AVTOZMA162mg solution for injection in pre-filled pen medication leaflet

Avtozma 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 humanized, anti-human monoclonal antibody of the immunoglobulin G1(IgG1) sub-class directed against soluble and membrane-bound interleukin 6 receptors.

Polysorbate

Each 162 mg pre-filled syringe contains 0.2 mg of polysorbate 80.

For the full list of excipients, see section 6.1.

Solution for injection in pre-filled syringe.

Clear to slightly opalescent, colourless to yellow solution with pH of 5.7 - 6.3 and an osmolalityof 280 - 340 mmol/kg.

Rheumatoid arthritis (RA)

Avtozma, in combination with methotrexate (MTX), is indicated for

* the treatment of severe, active and progressive rheumatoid arthritis (RA) in adults notpreviously treated with MTX.

* the treatment of moderate to severe active RA in adult patients who have eitherresponded inadequately to, or who were intolerant to, previous therapy with one or moredisease-modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF)antagonists.

In these patients, Avtozma can be given as monotherapy in case of intolerance to MTX or wherecontinued treatment with MTX is inappropriate.

Avtozma has been shown to reduce the rate of progression of joint damage as measured by X-ray and toimprove physical function when given in combination with methotrexate.

Systemic juvenile idiopathic arthritis (sJIA)

Avtozma is indicated for the treatment of active systemic juvenile idiopathic arthritis (sJIA) inpatients 1 year of age and older, who have responded inadequately to previous therapy with NSAIDsand systemic corticosteroids. Avtozma can be given as monotherapy (in case of intolerance to MTXor where treatment with MTX is inappropriate) or in combination with MTX.

Avtozma in combination with methotrexate (MTX) is indicated for the treatment of juvenileidiopathic polyarthritis (pJIA; rheumatoid factor positive or negative and extended oligoarthritis) inpatients 2 years of age and older, who have responded inadequately to previous therapy with MTX.

Avtozma can be given as monotherapy in case of intolerance to MTX or where continued treatmentwith MTX is inappropriate.

Giant cell arteritis (GCA)

Avtozma is indicated for the treatment of Giant Cell Arteritis (GCA) in adult patients.

Tocilizumab SC formulation is administered with a single-use pre-filled syringe with needle safetydevice. Treatment should be initiated by healthcare professionals experienced in the diagnosis andtreatment of RA, sJIA, pJIA and/or GCA.

The first injection should be performed under the supervision of a qualified health care professional. Apatient or parent/guardian can self-inject Avtozma only if the physician determines that it is appropriateand the patient or parent/guardian agrees to medical follow-up as necessary and has been trained inproper injection technique.

Patients who transition from tocilizumab IV therapy to SC administration should administer the first

SC dose at the time of the next scheduled IV dose under the supervision of a qualified health careprofessional.

All patients treated with Avtozma should be given the Patient Alert 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 Avtozma intravenousformulation to Avtozma 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. Avtozma can be used alone following discontinuation of glucocorticoids.

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

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

RA and GCA

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

* Liver enzyme abnormalities

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

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

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

> 3 to 5 x ULN Interrupt Avtozma dosing until < 3 x ULN and follow recommendationsabove for > 1 to 3 x ULN.

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

> 5 x ULN Discontinue Avtozma.

* Low absolute neutrophil count (ANC)

In patients not previously treated with tocilizumab, initiation is not recommended in patients withan absolute neutrophil count (ANC) below 2 x 109/L

Laboratory Value Action(cells x 109/L)

ANC > 1 Maintain dose.

ANC 0.5 to 1 Interrupt Avtozma dosing.

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

ANC < 0.5 Discontinue Avtozma.

* Low platelet count

Laboratory Value Action(cells x 103/μL)50 to 100 Interrupt Avtozma dosing.

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

< 50 Discontinue Avtozma.

RA and GCA

If a patient misses a subcutaneous weekly injection of Avtozma within 7 days of the scheduled dose,he/she should be instructed to take the missed dose on the next scheduled day. If a patient misses asubcutaneous once every other week injection of Avtozma 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. Avtozma has notbeen studied in patients with severe renal impairment (see section 5.2). Renal function should bemonitored closely in these patients.

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

The safety and efficacy of Avtozma subcutaneous formulation in children from birth to less than 1year 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.

Avtozma 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 Avtozma subcutaneously.

pJIA Patients:

The recommended posology in patients above 2 years of age is subcutaneous 162 mg once every 2weeks in patients weighing greater than or equal to 30 kg or subcutaneous 162 mg once every 3 weeks inpatients weighing less than 30 kg.

Dose adjustments due to laboratory abnormalities (sJIA and pJIA)

If appropriate, the dose of concomitant MTX and/or other medications should be modified or dosingstopped and tocilizumab dosing interrupted until the clinical situation has been evaluated. As there aremany co-morbid conditions that may affect laboratory values in sJIA or pJIA, the decision to discontinuetocilizumab for a laboratory abnormality should be based upon the medical assessment of the individualpatient.

* Liver enzyme abnormalities

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

For persistent increases in this range, interrupt Avtozma until ALT/AST havenormalized.

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

ULN

Interrupt Avtozma dosing until < 3x ULN and follow recommendations abovefor >1 to 3x ULN.

> 5x ULN Discontinue Avtozma.

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

* Low absolute neutrophil count (ANC)

Laboratory Value Action(cells x 109/L)

ANC > 1 Maintain dose.

ANC 0.5 to 1 Interrupt Avtozma dosing.

When ANC increases to > 1 x 109/L resume Avtozma.

ANC < 0.5 Discontinue Avtozma.

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

* Low platelet count

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

Interrupt Avtozma dosing.

When platelet count is > 100 x 103/µL resume Avtozma.

< 50 Discontinue Avtozma.

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

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

The safety and efficacy of Avtozma subcutaneous formulation in children with conditions other thansJIA or pJIA have not been established.

