelong-term safety and maintenance of efficacy after 52 weeks of therapy, to explore the rate of relapseand the requirement for tocilizumab therapy beyond 52 weeks, and to gain insight into the potentiallong-term steroid-sparing effect of the medicinal product.

Two subcutaneous doses of tocilizumab (162 mg every week and 162 mg every other week) werecompared to two different placebo control groups randomised 2:1:1:1.

All patients received background glucocorticoid (prednisone) therapy. Each of the tocilizumab -treatedgroups and one of the placebo-treated groups followed a pre-specified prednisone-taper regimen over26 weeks, while the second placebo-treated group followed a pre-specified prednisone-taper regimenover 52 weeks, designed to be more in keeping with standard practice.

The duration of glucocorticoid therapy during screening and before tocilizumab (or placebo) wasinitiated, was similar in all 4 treatment groups (see Table 3).

Table 3. Duration of corticosteroid therapy during screening in Study WA28119

Placebo + Placebo + Tocilizumab Tocilizumab26 weeks 52 weeks 162 mg SC weekly 162 mg SC everyprednisone taper prednisone taper + 26 weeks other weekly +

N=50 N=51 prednisone taper 26 weeks

N=100 prednisone taper

N=49

Duration (days)

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

Median 42.0 41.0 41.0 42.0

Min - Max 6 - 63 12 - 82 1 - 87 9 - 87

SC = subcutaneous

The primary efficacy endpoint assessed by the proportion of patients achieving steroid free sustainedremission at week 52 on tocilizumab plus 26 weeks prednisone taper compared with placebo plus26 weeks prednisone taper, was met (Table 4).

The key secondary efficacy endpoint also based on the proportion of patients achieving sustainedremission at week 52, comparing tocilizumab plus 26 weeks prednisone taper with placebo plus52 weeks prednisone taper, was also met (Table 4).

A statistically significant superior treatment effect was seen in favour of tocilizumab over placebo inachieving steroid-free sustained remission at week 52 on tocilizumab plus 26 weeks prednisone tapercompared with placebo plus 26 weeks prednisone taper and with placebo plus 52 weeks prednisonetaper.

The percentage of patients achieving sustained remission at week 52, are shown in the Table 4.

Secondary endpoints

The assessment of the time to first GCA flare showed a significantly lower risk of flare forthe tocilizumab subcutaneous weekly group compared to placebo plus 26 weeks prednisone andplacebo plus 52 weeks prednisone taper groups and for the tocilizumab subcutaneous every otherweekly group compared to placebo plus 26 weeks prednisone (when compared at a 0.01 significancelevel). Tocilizumab subcutaneous weekly dose also showed a clinically meaningful decrease in therisk for flare compared to placebo plus 26 weeks prednisone in patients who entered the trial withrelapsing GCA as well as those with new-onset disease (Table 4).

Cumulative glucocorticoid dose

The cumulative prednisone dose at week 52 was significantly lower in the two tocilizumab dosegroups compared to the two placebo groups (Table 4). In a separate analysis of the patients whoreceived escape prednisone to treat GCA flare during the first 52 weeks, the cumulative prednisonedose varied greatly. The median doses for escape patients in the tocilizumab weekly and every otherweekly groups were 3129.75 mg and 3847 mg, respectively. Both considerably lower than in theplacebo plus 26 weeks and the placebo plus 52 weeks prednisone taper groups, 4023.5 mg and5389.5 mg respectively.

Table 4. Efficacy results from Study WA28119

Placebo + Placebo + Tocilizumab Tocilizumab26 weeks 52 weeks 162 mg SC 162 mg SC everyprednison prednison weekly + other weekly +e taper e taper 26 weeks 26 weeks

N=50 N=51 prednisone prednisone tapertaper N=49

N=100

Primary endpoint

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

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

Unadjusted difference in proportions N/A N/A 42%* 39.06%*(99.5% CI) (18.00, 66.00) (12.46, 65.66)

Key secondary endpoint

Sustained remission (Tocilizumab groups vs Placebo+52)

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

Unadjusted difference in proportions N/A N/A 38.35%* 35.41%**(99.5% CI) (17.89, 58.81) (10.41 ,60.41)

Other secondary endpoints

Time to first GCA flare¹ (Tocilizumab groups vs N/A N/A 0.23* 0.28**

Placebo+26) (0.11, 0.46) (0.12, 0.66)

HR (99% CI)

Time to first GCA flare¹ (Tocilizumab groups vs N/A N/A 0.39** 0.48

Placebo+52) (0.18, 0.82) (0.20, 1.16)

HR (99% CI)

Time to first GCA flare¹ (Relapsing patients; N/A N/A 0.23*** 0.42

Tocilizumab groups vs Placebo + 26) HR (99% CI) (0.09,0.61) (0.14, 1.28)

Time to first GCA flare¹ (Relapsing patients; N/A N/A 0.36 0.67

Tocilizumab groups vs Placebo + 52) HR (99% CI) (0.13, 1.00) (0.21,2.10)

Time to first GCA flare¹ (New-onset patients; N/A N/A 0.25*** 0.20***

Tocilizumab groups vs Placebo + 26) HR (99% CI) (0.09, 0.70) (0.05, 0.76)

Time to first GCA flare¹ (New-onset patients; N/A N/A 0.44 0.35

Tocilizumab groups vs Placebo + 52) HR (99% CI) (0.14, 1.32) (0.09, 1.42)

Cumulative glucocorticoid dose (mg)median at week 52 (Tocilizumab groups vs 3296.00 N/A 1862.00* 1862.00*

Placebo + 262)median at week 52 (Tocilizumab groups vs N/A 3817.50 1862.00* 1862.00*

Placebo + 522)

Exploratory endpoints

Annualised relapse rate, week 52§

Mean (SD) 1.74 1.30 0.41 0.67(2.18) (1.84) (0.78) (1.10)

* p < 0.0001

** p < 0.005 (threshold for significance for primary and key secondary tests of superiority)

***Descriptive p value < 0.005

****Flare: recurrence of GCA signs or symptoms and/or ESR ≥ 30 mm/h - Increase in the prednisone dose required

Remission: absence of flare and normalization of the CRP

Sustained remission: remission from week 12 to week 52 -Patients must adhere to the protocol-defined prednisone taper¹ analysis of the time (in days) between clinical remission and first disease flare2 p-values are determined using a Van Elteren analysis for non-parametric data§ statistical analyses has not been performed

N/A=Not applicable

HR=Hazard Ratio

CI=Confidence Interval

SC=subcutaneous

Quality of life outcomes

In study WA28119, the SF-36 results were separated into the physical and mental componentsummary scores (PCS and MCS, respectively). The PCS mean change from baseline to week 52 washigher (showing more improvement) in the tocilizumab weekly and every other weekly dose groups[4.10, 2.76, respectively] than in the two placebo groups [placebo plus 26 weeks; -0.28, placebo plus52 weeks; -1.49], although only the comparison between tocilizumab weekly plus 26 weeksprednisone taper group and placebo plus 52 weeks prednisone taper group (5.59, 99% CI: 8.6, 10.32)showed a statistically significant difference (p=0.0024). For MCS, the mean change from baseline toweek 52 for both tocilizumab weekly and every other weekly dose groups [7.28, 6.12, respectively]were higher than the placebo plus 52 weeks prednisone taper group [2.84] (although the differenceswere not statistically significant [weekly p=0.0252 for weekly, p=0.1468 for every other weekly]) andsimilar to the placebo plus 26 weeks prednisone taper group [6.67].

