RoActemra 162 mg solution for injection in pre-filled syringe.

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

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

For the full list of excipients, see section 6.1.

Solution for injection (injection).

A colourless to slightly yellowish 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.

Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of RA. All patients treated with RoActemra should be given the Patient Alert Card. Suitability of the patient for subcutaneous home use should be assessed and instruct patients to inform a healthcare professional if they experience symptoms of an allergic reaction before administering the next dose. Patients should seek immediate medical attention if developing symptoms of serious allergic reactions (see section 4.4).

Posology

The recommended posology is subcutaneous 162mg once every week.

Limited information is available regarding switching patients from RoActemra intravenous formulation to RoActemra 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.

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

Missed dose

If a patient misses a subcutaneous weekly injection of RoActemra 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 RoActemra 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 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 moderat 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.

Paediatric patients

The safety and efficacy of RoActemra subcutaneous formulation in children from birth to less than 18 years have not been established. No data are available.

Method of administration

RoActemra is for subcutaneous use.

After proper training in injection technique, patients may self-inject with RoActemra if their physician determines that it is appropriate. The total content (0.9 ml) of the pre-filled syringe should be administered as a subcutaneous injection. The recommended injection sites (abdomen, 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 syringe should not be shaken.

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

Infections

Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including RoActemra (see section 4.8, Undesirable effects). RoActemra treatment must 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 and interstitial lung disease 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 as signs and symptoms of acute inflammation may be lessened, associated with 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 eva luating a patient for a potential infection. 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, 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. 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 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 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, including anaphylaxis have been reported in association with RoActemra (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 premedication with steroids and antihistamines. If an anaphylactic reaction or other serious hypersensitivity reaction occurs, administration of RoActemra should be stopped immediately, appropriate therapy initiated and tocilizumab 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, RoActemra 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 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.

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 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. In a randomized open-label study, adult RA patients treated with RoActemra 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, 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 patients. RoActemra is not recommended for use with other biological agents.

Traceability

In order to improve the traceability of biological medicinal products, the tradename of the administered product should be clearly recorded (or stated) in the patient file.

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.

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, 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 (t_1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.