Available data with the IV formulation suggest that clinical improvement is observed within 12 weeks ofinitiation of treatment with tocilizumab. Continued therapy should be carefully reconsidered in a patientexhibiting no improvement within this timeframe.

If a sJIA patient misses a subcutaneous weekly injection of Avtozma 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 Avtozma 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 Avtozma 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 Avtozma by more than 7 days of thescheduled dose or is unsure when to inject Avtozma, call the doctor or pharmacist.

Avtozma is for subcutaneous use.

After proper training in injection technique, patients may self-inject with Avtozma if their physiciandetermines that it is appropriate. The total content (0.9 mL) of the pre-filled syringe should beadministered 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 Avtozma 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).

Avtozma subcutaneous formulation is not intended for intravenous administration.

Avtozma 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, Undesirable effects). Avtozma treatment must not beinitiated in patients with active infections (see section 4.3). Administration of tocilizumab should beinterrupted if a patient develops a serious infection until the infection is controlled (see section 4.8).

Healthcare professionals should exercise caution when considering the use of Avtozma in patientswith a history of recurring or chronic infections or with underlying conditions (e.g.) diverticulitis,diabetes and interstitial lung disease which may predispose patients to infections.

Vigilance for the timely detection of serious infection is recommended for patients receivingimmunosuppressive agents such as Avtozma 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 should be considered when evaluatinga patient for a potential infection. Patients (which includes younger children with sJIA or pJIA whomay be less able to communicate their symptoms) and parents/guardians of sJIA or pJIA patients,should be instructed to contact their healthcare professional immediately when any symptomssuggesting infection 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 Avtozma therapy. Patients with latent TB should be treated with standardanti-mycobacterial therapy before initiating Avtozma. Prescribers are reminded of the risk of falsenegative tuberculin skin and interferon-gamma TB blood test results, especially in patients who areseverely 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 Avtozma.

Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinicalstudies 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). Avtozma should be used with caution inpatients with previous history of intestinal ulceration or diverticulitis. Patients presenting withsymptoms potentially indicative of complicated diverticulitis, such as abdominal pain, haemorrhageand/or unexplained change in bowel habits with fever should be evaluated promptly for earlyidentification 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 patientswho have experienced hypersensitivity reactions during previous treatment with Avtozma even if theyhave received premedication with steroids and antihistamines. If an anaphylactic reaction or otherserious hypersensitivity reaction occurs, administration of Avtozma should be stopped immediately,appropriate therapy initiated and Avtozma 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 drugs (e.g. MTX) were used in combination withtocilizumab. 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 tomore than 5 years after initiation of tocilizumab. Cases of liver failure resulting in livertransplantation have been reported. Patients should be advised to immediately seek medical help ifthey experience signs and symptoms of hepatic injury.

Caution should be exercised when considering initiation of Avtozma treatment in patients withelevated ALT or AST > 1.5 x ULN. In patients with baseline ALT or AST > 5 x ULN, treatment isnot 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 Avtozma discontinuation, based on transaminases levels see section 4.2. For ALT or ASTelevations > 3-5 x ULN, Avtozma treatment should be interrupted.

Decreases in neutrophil and platelet counts have occurred following treatment with tocilizumab 8mg/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 x 109/L. Caution should be exercised when considering initiation of Avtozmatreatment in patients with a low platelet count (i.e. platelet count below 100 x 103/μL). In patientswho develop an ANC < 0.5 x 109/L or a platelet count < 50 x 103/μL, continued treatment is notrecommended.

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-density lipoprotein (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 elevationsin total cholesterol responded to treatment with lipid lowering agents.

In all patients, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of

Avtozma therapy. 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 Avtozma is currently unknown.

The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products mayincrease the risk of malignancy.

Live and live attenuated vaccines should not be given concurrently with Avtozma as clinical safety hasnot been established. In a randomised open-label study, adult RA patients treated with tocilizumab and

MTX were able to mount an effective response to both the 23-valent pneumococcal polysaccharide andtetanus toxoid vaccines which was comparable to the response seen in patients on MTX only. It isrecommended that all patients particularly paediatric or elderly patients, be brought up to date with allimmunisations in agreement with current immunisation guidelines prior to initiating Avtozma therapy.

The interval between live vaccinations and initiation of Avtozma therapy should be in accordance withcurrent vaccination guidelines regarding immunosuppressive agents.

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

Combination with TNF antagonists

There is no experience with the use of Avtozma with TNF antagonists or other biological treatmentsfor RA patients. Avtozma is not recommended for use with other biological agents.

GCA

Avtozma 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 judgementand practice 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 ofactive MAS.

Polysorbate

Each 162 mg pre-filled syringe contains 0.2 mg of polysorbate 80.

Polysorbates may cause allergic reactions. Patients with polysorbate allergy should not take thismedicine.

Interaction studies have only been performed in adults.

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

Population pharmacokinetic analyses did not detect any effect of MTX, non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids on tocilizumab clearance in RA patients. In GCApatients, no effect of cumulative corticosteroid dose on tocilizumab exposure was observed.

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

In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in

CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. tocilizumab normalises expressionof these enzymes.

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

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) should be monitored as doses may need to be increased to maintain therapeuticeffect. Given its long elimination half-life (t1/2), the effect of tocilizumab on CYP450 enzyme activitymay persist for several weeks after stopping therapy.

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

There are no adequate data from the use of Avtozma 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.

Avtozma should not be used during pregnancy unless clearly necessary.

It is unknown whether tocilizumab is excreted in human breast milk. The excretion of Avtozma inmilk has not been studied in animals. A decision on whether to continue/discontinue breast-feedingor to continue/discontinue therapy with Avtozma should be made taking into account the benefit ofbreast-feeding to the child and the benefit of Avtozma therapy to the woman.

