Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Actemra subcutaneous formulation is not intended for intravenous administration.
Actemra subcutaneous formulation is not intended to be given to children with sJIA weighing less than 10 kg.

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

Infections
Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including Actemra (see section 4.8, Undesirable effects). Actemra treatment must not be initiated in patients with active infections (see section 4.3). Administration of Actemra 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 Actemra 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 Actemra 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 (which includes younger children with sJIA or pJIA who may 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 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 Actemra therapy. Patients with latent TB should be treated with standard anti-mycobacterial therapy before initiating Actemra. 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 Actemra.


Viral reactivation
Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinical studies with Actemra, 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 Actemra (see section 4.8). Actemra 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 Actemra (see section 4.8). Such reactions may be more severe, and potentially fatal in patients who have experienced hypersensitivity reactions during previous treatment with Actemra even if they have received premedication with steroids and antihistamines. If an anaphylactic reaction or other serious hypersensitivity reaction occurs, administration of Actemra should be stopped immediately, appropriate therapy initiated and tocilizumab should be permanently discontinued.

Active hepatic disease and hepatic impairment
Treatment with Actemra, 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 Actemra treatment (see section 4.8). An increased frequency of these elevations was observed when potentially hepatotoxic drugs (e.g. MTX) were used in combination with Actemra.
When clinically indicated, other liver function tests including bilirubin should be considered.

Serious drug-induced liver injury, including acute liver failure, hepatitis and jaundice, have been observed with Actemra (see section 4.8). Serious hepatic injury occurred between 2 weeks to more than 5 years after initiation of Actemra. 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 Actemra 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 Actemra discontinuation, based on transaminases levels see section 4.2. For ALT or AST elevations > 3–5 x ULN, Actemra 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 Actemra, initiation is not recommended in patients with an ANC below 2 x 109/L. Caution should be exercised when considering initiation of Actemra 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 Actemra 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 Actemra (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 all patients, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of Actemra 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 Actemra 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 Actemra as clinical safety has not been established. In a randomized open-label study, adult RA patients treated with Actemra 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 paediatric or elderly patients, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating Actemra therapy.
The interval between live vaccinations and initiation of Actemra 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 Actemra with TNF antagonists or other biological treatments for RA patients. Actemra is not recommended for use with other biological agents.

GCA
Actemra 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 trials, Actemra has not been studied in patients during an episode of active MAS.

Effects on Driving

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