4.1. Therapeutic indications

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

• the treatment of severe, active and progressive rheumatoid arthritis (RA) in adults not previously treated with MTX.

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

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

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

Tyenne is indicated for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in patients 12 years of age and older, who have responded inadequately to previous therapy with NSAIDs and systemic corticosteroids (see Section 4.2). Tyenne can be given as monotherapy (in case of intolerance to MTX or where treatment with MTX is inappropriate) or in combination with MTX.

Tyenne in combination with methotrexate (MTX) is indicated for the treatment of juvenile idiopathic polyarthritis (pJIA; rheumatoid factor positive or negative and extended oligoarthritis) in patients 12 years of age and older, who have responded inadequately to previous therapy with MTX (see Section 4.2).

Tyenne can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.

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

4.2. Posology and method of administration

Tyenne subcutaneous formulation is administered with a single-use pre-filled pen. Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of RA, sJIA, pJIA and/or GCA.

The pre-filled pen should not be used to treat paediatric patients < 12 years of age since there is a potential risk of intramuscular injection due to thinner subcutaneous tissue layer.

The first injection should be performed under the supervision of a qualified healthcare professional. A patient or parent/guardian can inject Tyenne only if the physician determines that it is appropriate and the patient or parent/guardian agrees to medical follow-up as necessary and has been trained in proper injection technique.

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

All patients treated with Tyenne should be given the Patient Alert Card.

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

Posology

RA

The recommended posology is subcutaneous 162 mg once every week.

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

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

GCA

The recommended posology is subcutaneous 162 mg once every week in combination with a tapering course of glucocorticoids. Tyenne can be used alone following discontinuation of glucocorticoids. Tyenne monotherapy should not be used for the treatment of acute relapses (see 4.4).

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

RA and GCA

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

. Liver enzyme abnormalities

Laboratory Value

Action

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

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

For persistent increases in this range, reduce Tyenne dose frequency to every other week injection or interrupt Tyenne 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 Tyenne dosing until <3 x ULN and follow recommendations above for > 1 to 3 x ULN.

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

> 5 x ULN

Discontinue Tyenne.

. Low absolute neutrophil count (ANC)

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

Laboratory Value

(cells x 109/ L )

Action

ANC > 1

Maintain dose.

ANC 0.5 to 1

Interrupt Tyenne dosing.

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

ANC < 0.5

Discontinue Tyenne.

▯ Low platelet count

Laboratory Value

(cells x 103/ μL)

Action

50 to 100

Interrupt Tyenne dosing.

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

< 50

Discontinue Tyenne.

RA and GCAMissed dose

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

Special populations

Elderly

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

Renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment. Tocilizumab has not been studied in patients with severe renal impairment (see section 5.2). Renal function should be monitored closely in these patients.

Hepatic impairment

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

Paediatric patients

The safety and efficacy of tocilizumab subcutaneous formulation in children from birth to less than 1 year have not been established. No data are available.

A change in dose should only be based on a consistent change in the patient's body weight over time. Tocilizumab can be used alone or in combination with MTX.

sJIA Patients

The recommended posology in patients above 12 years of age is 162 mg subcutaneously once every week in patients weighing greater than or equal to 30 kg or 162 mg subcutaneously once every 2 weeks in patients weighing less than 30 kg.

The pre-filled pen should not be used to treat paediatric patients < 12 years of age.

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

pJIA Patients

The recommended posology in patients above 12 years of age is 162 mg subcutaneously once every 2 weeks in patients weighing greater than or equal to 30 kg or 162 mg subcutaneously once every 3 weeks in patients weighing less than 30 kg.

The pre-filled pen should not be used to treat paediatric patients < 12 years of age.

Dose adjustments due to laboratory abnormalities (sJIA and pJIA)

If appropriate, the dose of concomitant MTX and/or other medicines should be modified or dosing stopped and tocilizumab dosing interrupted until the clinical situation has been evaluated. As there are many co-morbid conditions that may affect laboratory values in sJIA or pJIA, the decision to discontinue Tyenne for a laboratory abnormality should be based upon the medical assessment of the individual patient.

. Liver enzyme abnormalities

Laboratory Value

Action

> 1 to 3 x ULN

Modify the dose of the concomitant MTX if appropriate

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

> 3 x ULN to 5x ULN

Modify the dose of the concomitant MTX if appropriate

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

> 5x ULN

Discontinue Tyenne.

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

. Low absolute neutrophil count (ANC)

Laboratory Value

(cells x 109/ L )

Action

ANC > 1

Maintain dose

ANC 0.5 to 1

Interrupt Tyenne dosing

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

ANC < 0.5

Discontinue Tyenne

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

. Low platelet count

Laboratory Value

(cells x 103/μL)

Action

50 to 100

Modify the dose of the concomitant MTX if appropriate

Interrupt Tyenne dosing

When platelet count is > 100 x 103/μL resume Tyenne

< 50

Discontinue Tyenne.

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

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

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

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

Missed dose

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

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

Method of administration

Tyenne is for subcutaneous use.

After proper training in injection technique, patients may self-inject with Tyenne if their physician determines that it is appropriate. The total content (0.9 mL) of the pre-filled pen should be administered as a subcutaneous injection. The recommended injection sites (abdomen except for 5 cm around the navel, thigh and upper arm) should be rotated and injections should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

The pre-filled pen should not be shaken.

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

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Tocilizumab subcutaneous formulation is not intended for intravenous administration.

Traceability

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

Infections

Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including tocilizumab (see section 4.8, Undesirable effects). Tocilizumab treatment must not be initiated in patients with active infections (see section 4.3). Administration of tocilizumab should be interrupted if a patient develops a serious infection until the infection is controlled (see section 4.8). Healthcare professionals should exercise caution when considering the use of tocilizumab in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes and interstitial lung disease which may predispose patients to infections.

Vigilance for the timely detection of serious infection is recommended for patients receiving immunosuppressive agents such as tocilizumab as signs and symptoms of acute inflammation may be lessened, due to suppression of the acute phase reactants. The effects of tocilizumab on C-reactive protein (CRP), neutrophils and signs and symptoms of infection should be considered when evaluating a patient for a potential infection. Patients, and parents/guardians of sJIA or pJIA patients, should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.

Tuberculosis

As recommended for other biological treatments, all patients should be screened for latent tuberculosis (TB) infection prior to starting tocilizumab therapy. Patients with latent TB should be treated with standard anti-mycobacterial therapy before initiating tocilizumab. Prescribers are reminded of the risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in patients who are severely ill or immunocompromised.

Patients, and parents/guardians of sJIA or pJIA patients should be advised to seek medical advice if signs/symptoms (e.g., persistent cough, wasting/weight loss, low grade fever) suggestive of a tuberculosis infection occur during or after therapy with tocilizumab.

Viral reactivation

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

Complications of diverticulitis

Events of diverticular perforations as complications of diverticulitis have been reported uncommonly in patients treated with tocilizumab (see section 4.8). Tocilizumab should be used with caution in patients with previous history of intestinal ulceration or diverticulitis. Patients presenting with symptoms potentially indicative of complicated diverticulitis, such as abdominal pain, haemorrhage and/or unexplained change in bowel habits with fever should be evaluated promptly for early identification of diverticulitis which can be associated with gastrointestinal perforation.

Hypersensitivity reactions

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

Active hepatic disease and hepatic impairment

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

Hepatotoxicity

Transient or intermittent mild and moderate elevations of hepatic transaminases have been reported commonly with tocilizumab treatment (see section 4.8). An increased frequency of these elevations was observed when potentially hepatotoxic medicines (e.g. MTX) were used in combination with tocilizumab. When clinically indicated, other liver function tests including bilirubin should be considered.

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

Caution should be exercised when considering initiation of tocilizumab treatment in patients with elevated ALT or AST > 1.5 x ULN. In patients with baseline ALT or AST > 5 x ULN, treatment is not recommended.

In RA, GCA, pJIA and sJIA patients, ALT/AST should be monitored every 4 to 8 weeks for the first 6 months of treatment followed by every 12 weeks thereafter. For recommended modifications, including tocilizumab discontinuation, based on transaminases levels see section 4.2. For ALT or AST elevations > 3–5 x ULN, tocilizumab treatment should be interrupted.

Haematological abnormalities

Decreases in neutrophil and platelet counts have occurred following treatment with tocilizumab 8 mg/kg in combination with MTX (see section 4.8). There may be an increased risk of neutropenia in patients who have previously been treated with a TNF antagonist.