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

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

The safety profile comes from 4 510 patients exposed to tocilizumab in clinical trials; the majority ofthese patients were participating in adult RA studies (n=4 009), while the remaining experiencecomes from GCA (n=149), pJIA (n=240) and sJIA (n=112) studies. The safety profile of tocilizumabacross these indications remains similar and undifferentiated.

The most commonly reported Adverse Drug Reactions (ADRs) were upper respiratory tract infections,nasopharyngitis, headache, hypertension and increased ALT.

The most serious ADRs were serious infections, complications of diverticulitis, and hypersensitivityreactions.

ADRs from clinical trials and/or post marketing experience with tocilizumab based on spontaneouscase reports, literature cases and cases from non-interventional study programs are listed in Table 1and are presented by MedDRA system organ class. The corresponding frequency category for each

AR is based on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10),uncommon (≥ 1/1 000 to < 1/100) rare, (≥ 1/10 000 to < 1/1 000) or very rare (< 1/10 000). Withineach frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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

MedDRA Frequency categories with preferred terms

System Organ Very common Common Uncommon Rare

Class

Infections and Upper respiratory Cellulitis, Diverticulitisinfestations tract infections Pneumonia, Oralherpes simplex,

Herpes zoster

Blood and Leukopenia,lymphatic Neutropenia,system Hypofibrinogenaedisorders mia

Immune system Anaphylaxisdisorders (fatal)1, 2 ,3

Endocrine Hypothyroidismdisorders

Metabolism and Hypercholesterola Hypertriglyceridaenutrition emia* miadisorders

Nervous system Headache,disorders Dizziness

Eye disorders Conjunctivitis

Vascular Hypertensiondisorders

Respiratory, Cough, Dyspnoeathoracic andmediastinaldisorders

MedDRA Frequency categories with preferred terms

System Organ Very common Common Uncommon Rare

Class

Gastrointestinal Abdominal pain, Stomatitis, Gastricdisorders Mouth ulceration, ulcer

Gastritis

Hepatobiliary Drug-induced liverdisorders injury, Hepatitis,

Jaundice,

Very rare: Hepaticfailure

Skin and Rash, Pruritus, Stevens-Johnson-subcutaneous Urticaria Syndrome3tissue disorders

Renal and Nephrolithiasisurinarydisorders

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

Investigations Hepatictransaminasesincreased, Weightincreased, Total

* 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 clinicaltrials. The frequency category was estimated as the upper limit of the 95% confidence interval calculated on thebasis of the total number of patients exposed to TCZ in clinical trials.

Subcutaneous use

RA

The safety of subcutaneous tocilizumab in RA includes a double-blind, controlled, multicenterstudy, SC-I. SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab162 mg administered every week versus 8 mg/kg intravenous in 1 262 patients with RA. Allpatients received background non-biologic DMARD(s). The safety and immunogenicityobserved for tocilizumab administered subcutaneous was consistent with the known safety profileof intravenous tocilizumab and no new or unexpected adverse drug reactions were observed (see

Table 1). A higher frequency of injection site reactions was observed in the subcutaneous armscompared with placebo subcutaneous injections in the 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 drug discontinuation.

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 subcutaneousweekly dose.

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

Platelets

During routine laboratory monitoring in the tocilizumab 6 month clinical trial SC-I, none of the patientson the SC 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 x 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 (SC)

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

The rate of infection in sJIA patients treated with SC tocilizumab was comparable to sJIA patientstreated with IV tocilizumab.

Injection Site Reactions (ISRs)

In the SC Study (WA28118), a total of 41.2% (21/51) sJIA patients experienced ISRs to tocilizumab

SC. The most common ISRs were erythema, pruritus, pain, and swelling at the injection site. Themajority of ISRs reported were Grade 1 events and all ISRs reported were non-serious and nonerequired patient withdrawal from treatment or dose interruption.

Laboratory Abnormalities

In the 52-week open-label SC Study (WA28118), neutrophil count decrease to below 1 × 109/Loccurred in 23.5% of patients treated with tocilizumab SC. Decreases in platelet counts to below 100× 103/μL occurred in 2% of the patients treated with tocilizumab SC. An elevation in ALT or AST to≥3 x ULN occurred in 9.8% and 4.0% patients treated with tocilizumab SC, respectively.

Lipid parameters

In the 52-week open-label SC Study (WA28118), 23.4% and 35.4% of patients experienced a post-baseline elevation of their LDL-cholesterol value to ≥130 mg/dL and total cholesterol value to ≥200mg/dL at any time during study treatment, respectively.

pJIA (SC)

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 IV and 50.4 patient years for SC tocilizumab. In general, the safety profile observed in patientswith pJIA was consistent with the known safety profile of tocilizumab with the exception of ISRs (see

Table 1). A higher frequency of pJIA patients experienced ISRs following SC tocilizumab injectionscompared to adult RA.

In the SC tocilizumab study, the rate of infection in pJIA patients treated with SC tocilizumab wascomparable with pJIA patients treated with IV tocilizumab.

Injection Site Reactions

A total of 28.8% (15/52) pJIA patients experienced ISRs to tocilizumab SC. These ISRs occurred ina 44% of patients ≥30 kg compared to 14.8% of patients below 30 kg. The most common ISRs wereinjection site erythema, swelling, hematoma, pain and pruritis. All ISRs reported were non-serious

Grade 1 events, and none of the ISRs required patient withdrawal from treatment or doseinterruption.

Laboratory Abnormalities

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 SC tocilizumab. Anelevation in ALT or AST ≥3 x ULN occurred in 9.6% and 3.8% patients treated with tocilizumab

SC, respectively. No patients treated with SC tocilizumab experienced a decrease in platelet count to≤50 × 103/μL.

Lipid parameters

In the SC Study, 14.3% and 12.8% of patients experienced a post-baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time during studytreatment, respectively.

GCA (SC)

The safety of subcutaneous tocilizumab has been studied in one Phase III study (WA28119) with251 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 tocilizumab treatment groups was consistent with the knownsafety profile of tocilizumab (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.

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 occurrence ofdecrease in platelet count to <100 × 103/μL without associated bleeding events. A decrease inplatelet count below 100 × 103/μL was not observed in either of the placebo plus prednisone tapergroups.

Hepatic transaminase elevations

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

ALT ≥3 x 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% ofpatients experienced sustained elevations in total cholesterol > 6.2 mmol/L (240 mg/dL), with 15%experiencing a sustained increase in LDL to ≥ 4.1 mmol/L (160 mg/dL) in the tocilizumabsubcutaneous weekly group.

RA

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 studies was 6 months and in 1 study was up to 2 years. In the double-blindcontrolled studies 774 patients received tocilizumab 4 mg/kg in combination with MTX, 1 870patients received tocilizumab 8 mg/kg in combination with MTX/other DMARDs and 288 patientsreceived tocilizumab 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 studies. Of the 4 009 patients inthis population, 3 577 received treatment for at least 6 months, 3 296 for at least one year; 2 806received treatment for at least 2 years and 1 222 for 3 years.

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

DMARD treatment was 127 events per 100 patient years compared to 112 events per 100 patientyears in the placebo plus DMARD group. In the long-term exposure population, the overall rate ofinfections with tocilizumab was 108 events per 100 patient years exposure.

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

DMARDs was 5.3 events per 100 patient years exposure compared to 3.9 events per 100 patientyears exposure in the placebo plus DMARD group. In the monotherapy study the rate of seriousinfections was 3.6 events per 100 patient years of exposure in the tocilizumab group and 1.5 eventsper 100 patient years of exposure in the MTX group.

In the all exposure population the overall rate of serious infections was 4.7 events per 100 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 been post-marketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some ofwhich had fatal outcomes.

Gastrointestinal perforation

During the 6-month controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26events 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 tocilizumab were primarily reported as complications of diverticulitisincluding generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess.

Infusion Related Reactions

In the 6-month controlled trials adverse events associated with infusion (selected events 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 6/3 778patients, 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 3 778 patients (0.3%) treated with tocilizumab during the controlled and open labelclinical studies. These reactions were generally observed during the second to fifth infusions oftocilizumab (see section 4.4). Fatal anaphylaxis has been reported after marketing authorisation duringtreatment with intravenous tocilizumab (see section 4.4).

In the 6-month controlled trials decreases in neutrophil counts below 1 x 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 x 109/L did so within 8weeks after starting therapy. Decreases below 0.5 x 109/L were reported in 0.3% patients receivingtocilizumab 8 mg/kg plus DMARDs. Infections with neutropenia have been reported.

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

Platelets

In the 6-month controlled trials decreases in platelet counts below 100 x 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 x 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 drugs (e.g. MTX) to tocilizumab monotherapy resulted inincreased frequency of these elevations. Elevations of ALT/AST > 5 x ULN were observed in 0.7%of tocilizumab monotherapy patients and 1.4% of tocilizumab plus DMARD patients, the majority ofwhom were discontinued permanently from tocilizumab treatment. During the double-blind controlledperiod, the incidence of indirect bilirubin greater than the upper limit of normal, collected as a routinelaboratory parameter, is 6.2% in patients treated with 8 mg/kg tocilizumab + DMARD. A total of5.8% of patients experienced an elevation of indirect bilirubin of > 1 to 2 x ULN and 0.4% had anelevation of > 2 x 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 inclinical trials experienced sustained elevations in total cholesterol ≥ 6.2 mmol/L, with 15%experiencing a sustained increase in LDL to ≥ 4.1 mmol/L. Elevations in lipid parameters respondedto treatment with lipid-lowering agents.

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

The clinical data are insufficient to assess the potential incidence of malignancy following exposure totocilizumab. Long-term safety evaluations are ongoing.

Skin Reactions

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

Anti-tocilizumab antibodies may develop during tocilizumab treatment. Correlation of antibodydevelopment to clinical response or adverse events may be observed.

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 to 28mg/kg, although dose limiting neutropenia was observed.

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

Avtozma is a biosimilar medicinal product. Detailed information is available on the websiteof the European Medicines Agency https://www.ema.europa.eu.

Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6Rand mIL-6R). Tocilizumab has been shown to inhibit sIL-6R and mIL-6R-mediated signalling.

IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including

T- and B-cells, monocytes and fibroblasts. IL-6 is involved in diverse physiological processessuch as T-cell activation, induction of immunoglobulin secretion, induction of hepatic acutephase protein synthesis and stimulation of haemopoiesis. IL-6 has been implicated in thepathogenesis of diseases including inflammatory diseases, osteoporosis and neoplasia.

In clinical studies with tocilizumab, rapid decreases in CRP, erythrocyte sedimentation rate (ESR),serum amyloid A (SAA) and fibrinogen were observed. Consistent with the effect on acute 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 tocilizumab-treated patients, decreasesin the levels of CRP to within normal ranges were seen as early as week 2, with decreases maintainedwhile on treatment.

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).

Subcutaneous use

RA

The efficacy of subcutaneous administered tocilizumab in alleviating the signs and symptomsof RA and radiographic response, was assessed in two randomised, double-blind, controlled,multi-center studies. For study I (SC-I), patients were required to be >18 years of age withmoderate to severe active RA diagnosed according to ACR criteria who had at least 4 tenderand 4 swollen joints at baseline. All patients received background non-biologic DMARD(s).

