RoActemra 20 mg/ml concentrate for solution for infusion.

Each ml concentrate contains 20 mg tocilizumab*.

Each vial contains 80 mg of tocilizumab* in 4 ml (20 mg/ml).

Each vial contains 200 mg of tocilizumab* in 10 ml (20 mg/ml).

Each vial contains 400 mg of tocilizumab* in 20 ml (20 mg/ml).

*humanised IgG1 monoclonal antibody against the human interleukin-6 (IL-6) receptor produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.

Excipients:

Each 80 mg vial contains 0.10 mmol (2.21 mg) sodium.

Each 200 mg vial contains 0.20 mmol (4.43 mg) sodium.

Each 400 mg vial contains 0.39 mmol (8.85 mg) sodium.

For a full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear to opalescent, colourless to pale yellow solution.

RoActemra, in combination with methotrexate (MTX), is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists. In these patients, RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.

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

RoActemra is indicated for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in patients 2 years of age and older, who have responded inadequately to previous therapy with NSAIDs and systemic corticosteroids. RoActemra can be given as monotherapy (in case of intolerance to MTX or where treatment with MTX is inappropriate) or in combination with MTX.

Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of RA or sJIA. All patients treated with RoActemra should be given the Patient Alert Card.

RA Patients

Posology

The recommended posology is 8 mg/kg body weight, given once every four weeks.

For individuals whose body weight is more than 100 kg, doses exceeding 800 mg per infusion are not recommended (see Section 5.2).

Doses above 1.2 g have not been eva luated in clinical studies (see section 5.1).

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

• Liver enzyme abnormalities

• Low absolute neutrophil count (ANC)

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

• Low platelet count

Special populations

Paediatric patients:

sJIA patients:

The safety and efficacy of RoActemra in patients below 2 years of age has not been established.

No data are available.

The recommended posology is 8 mg/kg once every 2 weeks in patients weighing greater than or equal to 30 kg or 12 mg/kg once every 2 weeks in patients weighing less than 30 kg. The dose should be calculated based on the patient's body weight at each administration. A change in dose should only be based on a consistent change in the patient's body weight over time.

Dose interruptions of tocilizumab for the following laboratory abnormalities are recommended in sJIA patients in the tables below. If appropriate, the dose of concomitant MTX and/or other medications should be modified or dosing stopped and tocilizumab dosing interrupted until the clinical situation has been eva luated. As there are many co-morbid conditions that may effect laboratory values in sJIA, the decision to discontinue tocilizumab for a laboratory abnormality should be based upon the medical assessment of the individual patient.

• Liver enzyme abnormalities

• Low absolute neutrophil count (ANC)

• Low platelet count

Reduction of tocilizumab dose due to laboratory abnormalities has not been studied in sJIA patients.

Available data suggest that clinical improvement is observed within 6 weeks of initiation of treatment with RoActemra. Continued therapy should be carefully reconsidered in a patient exhibiting no improvement within this timeframe.

Elderly patients: No dose adjustment is required in patients aged 65 years and older.

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

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

Method of administration

After dilution, RoActemra for RA and sJIA patients should be administered as an intravenous infusion over 1 hour.

RA Patients, and SJIA Patients 30 kg

RoActemra should be diluted to a final volume of 100 ml with sterile, non-pyrogenic sodium chloride 9 mg/ml (0.9%) solution for injection using aseptic technique.

For further information on dilution prior to administration, see section 6.6.

SJIA Patients < 30 kg

RoActemra should be diluted to a final volume of 50 ml with sterile, non-pyrogenic sodium chloride 9 mg/ml (0.9%) solution for injection using aseptic technique.

For further information on dilution prior to administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients.

Active, severe infections (see section 4.4).

Infections

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

Vigilance for the timely detection of serious infection is recommended for patients receiving biological treatments for moderate to severe RA or sJIA as signs and symptoms of acute inflammation may be lessened, associated with suppression of the acute phase reaction. The effects of tocilizumab on C-reactive protein (CRP), neutrophils and signs and symptoms of infection should be considered when eva luating a patient for a potential infection. Patients (which includes younger children with sJIA who may be less able to communicate their symptoms) and parents/guardians of sJIA patients, should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid eva luation and appropriate treatment.

Tuberculosis

As recommended for other biological treatments, RA and sJIA patients should be screened for latent tuberculosis (TB) infection prior to starting RoActemra therapy. Patients with latent TB should be treated with standard anti-mycobacterial therapy before initiating RoActemra.

Viral reactivation

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

Complications of diverticulitis

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

Hypersensitivity reactions

Serious hypersensitivity reactions have been reported in association with infusion of RoActemra (see section 4.8). Such reactions may be more severe, and potentially fatal in patients who have experienced hypersensitivity reactions during previous infusions even if they have received premedication with steroids and antihistamines. Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during treatment with RoActemra. If an anaphylactic reaction or other serious hypersensitivity / serious infusion related reaction occurs, administration of RoActemra should be stopped immediately and RoActemra should be permanently discontinued.

Active hepatic disease and hepatic impairment

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

Hepatic transaminase elevations

In clinical trials, transient or intermittent mild and moderate elevations of hepatic transaminases have been reported commonly with RoActemra treatment, without progression to hepatic injury (see section 4.8). An increased frequency of these elevations was observed when potentially hepatotoxic drugs (e.g. MTX) were used in combination with RoActemra. When clinically indicated, other liver function tests including bilirubin should be considered.

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

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

In sJIA patients, ALT and AST levels should be monitored at the time of the second infusion and thereafter according to good clinical practice, see section 4.2.

Haematological abnormalities

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

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

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

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

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

Lipid parameters

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

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

Neurological disorders

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

Malignancy

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

Vaccinations

Live and live attenuated vaccines should not be given concurrently with RoActemra as clinical safety has not been established. It is recommended that all patients, particularly sJIA patients, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating RoActemra therapy. The interval between live vaccinations and initiation of RoActemra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Cardiovascular risk

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

Combination with TNF antagonists

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

Sodium

This medicinal product contains 1.17 mmol (or 26.55 mg) sodium per maximum dose of 1200 mg. To be taken into consideration by patients on a controlled sodium diet. Doses below 1025 mg of this medicinal product contain less than 1 mmol sodium (23 mg), i.e. essentially 'sodium free'.

SJIA Patients

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

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.

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. atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, ciclosporin, or benzodiazepines) should be monitored as doses may need to be increased to maintain therapeutic effect. Given its long elimination half-life (t_1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.

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

RoActemra should not be used during pregnancy unless clearly necessary.

Lactation

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

No studies on the effects on the ability to drive and use machines have been performed. However, given that dizziness has been commonly reported, patients who experience this adverse reaction should be advised not to drive or use machines until it has resolved.

RA Patients

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, 1870 patients received tocilizumab 8 mg/kg in combination with MTX or other DMARDs and 288 patients received tocilizumab 8 mg/kg monotherapy.

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

The most commonly reported ADRs (occurring in 5% of patients treated with tocilizumab monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.

The ADRs listed in Table 1 are presented by system organ class and frequency categories, defined using the following convention: very common ( 1/10); common ( 1/100 to < 1/10) or uncommon ( 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. Summary of ADRs occurring in patients with RA receiving tocilizumab as monotherapy or in combination with MTX or other DMARDs in the double-blind controlled period