Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

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

RA, pJIA and sJIA Patients

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 biological treatments 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 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, RA, sJIA and pJIA 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 should be instructed 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 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 Actemra in RA patients (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 have been reported in association with infusion of Actemra (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 Actemra. If an anaphylactic reaction or other serious hypersensitivity / serious infusion related reaction occurs, administration of Actemra should be stopped immediately and Actemra 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 RA, pJIA and sJIA patients with baseline ALT or AST > 5 x ULN, treatment is not recommended.
In RA, 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, confirmed by repeat testing, 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 absolute neutrophil count (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 RA, sJIA and pJIA 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 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 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, pJIA and RA 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 sJIA and pJIA 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, sJIA or pJIA patients. Actemra 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’.

COVID-19 Patients

•     The efficacy of Actemra has not been established in the treatment of COVID-19 patients who do not have elevated CRP levels, see section 5.1
•     Actemra should not be administered to COVID-19 patients who are not receiving systemic corticosteroids as an increase in mortality cannot be excluded in this subgroup, see section 5.1.

Infections
In COVID-19 patients, Actemra should not be administered if they have any other concurrent severe active infection. 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.

Hepatotoxicity
Patients hospitalized with COVID-19 may have elevated ALT or AST levels. Multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19. The decision to administer tocilizumab should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with tocilizumab. In COVID-19 patients with elevated ALT or AST above 10 x ULN, administration of Actemra treatment is not recommended. In COVID-19 patients, ALT /AST should be monitored according to current standard clinical practices.

Haematological abnormalities
In COVID-19 patients who develop an ANC < 1 x 109 /L or a platelet count < 50 x 103 /μL, administration of treatment is not recommended. Neutrophil and platelet counts should be monitored according to current standard clinical practices, see section 4.2.

Paediatric population
 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.

Effects on Driving

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