For study II (SC-II), patients were required to be > 18 years of age with moderate to severeactive RA diagnosed according to ACR criteria who had at least 8 tender and 6 swollenjoints 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, 1 262patients were randomised 1:1 to receive tocilizumab subcutaneous 162 mg every week or tocilizumabintravenous 8 mg/kg every four weeks in combination with non-biologic DMARD(s). The primaryendpoint in the study was the difference in the proportion of patients who achieved an ACR20response 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

ACR20 Week 24 69.4% 73.4%

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

ACR50 Week 24 47.0% 48.6%

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

ACR70 Week 24 24.0% 27.9%

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

TCZ = tocilizumaba = 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 DAS28from baseline (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 IV (36.9%) arms.

The radiographic response of subcutaneous administered tocilizumab was assessed in a double-blind,controlled, multicenter 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 expressedas a change from baseline in the van der Heijde modified mean total Sharp score (mTSS). At week24, inhibition of structural damage was shown, with significantly less radiographic progression inpatients receiving 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 withintravenous tocilizumab.

In study SC-II, at week 24 there was ACR20 of 60.9%, ACR50 of 39.8% and ACR70 of 19.7% forpatients treated with tocilizumab subcutaneous every other week versus placebo ACR20 of 31.5%,

ACR50 of 12.3% and ACR70 of 5.0%. Patients had mean DAS28 at baseline of 6.7 on 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).

Proportion of patients achieving a clinically relevant improvement in HAQ-DI at week 24 (changefrom baseline of ≥ 0.3 units) was higher for tocilizumab subcutaneous every other week (58%) versusplacebo (46.8%). SF-36 (mean change in mental and physical component scores) was significantlygreater with tocilizumab subcutaneous group (6.5 and 5.3) versus placebo (3.8 and 2.9).

sJIA (SC)

Clinical Efficacy

A 52-week, open-label, multi-centre, PK/PD and safety study (WA28118) was conducted inpaediatric patients with sJIA, aged 1 to 17 years, to determine the appropriate SC dose oftocilizumab that achieved comparable PK/PD and safety profiles to the IV regimen.

Eligible patients received tocilizumab dosed according to body weight (BW), with patients weighing≥30 kg (n=26) dosed with 162 mg of tocilizumab every week (QW) and patients weighing below 30kg (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 tocilizumab and 25 (49%) hadbeen receiving tocilizumab IV and switched to tocilizumab SC at baseline.

Exploratory efficacy results showed that tocilizumab SC improved all exploratory efficacy parametersincluding Juvenile Arthritis Disease Activity Score (JADAS)-71, for TCZ naïve patients andmaintained all exploratory efficacy parameters for patients who switched from tocilizumab IV totocilizumab SC treatment over the entire course of the study for patients in both body weight groups(below 30 kg and ≥30 kg).

pJIA (SC)

A 52-week, open-label, multicenter, PK-PD and safety study was conducted in paediatric patientswith pJIA, aged 1 to 17 years old, to determine the appropriate subcutaneous dose of tocilizumabthat achieved comparable PK/PD and safety profiles to the IV regimen.

Eligible patients received tocilizumab dosed according to body weight (BW), with patients weighing≥ 30 kg (n = 25) dosed with 162 mg of tocilizumab every 2 weeks (Q2W) and patients weighingbelow 30 kg (n = 27) dosed with 162 mg of tocilizumab every 3 weeks (Q3W) for 52 weeks. Ofthese 52 patients, 37 (71%) were naive to tocilizumab and 15 (29%) had been receiving tocilizumab

IV and switched to tocilizumab SC at baseline.

The tocilizumab SC regimens of 162 mg Q3W for patients weighing below 30 kg and of 162 mg

Q2W for patients weighing ≥ 30 kg respectively provide PK exposure and PD responses to supportefficacy and safety outcomes similar to those achieved with the approved tocilizumab IV regimensfor pJIA.

Exploratory efficacy results showed that tocilizumab SC improved median Juvenile Arthritis

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

JADAS-71 for patients who switched from IV to SC tocilizumab treatment over the entire course ofthe study for patients in both body weight groups (below 30 kg and ≥ 30 kg).

GCA (SC)

Study WA28119 was a randomised, multi-center, 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 the long-term safety and maintenance of efficacy after 52 weeks of tocilizumab therapy, to explore the rate ofrelapse and the requirement for tocilizumab therapy beyond 52 weeks, and to gain insight into thepotential long-term steroid-sparing effect of tocilizumab.

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-treated groups and one of the placebo-treated groups followed a pre-specified prednisone-taperregimen over 26 weeks, while the second placebo-treated group followed a pre-specifiedprednisone-taper regimen over 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

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 plus 52weeks 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 for thetocilizumab 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 everyother weekly groups were 3 129.75 mg and 3 847 mg, respectively. Both considerably lower than inthe placebo plus 26 weeks and the placebo plus 52 weeks prednisone taper groups, 4 023.5 mg and5 389.5 mg respectively.

Table 4. Efficacy results from Study WA28119

Placebo + Placebo + Tocilizuma Tocilizumab26 weeks 52 weeks b 162 mg 162 mg SC everyprednison predniso SC other weekly +e taper ne taper weekly + 26 weeks

N=50 N=51 26 weeks prednisone taperprednisone N=49taper

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

Annualized 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 doserequired Remission: absence of flare and normalization of the CRP

Sustained remission: remission from week 12 to week 52 -Patients must adhere to the protocol-definedprednisone taper ¹ 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 beenperformed N/A= Not applicable

HR = Hazard Ratio

CI = Confidence Interval

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 52was higher (showing more improvement) in the tocilizumab weekly and every other weekly dosegroups [4.10, 2.76, respectively] than in the two placebo groups [placebo plus 26 weeks; -0.28,placebo plus 52 weeks; -1.49], although only the comparison between tocilizumab weekly plus 26weeks prednisone taper group and placebo plus 52 weeks prednisone taper group (5.59, 99% CI:8.6, 10.32) showed a statistically significant difference (p=0.0024). For MCS, the mean changefrom baseline to week 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 differences were not statistically significant [weekly p=0.0252 for weekly, p=0.1468for every other weekly]) and similar to the placebo plus 26 weeks prednisone taper group [6.67].