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

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

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

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

Lipid parameters

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

In RA and GCA patients, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of tocilizumab therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidaemia.

Neurological disorders

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

Malignancy

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

Vaccinations

Live and live attenuated vaccines should not be given concurrently with tocilizumab as clinical safety has not been established. In a randomized 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 and tetanus toxoid vaccines which was comparable to the response seen in patients on MTX only. It is recommended that all patients particularly elderly patients, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating tocilizumab therapy. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Cardiovascular risk

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

Combination with TNF antagonists

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

GCA

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

sJIA

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

Excipients with known effect

Sodium

This medicinal product contains less than 1 mmol of sodium (23 mg) per 0.9 mL dose, That is to say essentially 'sodium-free'

Polysorbate 80

This medicinal product contains 0.18 mg of polysorbate 80 in each 162 mg/0.9 mL pen which is equivalent to 0.2 mg/mL. Polysorbates may cause allergic reactions. Patients' known allergies shall be taken into consideration.

4.5. Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

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

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 GCA patients, no effect of cumulative corticosteroid dose on tocilizumab exposure was observed.

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

In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. Tocilizumab normalises expression of these enzymes.

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

When starting or stopping therapy with tocilizumab, patients taking medicinal products which are individually adjusted and are metabolised via CYP450 3A4, 1A2 or 2C9 (e.g. methylprednisolone, dexamethasone, (with the possibility for oral glucocorticoid withdrawal syndrome), atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, ciclosporin, or benzodiazepines) should be monitored as doses may need to be increased to maintain therapeutic effect. Given its long elimination half-life (t1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

There are no adequate data from the use of tocilizumab in pregnant women. A study in animals has shown an increased risk of spontaneous abortion/embryo-foetal death at a high dose (see section 5.3). The potential risk for humans is unknown.

Tocilizumab should not be used during pregnancy unless clearly necessary.Breast-feeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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

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

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

Tabulated list of adverse reactions

ADRs from clinical studies and/or post marketing experience with tocilizumab based on spontaneous case reports, literature cases and cases from non-interventional study programs are listed in Table 1 and are presented by MedDRA system organ class. The corresponding frequency category is based on the following convention: very common (? 1/10); common (? 1/100 to < 1/10), uncommon (? 1/1 000 to < 1/100) rare (? 1/10 000 to < 1/1 000) or very rare (< 1/10 000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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

MedDRA

System Organ Class

Frequency categories with preferred terms

Very common

Common

Uncommon

Rare

Infections and infestations

Upper respiratory tract infections

Cellulitis, Pneumonia, Oral herpes simplex, Herpes zoster

Diverticulitis

Blood and lymphatic system disorders

Leukopenia, Neutropenia, Hypofibrinogenaemia

Immune system disorders

Anaphylaxis (fatal)1, 2, 3

Endocrine disorders

Hypothyroidism

Metabolism and nutrition disorders

Hypercholesterolemia *

Hypertriglyceridemia

Nervous system disorders

Headache, Dizziness

Eye disorders

Conjunctivitis

Vascular disorders

Hypertension

Respiratory, thoracic and mediastinal disorders

Cough, Dyspnoea

Gastrointestinal disorders

Abdominal pain, Mouth ulceration, Gastritis

Stomatitis, Gastric ulcer

Hepatobiliary disorders

Treatment-induced liver injury, Hepatitis, Jaundice,

Very rare: Hepatic failure

Skin and subcutaneous tissue disorders

Rash, Pruritus, Urticaria

Stevens-Johnson-Syndrome3

Renal and urinary disorders

Nephrolithiasis

General disorders and administration site conditions

Injection site reaction

Peripheral oedema, Hypersensitivity reactions

Investigations

Hepatic transaminases increased, Weight increased, Total bilirubin increased*

* Includes elevations collected as part of routine laboratory monitoring (see text below)

1 See section 4.3

2 See section 4.4

3 This adverse reaction was identified through post marketing surveillance but not observed in controlled clinical studies. The frequency category was estimated as the upper limit of the 95% confidence interval calculated on the basis of the total number of patients exposed to TCZ in clinical studies.

RA (Subcutaneous use)

The safety of subcutaneous tocilizumab in RA includes a double-blind, controlled, multicenter study, SC-I. SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week versus 8 mg/kg intravenous in 1 262 patients with RA. All patients received background non-biologic DMARD(s). The safety and immunogenicity observed for tocilizumab administered subcutaneous was consistent with the known safety profile of intravenous tocilizumab and no new or unexpected adverse drug reactions were observed (see Table 1). A higher frequency of injection site reactions was observed in the subcutaneous arms compared with placebo subcutaneous injections in the intravenous arms.

Injection site reactions

During the 6-month controlled period, in SC-I, the frequency of injection site reactions was 10.1% (64/631) and 2.4% (15/631) for the subcutaneous tocilizumab and the subcutaneous placebo (intravenous group) weekly injections, respectively. These injection site reactions (including erythema, pruritus, pain and haematoma) were mild to moderate in severity. The majority was resolved without any treatment and none necessitated treatment discontinuation.

Haematological abnormalities

Neutrophils

During routine laboratory monitoring in the tocilizumab 6 month controlled clinical study SC-I, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% of patients on the subcutaneous weekly dose.

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

Platelets

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

Hepatic transaminase elevations

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

Lipid parameters

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

sJIA (Subcutaneous Use)

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

Infections

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

Injection Site Reactions (ISRs)

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

Laboratory Abnormalities

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

Lipid parameters

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

pJIA (Subcutaneous Use)

The safety profile of subcutaneous tocilizumab was also evaluated in 52 paediatric patients with pJIA. The total patient exposure to tocilizumab in the pJIA all exposure population was 184.4 patient years for intravenous and 50.4 patient years for subcutaneous tocilizumab. In general, the safety profile observed in patients with pJIA was consistent with the known safety profile of tocilizumab with the exception of ISRs (see Table 1). A higher frequency of pJIA patients experienced ISRs following subcutaneous tocilizumab injections compared to adult RA.

Infections

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

Injection Site Reactions

A total of 28.8% (15/52) pJIA patients experienced ISRs to tocilizumab subcutaneous. These ISRs occurred in a 44% of patients ? 30 kg compared to 14.8% of patients below 30 kg. The most common ISRs were injection site erythema, swelling, hematoma, pain and pruritis. All ISRs reported were non-serious Grade 1 events, and none of the ISRs required patient withdrawal from treatment or dose interruption.

Laboratory Abnormalities

During routine laboratory monitoring in the tocilizumab all exposure population, a decrease in neutrophil count below 1 × 109/L occurred in 15.4% of patients treated with subcutaneous tocilizumab. An elevation in ALT or AST ? 3 x ULN occurred in 9.6% and 3.8% patients treated with tocilizumab subcutaneous, respectively. No patients treated with subcutaneous tocilizumab experienced a decrease in platelet count to ≤ 50 × 103 / μL.

Lipid parameters

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

GCA (Subcutaneous Use)

The safety of subcutaneous tocilizumab has been studied in one Phase III study (WA28119) with 251 GCA patients. The total patient years duration in the tocilizumab all exposure population was 138.5 patient years during the 12 month double blind, placebo controlled phase of the study. The overall safety profile observed in the tocilizumab treatment groups was consistent with the known safety profile of tocilizumab (see Table 1).

Infections

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

Injection site reactions

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

Haematological abnormalities

Neutrophils

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

Platelets

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

Hepatic transaminase elevations

During routine laboratory monitoring in the tocilizumab 12 month controlled clinical study, elevation in ALT ? 3 x ULN occurred in 3% of patients in the tocilizumab subcutaneous weekly group compared to 2% in the placebo plus 52 week prednisone taper group and none in the placebo plus 26 week prednisone taper group. An elevation in AST > 3 ULN occurred in 1% of patients in the tocilizumab subcutaneous weekly group, compared to no patients in either of the placebo plus prednisone taper groups.

Lipid parameters

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

RA (Intravenous use)

The safety of tocilizumab has been studied in 4 placebo-controlled studies (studies II, III, IV and V), 1 mTX-controlled study (study I) and their extension periods (see section 5.1).

The double-blind controlled period was 6 months in four studies (studies I, III, IV and V) and was up to 2 years in one study (study II). In the double-blind controlled studies, 774 patients received tocilizumab 4 mg/kg in combination with MTX, 1 870 patients received tocilizumab 8 mg/kg in combination with MTX or other DMARDs and 288 patients received tocilizumab 8 mg/kg monotherapy.

