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.

Cytokine release syndrome (CRS)

CRS, including life-threatening or fatal reactions, may occur in patients receiving TALVEY (see section 4.8). Clinical signs and symptoms of CRS may include but are not limited to pyrexia, hypotension, chills, hypoxia, headache, tachycardia and elevated transaminases. Potentially life-threatening complications of CRS may include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).

TALVEY therapy should be initiated with step-up phase dosing and pre-treatment medicinal products (corticosteroids, antihistamine, and antipyretics) should be administered prior to each dose of TALVEY during the step-up phase to reduce the risk of CRS. Patients should be monitored following administration accordingly. In patients who experience CRS following their previous dose, pre-treatment medicinal products should be administered prior to the next TALVEY dose (see section 4.2).

Subjects who experienced Grade 3 or higher CRS with any previous T cell redirection therapy were excluded from clinical studies. It cannot be excluded that prior severe CRS with chimeric antigen receptor (CAR) T-cell therapy or other T-cell engagers might impact on the safety of TALVEY. The potential benefits of treatment should be carefully weighed against the risk of neurologic events, and heightened caution should be exercised when administering TALVEY to these patients.

Patients should be counselled to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, patients should be immediately evaluated for hospitalisation and treatment with supportive care, tocilizumab and/or corticosteroids, should be instituted based on severity. The use of myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor (GM-CSF), should be avoided during CRS. TALVEY should be withheld until CRS resolves (see section 4.2).

Neurologic toxicity, including ICANS

Serious or life-threatening neurologic toxicities, including ICANS have occurred following treatment with TALVEY (see section 4.8).

ICANS, including fatal reactions, have occurred following treatment with TALVEY. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Clinical signs and symptoms of ICANS may include but are not limited to confusional state, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.

Patients should be monitored for signs and symptoms of neurologic toxicities and treated promptly.
Patients should be counselled to seek medical attention should signs or symptoms of neurologic toxicities including ICANS occur. At the first sign of neurologic toxicities including ICANS, the patient should be immediately evaluated and supportive care should be provided based on severity.
Patients who experience Grade 2 or higher ICANS should be instructed to remain within proximity of a healthcare facility and monitored for signs and symptoms for 48 hours following the next dose of TALVEY.

For ICANS and other neurologic toxicities, TALVEY should be withheld or discontinued based on severity and management recommendations should be followed as indicated in Table 4 (see section 4.2).

There are no data on use of talquetamab in patients with CNS involvement of myeloma or other clinically relevant CNS pathologies as a result of their exclusion from the study due to the potential risk of ICANS.

Due to the potential for ICANS, patients should be instructed to avoid driving or operating machines during the step-up phase and for 48 hours after completion of the step-up phase, and in the event of new onset of any neurological symptoms, until symptoms resolve (see section 4.7).

Management of neurologic toxicities
At the first sign of neurologic toxicity, including ICANS, neurology evaluation should be considered.
Other causes of neurologic symptoms should be ruled out. TALVEY should be withheld until adverse reaction resolves (see Table 4). Intensive care and supportive therapy should be provided for severe or life-threatening neurologic toxicities.


Oral toxicity
Oral toxicities, including dysgeusia, dry mouth, dysphagia, and stomatitis occur very commonly following treatment with TALVEY (see section 4.8).

Patients should be monitored for signs and symptoms of oral toxicity. Patients should be counselled to seek medical attention should signs or symptoms of oral toxicity occur, and supportive care should be provided. Supportive care may include saliva stimulating agents, steroid mouth wash, or consultation with a nutritionist. TALVEY should be interrupted or less frequent dosing should be considered (see section 4.2).

Over time, notable weight loss may occur (see section 4.8). Weight change should be monitored regularly during therapy. Clinically significant weight loss should be further evaluated. TALVEY should be interrupted or less frequent dosing should be considered (see section 4.2).

Serious infections

Serious infections, including life-threatening or fatal infections, have been reported in patients receiving TALVEY (see section 4.8). Patients should be monitored for signs and symptoms of infection prior to and during treatment with TALVEY and treated appropriately. Prophylactic antimicrobials should be administered according to local guidelines. TALVEY should not be administered in patients with active serious infection. TALVEY should be withheld as indicated (see section 4.2). Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur.

Hypogammaglobulinaemia

Hypogammaglobulinaemia has been reported in patients receiving TALVEY (see section 4.8).
Immunoglobulin levels should be monitored during treatment with TALVEY. Intravenous or subcutaneous immunoglobulin therapy was used to treat hypogammaglobulinaemia patients. Patients should be treated according to local institutional guidelines, including infection precautions, antibiotic or antiviral prophylaxis, and administration of immunoglobulin replacement.

Cytopenias

Treatment-emergent Grade 3 or 4 neutropenia, febrile neutropenia and thrombocytopenia have been observed in patients who received TALVEY. A majority of cytopenias occurred during the first 8 to 10 weeks. Complete blood counts should be monitored at baseline and periodically during treatment.
Supportive care should be provided per local institutional guidelines.
Patients with neutropenia should be monitored for signs of infection. TALVEY should be withheld as warranted (see section 4.2).

Skin reactions

TALVEY can cause skin reactions including rash, maculo-papular rash, erythema, erythematous rash, as well as nail disorders (see section 4.8). Skin reactions including rash progression should be monitored for early intervention and treatment with corticosteroids. For Grade 3 or higher, or worsening Grade 1 or 2 rashes, oral steroids should also be administered. For non-rash skin reactions dose modification may be considered (see Table 6).
For skin reactions and nail disorders, TALVEY should be withheld based on severity and institutional guidelines should be followed (see section 4.2).

Vaccines

Immune response to vaccines may be reduced when taking TALVEY. The safety of immunisation with live viral vaccines during or following TALVEY treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 4 weeks prior to the start of treatment, during treatment, and at least 4 weeks after treatment.
For unexpected exposure during pregnancy, see section 4.6.

Women of child-bearing potential/contraception

Pregnancy status of females of child-bearing potential should be verified prior to initiating treatment with TALVEY. Females of reproductive potential should use effective contraception during treatment and for 3 months after the last dose of TALVEY (see section 4.6).

Excipients

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

Effects on Driving

4.7    Effects on ability to drive and use machines

TALVEY has major influence on the ability to drive and use machines.
Due to the potential for ICANS, patients receiving TALVEY are at risk of depressed level of consciousness (see section 4.4). Patients should be instructed to avoid driving or operating machines during the step-up phase and for 48 hours after completion of the step-up phase (see section 4.2), and in the event of new onset of any neurological symptoms, until symptoms resolve.