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

Scale (VAS). The mean change in Patient’s global VAS from baseline at week 52 was lower(showing greater 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 52weeks -7.2], although only the tocilizumab every other weekly plus 26 weeks prednisone taper groupshowed a statistically significant difference compared to placebo [placebo plus 26 weeks taperp=0.0059, and placebo plus 52 weeks taper p=0.0081].

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

The efficacy of tocilizumab in alleviating the signs and symptoms of RA was assessed in fiverandomised, double-blind, multi-centre studies. Studies I-V enrolled patients ≥ 18 years of age withactive RA diagnosed according to the American College of Rheumatology (ACR) criteria and whohad at least eight tender and six swollen joints at baseline.

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

Studies II, III and V, tocilizumab was administered intravenously every four weeks in combinationwith MTX vs. placebo and MTX. In Study IV, tocilizumab was administered intravenously every 4weeks in combination with other DMARDs vs. placebo and other DMARDs. The primary endpointfor each of the five studies was the proportion of patients who achieved an ACR 20 response atweek 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. Dosesof 8 mg/kg of tocilizumab were given every four weeks as monotherapy. The comparator group wasweekly MTX (dose titrated from 7.5 mg to a maximum of 20 mg weekly over an eight week period).

Study II, a two year study with planned analyses at week 24, week 52 and week 104, evaluated1 196 patients who had an inadequate clinical response to MTX. Doses of 4 or 8 mg/kg oftocilizumab or placebo were given every four weeks as blinded therapy for 52 weeks in combinationwith stable MTX (10 mg to 25 mg weekly). After week 52, all patients could receive open-labeltreatment with tocilizumab 8 mg/kg. Of the patients who completed the study who were originallyrandomised to placebo + MTX, 86% received open-label tocilizumab 8 mg/kg in year 2. Theprimary endpoint at week 24 was the proportion of patients who achieved an ACR 20 response. Atweek 52 and week 104 the co-primary endpoints were prevention of joint damage and improvementin physical function.

Study III evaluated 623 patients who had an inadequate clinical response to MTX. Doses of 4 or 8mg/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 givenevery four 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 torandomisation. Doses of 4 or 8 mg/kg tocilizumab or placebo were given every four weeks incombination with stable MTX (10 mg to 25 mg weekly).

In all studies, patients treated with tocilizumab 8 mg/kg had statistically significant higher ACR 20,50, 70 response rates at 6 months compared to control (Table 5). In study I, superiority oftocilizumab 8 mg/kg was demonstrated against the active comparator MTX.

The treatment effect was similar in patients independent of rheumatoid factor status, age, gender,race, number of prior treatments or disease status. Time to onset was rapid (as early as week 2) and themagnitude of response continued to improve with duration of treatment. Continued durable responseswere seen for over 3 years in the open label extension studies I-V.

In patients treated with tocilizumab 8 mg/kg, significant improvements were noted on all 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 studies.

Patients in studies I - V had a mean Disease Activity Score (DAS28) of 6.5-6.8 at baseline.

Significant reduction in DAS28 from baseline (mean improvement) of 3.1-3.4 was observed intocilizumab-treated patients compared to control patients (1.3-2.1). The proportion of patientsachieving a DAS28 clinical remission (DAS28 < 2.6) was significantly higher in patients receivingtocilizumab (28-34%) compared to 1-12% of control patients at 24 weeks. In study II, 65% ofpatients achieved a DAS28 < 2.6 at week 104 compared to 48% at 52 weeks and 33% of patients atweek 24.

In a pooled analysis of studies II, III and IV, the proportion of patients achieving an ACR 20, 50 and70 response 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 studies (% patients)

Study I Study II Study III Study IV Study V

AMBITION LITHE OPTION TOWARD RADIATE

Week TCZ MTX TCZ PBO+ TCZ PBO+ TCZ PBO + TCZ PBO +8 mg/kg 8 mg/kg+ MTX 8 mg/kg+ MTX 8 mg/kg+ DMARD 8 mg/kg+ MTX

MTX MTX DMARD MTX

N = 286 N = 284 N = 398 N = 393 N = 205 N = 204 N = 803 N = 413 N = 170 N = 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 ACR70 response for 24 weeks or more).

In Study II, in patients with an inadequate response to MTX, inhibition of structural joint damagewas assessed radiographically and expressed as change in modified Sharp score and its components,the erosion score and joint space narrowing score. Inhibition of joint structural damage was shownwith significantly less radiographic progression in patients receiving tocilizumab compared tocontrol (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 orless, 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) ofpatients had no progression between week 52 and week 104.

Health-related and quality of life outcomes

Tocilizumab--treated patients reported an improvement in all patient-reported outcomes (Health

Assessment Questionnaire Disability Index - HAQ-DI), Short Form-36 and Functional Assessmentof Chronic Illness Therapy questionnaires. Statistically significant improvements in HAQ-DI scoreswere observed in patients treated with tocilizumab compared with patients treated with DMARDs.

During the open-label period of Study II, the improvement in physical function has beenmaintained for up to 2 years. At Week 52, the mean change in HAQ-DI was -0.58 in thetocilizumab 8 mg/kg plus MTX group compared with -0.39 in the placebo + MTX group. The meanchange in HAQ-DI was maintained at Week 104 in the tocilizumab 8 mg/kg plus MTX group (-0.61).

Haemoglobin levels

Statistically significant improvements in haemoglobin levels were observed with tocilizumabcompared with DMARDs (p< 0.0001) at week 24. Mean haemoglobin levels increased by week 2and remained within normal range through to week 24.