The Patient’s Global Assessment of disease activity was assessed on a 0-100 mm Visual Analogue

Scale (VAS). The mean change in Patient’s global VAS from baseline at week 52 was lower (showinggreater improvement) in the tocilizumab weekly and every other weekly dose groups [-19.0, -25.3,respectively] than in both placebo groups [placebo plus 26 weeks -3.4, placebo plus 52 weeks -7.2],although only the tocilizumab every other weekly plus 26 weeks prednisone taper group showed astatistically significant difference compared to placebo [placebo plus 26 weeks taper p=0.0059, andplacebo plus 52 weeks taper p=0.0081].

FACIT-Fatigue change from baseline to week 52 scores were calculated for all groups. The mean [SD]change scores were as follows: tocilizumab weekly plus 26 weeks 5.61 [10.115], tocilizumab everyother weekly plus 26 weeks 1.81 [8.836], placebo plus 26 weeks 0.26 [10.702], and placebo plus52 weeks -1.63 [6.753].

Change in EQ5D scores from baseline to week 52 were tocilizumab weekly plus 26 weeks 0.10[0.198], tocilizumab every other weekly plus 26 weeks 0.05 [0.215], placebo plus 26 weeks 0.07[0.293], and placebo plus 52 weeks -0.02 [0.159].

Higher scores signal improvement in both FACIT-Fatigue and EQ5D.

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, evaluated1196 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 mgto 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 5). 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 was 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 DAS 28 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 5. 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 MTX TCZ PBO TCZ PBO TCZ PBO + TCZ PBO +8 mg/ 8 mg/k + MTX 8 mg/k + MTX 8 mg/kg DMAR 8 mg/k MTXkg g g + D g+ MTX + MTX DMAR + MTX

D

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%

*

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 6).

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 6. 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 tocilizumab over adalimumabin control of disease activity from baseline to week 24 for the primary endpoint of change in DAS28and for all secondary endpoints (Table 7).

Table 7. Efficacy Results for Study VI (WA19924)

ADA + Placebo (IV) TCZ + Placebo (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% -1.5 (-1.8, -1.1) <0.0001

CI)

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) 0.0023ap 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

ADA = adalimumab

TCZ = tocilizumab

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).

The pharmacokinetics of tocilizumab is characterised by nonlinear elimination which is a combinationof linear clearance and Michaelis-Menten elimination. The nonlinear part of elimination leads to anincrease in exposure that is more than dose-proportional. The pharmacokinetic parameters oftocilizumab do not change with time. Due to the dependence of total clearance on tocilizumab serumconcentrations, the half-life of tocilizumab is also concentration-dependent and varies depending onthe serum concentration level. Population pharmacokinetic analyses in any patient population tested sofar indicate no relationship between apparent clearance and the presence of anti-drug antibodies.

RA

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) = 38000 ± 13000 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 concentrationsuch that clinically meaningful increases in efficacy were not demonstrated in patients treatedwith > 800 mg of tocilizumab. Therefore, doses exceeding 800 mg per infusion are not recommended(see section 4.2).

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.

Following intravenous administration, tocilizumab undergoes biphasic elimination from thecirculation. The total clearance of tocilizumab was concentration-dependent and is the sum of thelinear and non-linear clearance. The linear clearance was estimated as a parameter in the populationpharmacokinetic analysis and was 9.5 mL/h. The concentration-dependent non-linear clearance plays amajor role at low tocilizumab concentrations. Once the non-linear clearance pathway is saturated, athigher tocilizumab concentrations, clearance is mainly determined by the linear clearance.

The t1/2 of tocilizumab was concentration-dependent. At steady-state following a dose of 8 mg/kgevery 4 weeks, the effective t1/2 decreased with decreasing concentrations within a dosing intervalfrom 18 days to 6 days.

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.

Subcutaneous use

The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis ona database composed of 3552 RA patients treated with 162 mg subcutaneous every week, 162 mgsubcutaneous every other week, and or 4 or 8 mg/kg intravenous every 4 weeks for 24 weeks.

