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 and the batch number of the administered product should be clearly recorded.

BESPONSA is a cytotoxic drug. Follow applicable special handling and disposal procedures.

Hepatotoxicity, including VOD/SOS
Hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD/SOS, was reported in patients with relapsed or refractory ALL receiving BESPONSA (see section 4.8).
BESPONSA significantly increased the risk of VOD/SOS above that of standard chemotherapy regimens in this patient population. This risk was most marked in patients who underwent subsequent HSCT.


In the following subgroups, the reported frequency of VOD/SOS post-HSCT was ≥ 50%: - Patients who received an HSCT conditioning regimen containing 2 alkylating agents; - Patients aged ≥ 65 years; and
- Patients with a serum bilirubin ≥ ULN prior to HSCT.

The use of HSCT conditioning regimens containing 2 alkylating agents should be avoided. The benefit/risk should be carefully considered before administering BESPONSA to patients in whom the future use of HSCT conditioning regimens containing 2 alkylating agents is likely unavoidable.

In patients in whom the serum bilirubin is ≥ ULN prior to HSCT, HSCT post BESPONSA treatment should only be undertaken after careful consideration of the benefit/risk. If these patients do proceed to HSCT, signs and symptoms of VOD/SOS should be monitored closely (see section 4.2).

Other patient factors that appear to be associated with an increased risk of VOD/SOS after HSCT include a prior HSCT, age ≥ 55 years, a history of liver disease and/or hepatitis before treatment, later salvage lines, and a greater number of treatment cycles.

Careful consideration is required before administering BESPONSA to patients who have had a prior HSCT. No patients with relapsed or refractory ALL who were treated with BESPONSA in clinical studies had undergone HSCT within the previous 4 months.

Patients with a history of liver disease should be carefully evaluated (e.g., ultrasound scan, viral hepatitis testing) prior to treatment with BESPONSA to exclude serious ongoing hepatic disease (see section 4.3).
Due to the risk of VOD/SOS, for patients proceeding to HSCT, the recommended duration of treatment with inotuzumab ozogamicin is 2 cycles; a third cycle may be considered for those patients who do not achieve a CR or CRi and MRD negativity after 2 cycles (see section 4.2).

Signs and symptoms of VOD/SOS should be monitored closely in all patients, especially post HSCT.
Signs may include elevations in total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Monitoring only total bilirubin may not identify all patients at risk of VOD/SOS. In all patients, liver tests should be monitored, including, ALT, AST, total bilirubin, and alkaline phosphatase, prior to and following each dose of BESPONSA. For patients who develop abnormal liver tests, liver tests and clinical signs and symptoms of hepatotoxicity should be monitored more frequently. For patients who proceed to HSCT, liver tests should be monitored closely during the first month post-HSCT, then less frequently thereafter, according to standard medical practice. Elevation of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of BESPONSA (see section 4.2).

Treatment should be permanently discontinued if VOD/SOS occurs (see section 4.2). If severe VOD/SOS occurs, the patient should be treated according to standard medical practice.

Myelosuppression/cytopenias

In patients receiving inotuzumab ozogamicin, neutropenia, thrombocytopenia, anaemia, leukopenia, febrile neutropenia, lymphopenia, and pancytopenia, some of which were life-threatening, have been reported (see section 4.8).

In patients receiving inotuzumab ozogamicin, complications associated with neutropenia and thrombocytopenia (including infections and bleeding/haemorrhagic events, respectively) were reported in some patients (see section 4.8).

Complete blood counts should be monitored prior to each dose of BESPONSA and signs and symptoms of infection during treatment and after HSCT (see section 5.1), bleeding/haemorrhage, and 
other effects of myelosuppression should be monitored during treatment. As appropriate, prophylactic anti-infectives should be administered and surveillance testing should be employed during and after treatment.

Management of severe infection, bleeding/haemorrhage and other effects of myelosuppression, including severe neutropenia or thrombocytopenia, may require a dosing interruption, dose reduction, or discontinuation of treatment (see section 4.2).

Infusion- related reactions

In patients receiving inotuzumab ozogamicin, infusion- related reactions were reported (see section 4.8).

Pre-medication with a corticosteroid, antipyretic, and antihistamine is recommended prior to dosing (see section 4.2).

Patients should be monitored closely during and for at least 1 hour after the end of infusion for the potential onset of infusion- related reactions, including symptoms such as hypotension, hot flush, or breathing problems. If an infusion- related reaction occurs, the infusion should be interrupted and appropriate medical management should be instituted. Depending on the severity of the infusion - related reaction, discontinuation of the infusion or administration of steroids and antihistamines should be considered (see section 4.2). For severe or life-threatening infusion reactions, treatment should be permanently discontinued (see section 4.2).

Tumour lysis syndrome (TLS)

In patients receiving inotuzumab ozogamicin, TLS, which may be life-threatening or fatal, was reported (see section 4.8).

Pre-medication to reduce uric acid levels and hydration is recommended prior to dosing for patients with a high tumour burden (see section 4.2).

Patients should be monitored for signs and symptoms of TLS and treated according to standard medical practice.

QT interval prolongation

In patients receiving inotuzumab ozogamicin, QT interval prolongation was observed (see sections 4.8 and 5.2).

BESPONSA should be administered with caution in patients who have a history of, or predisposition to QT interval prolongation, who are taking medicinal products that are known to prolong QT interval (see section 4.5) and in patients with electrolyte disturbances. ECG and electrolytes should be obtained prior to the start of treatment and periodically monitored during treatment (see sections 4.8 and 5.2).

Increased amylase and lipase

In patients receiving inotuzumab ozogamicin, increases in amylase and lipase have been reported (see section 4.8).

Patients should be monitored for increases in amylase and lipase. Potential hepatobiliary disease should be evaluated and treated according to standard medical practice.


Immunisations
The safety of immunisation with live viral vaccines during or following BESPONSA therapy has not been studied. Vaccination with live viral vaccines is not recommended for at least 2 weeks prior to the start of BESPONSA treatment, during treatment, and until recovery of B lymphocytes following the last treatment cycle.

Excipients

Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per 1 mg inotuzumab ozogamicin.
that is to say essentially ‘sodium-free’.

This medicinal product may be further prepared for administration with sodium-containing solutions (see sections 4.2 and 6.6) and this should be considered in relation to the total sodium from all sources that will be administered to the patient.

Effects on Driving

4.7    Effects on ability to drive and use machines

BESPONSA has moderate influence on the ability to drive and use machines. Patients may experience fatigue during treatment with BESPONSA (see section 4.8). Therefore, caution is recommended when driving or operating machines.