Tocilizumab versus adalimumab in monotherapy Study VI (WA19924), a 24 week double-blindedstudy that compared tocilizumab monotherapy with adalimumab monotherapy, evaluated 326 patientswith RA who were intolerant of MTX or where continued treatment with MTX was consideredinappropriate (including MTX inadequate responders). Patients in the tocilizumab arm received anintravenous (IV) infusion of tocilizumab (8 mg/kg) every 4 weeks (q4w) and a subcutaneous (SC)placebo injection every 2 weeks (q2w). Patients in the adalimumab arm received an adalimumab SCinjection (40 mg) q2w plus an IV placebo infusion q4w.

A statistically significant superior treatment effect was seen in favour of tocilizumab overadalimumab in control of disease activity from baseline to week 24 for the primary endpoint ofchange in DAS28 and 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

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

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

ACR70 response, n (%) 29 (17.9) 53 (32.5) 0.0023ap 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

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 drug reactions in the tocilizumabarm were consistent with the known safety profile of tocilizumab and adverse drug reactions werereported at a similar frequency compared with Table 1. A higher incidence of infections andinfestations was reported in the tocilizumab arm (48% vs. 42%), with no difference in the incidenceof serious infections (3.1%). Both study treatments induced the same pattern of changes inlaboratory safety parameters (decreases in neutrophil and platelet counts, increases in ALT, ASTand lipids), however, the magnitude of change and the frequency of marked abnormalities washigher with tocilizumab compared with adalimumab. Four (2.5%) patients in the tocilizumab armand two (1.2%) patients in the adalimumab arm experienced CTC grade 3 or 4 neutrophil countdecreases. Eleven (6.8%) patients in the tocilizumab arm and five (3.1%) patients in theadalimumab arm experienced ALT increases of CTC grade 2 or higher. The mean LDL increasefrom baseline was 0.64 mmol/L (25 mg/dL) for patients in the tocilizumab arm and 0.19 mmol/L (7mg/dL) for patients in the adalimumab arm. The safety observed in the tocilizumab arm wasconsistent with the known safety profile of tocilizumab and no new or unexpected adverse drugreactions were observed (see Table 1).

The pharmacokinetics of tocilizumab is characterized by nonlinear elimination which is acombination of linear clearance and Michaelis-Menten elimination. The nonlinear part oftocilizumab elimination leads to an increase in exposure that is more than dose-proportional. Thepharmacokinetic parameters of tocilizumab do not change with time. Due to the dependence of totalclearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. Population pharmacokineticanalyses in any patient population tested so far indicate no relationship between apparent clearanceand the presence of anti-drug antibodies.

RA

The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysison a database composed of 3 552 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 eitheronce a week or every other week for 24 weeks.

The following parameters (predicted mean ± SD) were estimated for a dose of 8 mg/kg tocilizumabgiven every 4 weeks: steady-state area under curve (AUC) = 38 000 ± 13 000 h*µg/mL, troughconcentration (Cmin) = 15.9 ± 13.1 µg/mL and maximum concentration (Cmax) = 182 ± 50.4 µg/mL,and. the accumulation ratios for AUC and Cmax were small, 1.32 and 1.09, respectively. Theaccumulation ratio was higher for Cmin (2.49), which was expected based on the non-linear clearancecontribution at lower concentrations. Steady-state was reached following the first administration for

Cmax and after 8 and 20 weeks for AUC and Cmin, respectively. Tocilizumab AUC, Cmin and Cmaxincreased with increase of body weight. At body weight ≥ 100 kg, the predicted mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 50 000 ± 16 800 μg*h/mL, 24.4 ± 17.5 μg/mL, and226 ± 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 flattensat higher exposure, resulting in smaller efficacy gains for each incremental increase in tocilizumabconcentration such that clinically meaningful increases in efficacy were not demonstrated in patientstreated with > 800 mg of tocilizumab. Therefore, tocilizumab doses exceeding 800 mg per infusionare not recommended (see section 4.2).

In RA patients the central volume of distribution was 3.72 L, the peripheral volume of distributionwas 3.35 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 playsa major role at low tocilizumab concentrations. Once the non-linear clearance pathway is saturated,at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.

The t1/2 of tocilizumab was concentration-dependent. At steady-state following a dose of 8 mg/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 analysison a database composed of 3 552 RA patients treated with 162 mg subcutaneous every week, 162mg subcutaneous 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 everyweek dose, the predicted mean (±SD) steady-state AUC1week, Cmin and Cmax of tocilizumab were 7970± 3432 µg*h/mL, 43.0 ± 19.8 µg/mL, and 49.8 ± 21.0 µg/mL, respectively. The accumulation ratiosfor AUC, Cmin, and Cmax were 6.32, 6.30, and 5.27, respectively. Steady state was reached after 12weeks for AUC, Cmin, and Cmax.

For the 162 every other week dose, the predicted mean (±SD) steady-state AUC2week, Cmin, and Cmaxof tocilizumab were 3 430 ± 2 660 µg*h/mL, 5.7 ± 6.8 µg/mL, and 13.2 ± 8.8 µg/mL, respectively.

The accumulation ratios for AUC, Cmin, and Cmax were 2.67, 6.02, and 2.12, respectively. Steadystate was reached 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

Subcutaneous Use

The pharmacokinetics of tocilizumab in sJIA patients was characterized by a populationpharmacokinetic analysis which included 140 patients who were treated with 8 mg/kg IV every 2weeks (patients weighing ≥30 kg), 12 mg/kg IV every 2 weeks (patients weighing below 30 kg),162 mg SC every week (patients weighing ≥30 kg), 162 mg SC every 10 days or every 2 weeks(patients weighing below 30 kg).

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

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

Table 8. Predicted mean ± SD PK parameters at steady-state after SC 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 AUCτ* 4.28 2.27

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

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

Following SC dosing in sJIA patients, the absorption half-life was around 2 days, and thebioavailability for the SC 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

Subcutaneous use

The pharmacokinetics of tocilizumab in pJIA patients was characterized by a populationpharmacokinetic analysis which included 237 patients who were treated with 8 mg/kg IV every 4weeks (patients weighing ≥ 30 kg), 10 mg/kg IV every 4 weeks (patients weighing below 30 kg),162 mg SC every 2 weeks (patients weighing ≥ 30 kg), or 162 mg SC every 3 weeks (patientsweighing below 30 kg).

Table 9. Predicted mean ± SD PK parameters at steady-state after SC 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 SC regimens

After IV dosing, approximately 90% of the steady-state was reached by Week 12 for the 10 mg/kg(BW < 30 kg), and by Week 16 for the 8 mg/kg (BW ≥ 30 kg) dose. After SC dosing, approximately90% of the steady-state was reached by Week 12 for both the 162 mg SC Q2W and Q3W regimens.

Following SC dosing in pJIA patients, the absorption half-life was around 2 days, and thebioavailability for the SC 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 daysfor patients < 30 kg (162 mg SC Q3W) and up to 7 days for patients ≥ 30 kg (162 mg SC Q2W)during a dosing interval at steady state. Following intravenous administration, tocilizumab undergoesbiphasic elimination from the circulation. The total clearance of tocilizumab was concentration-dependent and is the sum of the linear and non-linear clearance. The linear clearance was estimated asa parameter in the population pharmacokinetic analysis and was 6.25 mL/h. The concentration-dependent non-linear clearance plays a major role at low tocilizumab concentrations. Once the non-linear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainlydetermined by the linear clearance.

GCA

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 162 mgevery other weekly weekly

Cmax (µg/mL) 19.3 ± 12.8 73 ± 30.4

Cmin (µg/mL) 11.1 ± 10.3 68.1± 29.5

Cmean (µg/mL) 16.2 ± 11.8 71.3 ± 30.1

Accumulation Cmax 2.18 8.88

Accumulation Cmin 5.61 9.59

Accumulation Cmean or AUCτ * 2.81 10.91

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

The steady-state profile following the 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 weekly and week 17 in the weekly dose groups.

Based on the current characterization of PK, tocilizumab trough concentration at steady state are50% higher in this population relative to average concentrations in a large dataset from the RApopulation. These differences occur due to unknown reasons. PK differences are not accompanied bymarked differences in PD parameters and so the clinical relevance is unknown.

In GCA patients, higher exposure was observed in patients with lower body weight. For the 162 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 SC formulation was 0.8. The median values of Tmax were 3 days after thetocilizumab 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 linearclearance and the nonlinear clearance. The linear clearance was estimated as a parameter in thepopulation pharmacokinetic 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.

At high serum concentrations, when total clearance of tocilizumab is dominated by linear clearance,an effective t ½ of approximately 32 days was derived from the population parameter estimates.

Renal impairment: No formal study of the effect of renal impairment on the pharmacokinetics oftocilizumab has been conducted. Most of the patients in the RA and GCA studies populationpharmacokinetic analysis had normal renal function or mild renal impairment. Mild renalimpairment (estimated creatinine clearance based on Cockcroft-Gault formula) did not impact thepharmacokinetics 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.

Hepatic impairment: No formal study of the effect of hepatic impairment on the pharmacokinetics oftocilizumab has been conducted.

Age, gender and ethnicity: Population pharmacokinetic analyses in RA and GCA patients, showedthat age, gender and ethnic origin 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. Effectson endocrine active and reproductive system organs were not observed in a chronic cynomolgusmonkey toxicity study and reproductive performance was not affected in IL-6 deficient mice.

Tocilizumab administered to cynomolgus monkeys during early gestation, was observed to have nodirect or indirect harmful effect on pregnancy or embryonal-foetal development. However, a slightincrease in abortion/embryonal-foetal death was observed with high systemic exposure (> 100 xhuman exposure) in the 50 mg/kg/day high-dose group compared to placebo and other low-dosegroups. Although IL-6 does not seem to be a critical cytokine for foetal growth or the immunologicalcontrol of the maternal/foetal interface, a relation of this finding to tocilizumab cannot be excluded.

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

The non-clinical safety profile of tocilizumab in the cynomolgus monkey does not suggesta difference between intravenous and subcutaneous routes of administration.

L-Histidine

L-Histidine monohydrochloride monohydrate

L-Threonine

L-Methionine

Polysorbate 80

Water for injections

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

4 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 3 weeks at or below 30°C. If necessary, the pre-filled syringe may bereturned to the refrigerator once within these 3 weeks and stored refrigerated until the expiry date.

The pre-filled syringe must be discarded if not used within the 3-week period.

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 bya rigid needle shield (polyisoprene rubber and polypropylene) and a sterile fluorotec-coatedelastomeric plunger stopper (with silicone).

The Avtozma pre-filled syringe for patient use is available in packs containing:

* 1 pre-filled syringe

* 2 pre-filled syringes

* 4 pre-filled syringes

* 12 (3 packs of 4) pre-filled syringes (Multipacks)

Not all pack sizes may be marketed.

Avtozma is supplied in a single use pre-filled syringe fitted into a needle safety device.

After removing the pre-filled syringe from the refrigerator, the pre-filled syringe should be allowedto reach room temperature (18 °C to 28 °C) by waiting for 30 minutes, before injecting Avtozma.

The syringe should not be shaken.

After removing the cap the injection must be started within 5 minutes, to prevent the medicine fromdrying out and blocking the needle. If the pre-filled syringe is not used within 5 minutes of removingthe cap, you must dispose of it in a puncture resistant container and use a new pre-filled syringe.

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

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

Comprehensive instructions for the administration of Avtozma 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.

Celltrion Healthcare Hungary Kft.1062 Budapest

Váci út 1-3. WestEnd Office Building B torony

Hungary

EU/1/24/1896/007

EU/1/24/1896/008

EU/1/24/1896/009

EU/1/24/1896/013

Date of first authorisation: 14 February 2025

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

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