The long-term exposure population includes all patients who received at least one dose of tocilizumab either in the double-blind control period or open label extension phase in the studies. Of the 4 009 patients in this population, 3 577 received treatment for at least 6 months, 3 296 for at least one year, 2806 received treatment for at least 2 years and 1 222 for 3 years.

Description of selected adverse reactionsInfections

In the 6-month controlled studies the rate of all infections reported with tocilizumab 8 mg/kg plus DMARD treatment was 127 events per 100 patient years compared to 112 events per 100 patient years in the placebo plus DMARD group. In the long-term exposure population, the overall rate of infections with 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 patient years exposure in the placebo plus DMARD group. In the monotherapy study the rate of serious infections was 3.6 events per 100 patient years of exposure in the tocilizumab group and 1.5 events per 100 patient years of exposure in the MTX group.

In the long-term exposure population, the overall rate of serious infections (bacterial, viral and fungal) was 4.7 events per 100 patient years. Reported serious infections, some with fatal outcome, included active tuberculosis, which may present with intrapulmonary or extrapulmonary disease, invasive pulmonary infections, including candidiasis, aspergillosis, coccidioidomycosis and pneumocystis jirovecii, pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported.

Interstitial lung disease

Impaired lung function may increase the risk for developing infections. There have been post-marketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.

Gastrointestinal perforation

During the 6-month controlled clinical studies, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient years with tocilizumab therapy. In the long-term exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 patient years. Reports of gastrointestinal perforation on tocilizumab were primarily reported as complications of diverticulitis including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess.

Infusion Related reactions

In the 6-month controlled studies adverse events associated with infusion (selected events occurring during or within 24 hours of infusion) were reported by 6.9% of patients in the tocilizumab 8 mg/kg plus DMARD group and 5.1% of patients in the placebo plus DMARD group. Events reported during the infusion were primarily episodes of hypertension; events reported within 24 hours of finishing an infusion were headache and skin reactions (rash, urticaria). These events were not treatment limiting.

The rate of anaphylactic reactions (occurring in a total of 8/4 009 patients, 0.2%) was several fold higher with the 4 mg/kg dose, compared to the 8 mg/kg dose. Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported in a total of 56 out of 4 009 patients (1.4%) treated with tocilizumab during the controlled and open label clinical studies. These reactions were generally observed during the second to fifth infusions of tocilizumab (see section 4.4). Fatal anaphylaxis has been reported after marketing authorisation during treatment with intravenous tocilizumab (see section 4.4).

Haematological abnormalities

Neutrophils

In the 6-month controlled studies decreases in neutrophil counts below 1 x 109/ L occurred in 3.4% of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 0.1% of patients on placebo plus DMARDs. Approximately half of the patients who developed an ANC < 1 x 109/ L did so within 8 weeks after starting therapy. Decreases below 0.5 x 109/ L were reported in 0.3% patients receiving tocilizumab 8 mg/kg plus DMARDs. Infections with neutropenia have been reported.

During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 6-month controlled clinical studies.

Platelets

In the 6-month controlled studies decreases in platelet counts below 100 x 103/μL occurred in 1.7% of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 1% on placebo plus DMARDs. These decreases occurred without associated bleeding events.

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

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

Hepatic transaminase elevations

During the 6-month controlled studies transient elevations in ALT/AST > 3 x ULN were observed in 2.1% of patients on tocilizumab 8 mg/kg compared to 4.9% of patients on MTX and in 6.5% of patients who received 8 mg/kg tocilizumab plus DMARDs compared to 1.5% of patients on placebo plus DMARDs.

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

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

Lipid parameters

During the 6-month controlled studies, increases of lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol have been reported commonly. With routine laboratory monitoring it was seen that approximately 24% of patients receiving tocilizumab in clinical studies experienced sustained elevations in total cholesterol ? 6.2 mmol/ l, with 15% experiencing a sustained increase in LDL to ? 4.1 mmol/ L. Elevations in lipid parameters responded to treatment with lipid-lowering agents.

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

Malignancies

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

Skin Reactions

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

Immunogenicity

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There are limited data available on overdose with tocilizumab. One case of accidental overdose was reported in which a patient with multiple myeloma received a single dose of 40 mg/kg administered intravenously. No adverse reactions were observed.

No serious adverse reactions were observed in healthy volunteers who received a single dose of tocilizumab up to 28 mg/kg, although dose limiting neutropenia was observed.