The pharmacokinetic parameters of tocilizumab did not change with time. For the 162 mg every weekdose, the predicted mean (±SD) steady-state AUC1week, Cmin and Cmax of tocilizumab were7970 ± 3432 µg*h/mL, 43.0 ± 19.8 µg/mL, and 49.8 ± 21.0 µg/mL, respectively. The accumulationratios for AUC, Cmin, and Cmax were 6.32, 6.30, and 5.27, respectively. Steady-state was reached after12 weeks for AUC, Cmin, and Cmax.

For the 162 every other week dose, the predicted mean (±SD) steady-state AUC2week, Cmin, and Cmax oftocilizumab were 3430 ± 2660 µg*h/mL, 5.7 ± 6.8 µg/mL, and 13.2 ± 8.8 µg/mL, respectively. Theaccumulation ratios for AUC, Cmin, and Cmax were 2.67, 6.02, and 2.12, respectively. Steady-state wasreached after 12 weeks for AUC and Cmin, and after 10 weeks for Cmax.

Following subcutaneous dosing in RA patients, the time to peak serum tocilizumab concentrations tmaxwas 2.8 days. The bioavailability for the subcutaneous formulation was 79%.

For subcutaneous administration, the effective t1/2 is up to 13 days for 162 mg every week and 5 daysfor 162 mg every other week in patients with RA at steady-state.

sJIA patients

Subcutaneous use

The pharmacokinetics of tocilizumab in sJIA patients was characterised by a populationpharmacokinetic analysis which included 140 patients who were treated with 8 mg/kg intravenousevery 2 weeks (patients weighing ≥ 30 kg), 12 mg/kg intravenous every 2 weeks (patients weighingbelow 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).

Limited data are available regarding exposures following subcutaneous administration of tocilizumabin sJIA patients below 2 years of age with a body weight less than 10 kg.

Patients with sJIA must have a minimum body weight of 10 kg when receiving tocilizumabsubcutaneously (see section 4.2).

Table 8. Predicted mean ± SD PK parameters at steady-state after subcutaneous dosing in sJIA

Tocilizumab PK parameter 162 mg QW ≥30 kg 162 mg Q2W below 30 kg

Cmax (µg/mL) 99.8 ± 46.2 134 ± 58.6

Cmin (µg/mL) 79.2 ± 35.6 65.9 ± 31.3

Cmean (µg/mL) 91.3 ± 40.4 101 ± 43.2

Accumulation Cmax 3.66 1.88

Accumulation Cmin 4.39 3.21

Accumulation Cmean or 4.28 2.27

AUCτ*

*τ = 1 week or 2 weeks for the two subcutaneous regimens

After subcutaneous dosing, approximately 90% of the steady-state was reached by week 12 for boththe 162 mg QW and Q2W regimens.

Following subcutaneous dosing in sJIA patients, the absorption half-life was around 2 days, and thebioavailability for the subcutaneous formulation in sJIA patients was 95%.

In paediatric patients with sJIA, the central volume of distribution was 1.87 L, the peripheral volumeof distribution was 2.14 L resulting in a volume of distribution at steady-state of 4.01 L.

The total clearance of tocilizumab was concentration-dependent and is the sum of the linear clearanceand the nonlinear clearance. The linear clearance was estimated as a parameter in the populationpharmacokinetic analysis and was 5.7 mL/h in paediatric patients with systemic juvenile idiopathicarthritis. Following subcutaneous administration, the effective t1/2 of tocilizumab in sJIA patients is upto 14 days for both the 162 mg QW and Q2W regimens during a dosing interval at steady-state.

pJIA patients

Subcutaneous use

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 9. Predicted mean ± SD PK parameters at steady-state after subcutaneous dosing in pJIA

Tocilizumab PK parameter 162 mg Q2W ≥ 30 kg 162 mg Q3W below 30 kg

Cmax (µg/mL) 29.4 ± 13.5 75.5 ± 24.1

Cmin (µg/mL) 11.8 ± 7.08 18.4 ± 12.9

Cavg (µg/mL) 21.7 ± 10.4 45.5 ± 19.8

Accumulation Cmax 1.72 1.32

Accumulation Cmin 3.58 2.08

Accumulation Cmean or AUCτ * 2.04 1.46

*τ = 2 week or 3 week for the two subcutaneous 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. Aftersubcutaneous dosing, approximately 90% of the steady-state was reached by week 12 for both the162 mg subcutaneous Q2W and Q3W regimens.

Following subcutaneous dosing in pJIA patients, the absorption half-life was around 2 days, and thebioavailability for the subcutaneous formulation in pJIA patients was 96%.

In paediatric patients with pJIA, the central volume of distribution was 1.97 L, the peripheral volumeof distribution was 2.03 L, resulting in a volume of distribution at steady-state of 4.0 L.

Population pharmacokinetic analysis for pJIA patients showed body size related impact on linearclearance so that body-weight based dosing should be taken into consideration (see Table 9).

After subcutaneous administration, the effective t1/2 of tocilizumab in pJIA patients is up to 10 days forpatients < 30 kg (162 mg subcutaneous Q3W) and up to 7 days for patients ≥ 30 kg (162 mgsubcutaneous Q2W) during a dosing interval at steady-state. Following intravenous administration,tocilizumab undergoes biphasic elimination from the circulation. The total clearance of tocilizumabwas concentration-dependent and is the sum of the linear and non-linear clearance. The linearclearance was estimated as a parameter in the population pharmacokinetic analysis and was6.25 mL/h. The concentration-dependent non-linear clearance plays a major role at low tocilizumabconcentrations. Once the non-linear clearance pathway is saturated, at higher tocilizumabconcentrations, clearance is mainly determined by the linear clearance.

GCA patients

Subcutaneous use

The PK of tocilizumab in GCA patients were determined using a population PK model from ananalysis dataset composed of 149 GCA patients treated with 162 mg subcutaneous every week or162 mg subcutaneous every other week. The developed model had the same structure as thepopulation PK model developed earlier based on data from RA patients (see Table 10).

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

Subcutaneous

Tocilizumab PK parameter 162 mg every 162 mg weeklyother weekly

Cmax (µg/mL) 19.3 ± 12.8 73 ± 30.4

Cmin (µg/mL) 11.1 ± 10.3 68.1± 29.5

Cmean (µg/mL) 16.2 ± 11.8 71.3 ± 30.1

Accumulation Cmax 2.18 8.88

Accumulation Cmin 5.61 9.59

Accumulation Cmean or AUCτ * 2.81 10.91

*τ = 2 week or 1 week for the two subcutaneous regimens

The steady-state profile following the tocilizumab weekly dose was almost flat, with very littlefluctuations between trough and peak values, while there were substantial fluctuations for thetocilizumab every other weekly dose. Approximately 90% of the steady-state (AUCτ) was reached byweek 14 in the every other week group and by week 17 in the weekly dose groups.

Based on the current characterization of PK, tocilizumab trough concentration at steady-state are 50%higher in this population relative to average concentrations in a large dataset from the RA population.

These differences occur due to unknown reasons. PK differences are not accompanied by markeddifferences in PD parameters and so the clinical relevance is unknown.

In GCA patients, higher exposure was observed in patients with lower body weight. For the 162 mgevery week dosing regimen, the steady-state Cavg was 51% higher in patients with body weight lessthan 60 kg compared to patients weighing between 60 to 100 kg. For the 162 mg every other weekregimen, the steady-state Cavg was 129% higher in patients with body weight less than 60 kgcompared to patients weighing between 60 to 100 kg. There is limited data for patients above 100 kg(n=7).

Following subcutaneous dosing in GCA patients, the absorption t½ was around 4 days. Thebioavailability for the subcutaneous formulation was 0.8. The median values of Tmax were 3 days afterthe tocilizumab weekly dose and 4.5 days after the tocilizumab every other week dose.

In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distributionwas 3.37 L, resulting in a volume of distribution at steady-state of 7.46 L.

The total clearance of tocilizumab was concentration-dependent and is the sum of the linear clearanceand the nonlinear clearance. The linear clearance was estimated as a parameter in the populationpharmacokinetic analysis and was 6.7 mL/h in GCA patients,

In GCA patients, at steady-state, the effective t ½ of tocilizumab varied between 18.3 and 18.9 daysfor 162 mg weekly regimen, and between 4.2 and 7.9 days for 162 mg every other weekly regimen. Athigh serum concentrations, when total clearance of tocilizumab is dominated by linear clearance, aneffective t½ of approximately 32 days was derived from the population parameter estimates.

No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab has beenconducted. Most of the patients in the RA and GCA population pharmacokinetic analyses had normalrenal function or mild renal impairment. Mild renal impairment (estimated creatinine clearance basedon Cockcroft-Gault formula) did not impact the pharmacokinetics of tocilizumab.

Approximately one-third of the patients in the GCA study had moderate renal impairment at baseline(estimated creatinine clearance of 30-59 mL/min). No impact on tocilizumab exposure was noted inthese patients.

No dose adjustment is required in patients with mild or moderate renal impairment.

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 GCA patients, showed that age, gender and ethnicorigin did not affect the pharmacokinetics of tocilizumab.

Results of the population PK analysis for sJIA and pJIA patients confirmed that body size is the onlycovariate which has an appreciable impact on the pharmacokinetics of tocilizumab includingelimination and absorption so that body-weight based dosing should be taken into consideration (see

Tables 8 and 9).

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

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 × humanexposure) in the 50 mg/kg/day high-dose group compared to placebo and other low-dose groups.

Although IL-6 does not seem to be a critical cytokine for foetal growth or the immunological controlof the maternal/foetal interface, a relation of this finding to tocilizumab cannot be excluded.

Treatment with a murine analogue did not exert toxicity in juvenile mice. In particular, there was noimpairment of skeletal growth, immune function and sexual maturation.

The non-clinical safety profile of tocilizumab in the cynomolgus monkey does not suggest a differencebetween intravenous and subcutaneous routes of administration.

L-Histidine (for pH-adjustment)

L-Histidine monohydrochloride monohydrate (for pH-adjustment)

L-Arginine/L-Arginine hydrochloride

L-Methionine

Polysorbate 80 (E 433)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years

Store in a refrigerator (2 °C - 8 °C). Do not freeze. Once removed from the refrigerator, the pre-filledsyringe can be stored up to 2 weeks at or below 30 °C.

Keep the pre-filled syringe in the outer carton in order to protect from light and moisture.

0.9 mL solution in a pre-filled syringe (type I glass) with a staked-in needle. The syringe is closed by arigid needle shield (elastomer seal with a polypropylene shell) and a plunger stopper (butyl rubberwith a fluororesin coating).

Pack sizes of 4 pre-filled syringes and multipacks containing 12 (3 packs of 4) pre-filled syringes.

Not all pack sizes may be marketed.

RoActemra is supplied in a single use pre-filled syringe fitted into a needle safety device. Afterremoving the pre-filled syringe from the refrigerator the pre-filled syringe should be allowed to reachroom temperature (18 °C to 28 °C) by waiting for 25 to 30 minutes, before injecting. The syringeshould not be shaken. After removing the cap the injection must be started within 5 minutes, to preventthe medicinal product from drying out and blocking the needle. If the pre-filled syringe is not usedwithin 5 minutes of removing the cap, you must dispose of it in a puncture resistant container and usea new pre-filled syringe.

If following insertion of the needle you cannot depress the plunger, you must dispose of the pre-filledsyringe in a puncture resistant container and use a new pre-filled syringe.

Do not use if the medicinal product is cloudy or contains particles, is any colour besides colourless toslightly yellowish, or any part of the pre-filled syringe appears to be damaged.

Comprehensive instructions for the administration of RoActemra in a pre-filled syringe are given inthe package leaflet.

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/1/08/492/007

EU/1/08/492/008

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.