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. It is recommended to record the batch number as well.


Benlysta has not been studied in the following adult and paediatric patient groups, and is not recommended in:
•     severe active central nervous system lupus (see section 5.1)
•     HIV
•     a history of, or current, hepatitis B or C
•     hypogammaglobulinaemia (IgG <400 mg/dL) or IgA deficiency (IgA <10 mg/dL)
•     a history of major organ transplant or hematopoietic stem cell /marrow transplant or renal transplant.


Concomitant use with B cell targeted therapy

Available data do not support the co-administration of rituximab with Benlysta in patients with SLE (see section 5.1).Caution should be exercised if Benlysta is co-administered with other B cell targeted therapy.

Infusion reactions and hypersensitivity

Administration of Benlysta may result in hypersensitivity reactions and infusion reactions which can be severe, and fatal. In the event of a severe reaction, Benlysta administration must be interrupted and appropriate medical therapy administered (see section 4.2). The risk of hypersensitivity reactions is greatest with the first two infusions; however the risk should be considered for every infusion administered. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk.

Premedication including an antihistamine, with or without an antipyretic, may be administered before the infusion of Benlysta. There is insufficient knowledge to determine whether premedication could diminish the frequency or severity of infusion reactions.

In clinical studies, serious infusion and hypersensitivity reactions affected approximately 0.9 % of adult patients, and included anaphylactic reaction, bradycardia, hypotension, angioedema, and dyspnoea. Infusion reactions occurred more frequently during the first two infusions and tended to decrease with subsequent infusions (see section 4.8). Patients have been reported to develop symptoms of acute hypersensitivity several hours after the infusion has been administered. Recurrence of clinically significant reactions after initial appropriate treatment of symptoms has also been observed (see sections 4.2 and 4.8). Therefore, Benlysta should be administered in an environment where resources for managing such reactions are immediately available. Patients should remain under clinical supervision for a prolonged period of time (for several hours), following at least the first 2 infusions, taking into account the possibility of a late onset reaction. Patients should be advised that hypersensitivity reactions are possible, on the day of, or several days after infusion, and be informed of potential signs and symptoms and the possibility of recurrence. Patients should be instructed to seek immediate medical attention if they experience any of these symptoms. The package leaflet should be provided to the patient each time Benlysta is administered (see section 4.2).

Delayed-type, non-acute hypersensitivity reactions have also been observed and included symptoms such as rash, nausea, fatigue, myalgia, headache, and facial oedema.

Infections

The mechanism of action of belimumab could increase the risk for the development of infections in adults and children with lupus, including opportunistic infections, and younger children may be at increased risk.
In controlled clinical studies, the incidence of serious infections was similar across the Benlysta and placebo groups; however, fatal infections (e.g. pneumonia and sepsis) occurred more frequently in patients receiving Benlysta compared with placebo (see section 4.8). Pneumococcal vaccination should be considered before initiating Benlysta treatment. Benlysta should not be initiated in patients with active serious infections (including serious chronic infections). Physicians should exercise caution and carefully assess if the benefits are expected to outweigh the risks when considering the use of Benlysta in patients with a history of recurrent infection. Physicians should advise patients to contact their health care provider if they develop symptoms of an infection. Patients who develop an infection while undergoing treatment with Benlysta should be monitored closely and careful consideration given to interrupting immunosuppressant therapy including Benlysta until the infection is resolved. The risk of using Benlysta in patients with active or latent tuberculosis is unknown.

Depression and suicidality

In controlled clinical intravenous and subcutaneous studies, psychiatric disorders (depression, suicidal ideation and behaviour including suicides) have been reported more frequently in patients receiving Benlysta (see section 4.8). Physicians should assess the risk of depression and suicide considering the patient’s medical history and current psychiatric status before treatment with Benlysta and continue to monitor patients during 
treatment. Physicians should advise patients (and caregivers where appropriate) to contact their health care provider about new or worsening psychiatric symptoms. In patients who experience such symptoms, treatment discontinuation should be considered.

Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) has been reported with Benlysta treatment for SLE.
Physicians should be particularly alert to symptoms suggestive of PML that patients may not notice (e.g., cognitive, neurological or psychiatric symptoms or signs). Patients should be monitored for any of these new or worsening symptoms or signs, and if such symptoms/signs occur, referral to a neurologist and appropriate diagnostic measures for PML should be considered as clinically indicated. If PML is suspected, immunosuppressant therapy, including Benlysta, must be suspended until PML has been excluded. If PML is confirmed, immunosuppressant therapy, including Benlysta, must be discontinued.


Immunisation
Live vaccines should not be given for 30 days before, or concurrently with Benlysta, as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving Benlysta.

Because of its mechanism of action, belimumab may interfere with the response to immunisations. However, in a small study evaluating the response to a 23-valent pneumococcal vaccine, overall immune responses to the different serotypes were similar in SLE patients receiving Benlysta compared with those receiving standard immunosuppressive treatment at the time of vaccination. There are insufficient data to draw conclusions regarding response to other vaccines.

Limited data suggest that Benlysta does not significantly affect the ability to maintain a protective immune response to immunisations received prior to administration of Benlysta. In a substudy, a small group of patients who had previously received either tetanus, pneumococcal or influenza vaccinations were found to maintain protective titres after treatment with Benlysta.

Malignancies and lymphoproliferative disorders

Immunomodulatory medicinal products, including Benlysta, may increase the risk of malignancy. Caution should be exercised when considering Benlysta therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop malignancy. Patients with malignant neoplasm within the last 5 years have not been studied, with the exception of those with basal or squamous cell cancers of the skin, or cancer of the uterine cervix, that has been fully excised or adequately treated.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium- free’.

Effects on Driving

4.7    Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. No detrimental effects on such activities are predicted from the pharmacology of belimumab. The clinical status of the subject and the adverse reaction profile of Benlysta should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills.