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.

Infusion reactions
Infusion reactions, mostly mild or moderate, have been observed in 38.2% of patients treated with SARCLISA in ICARIA-MM, and in 45.8% of patients treated with Isa-Kd in IKEMA (see section 4.8). In ICARIA-MM, all infusion reactions started during the first SARCLISA infusion and resolved on the same day in 98% of the infusions. The most common symptoms of an infusion reaction included dyspnoea, cough, chills and nausea. The most common severe signs and symptoms included hypertension, dyspnoea, and bronchospasm. In IKEMA, the infusion reactions occurred on the infusion day in 99.2% of episodes. In patients treated with Isa-Kd, 94.4% of those experiencing an IR experienced it during the first cycle of treatment . All infusion reactions resolved . The most common symptoms of an infusion reaction included cough, dyspnoea, nasal congestion, vomiting and nausea. , The most common severe signs and symptomsincluded hypertension and dyspnoea (see section 4.8). However, serious infusion reactions including severe anaphylactic reactions have also been observed after SARCLISA administration.

To decrease the risk and severity of infusion reactions, patients should be pre-medicated prior to SARCLISA infusion with acetaminophen, diphenhydramine or equivalent; dexamethasone is to be used as both premedication and anti-myeloma treatment (see section 4.2). Vital signs should be frequently monitored during the entire SARCLISA infusion. When required, interrupt SARCLISA infusion and provide appropriate medical and supportive measures (seesection 4.2). In case symptoms do not improve to grade ≤1 after interruption of SARCLISA infusion, persist or worsen despite appropriate medicinal products, require hospitalization or are life- threatening, permanently discontinue SARCLISA and institute appropriate management.

Neutropenia
In patients treated with Isa-Pd, neutropenia occurred as a laboratory abnormality in 96.1% of patients and as an adverse reaction (1) in 46.7% of patients, with Grade 3-4 neutropenia reported as a laboratory abnormality in 84.9% of patients and as an adverse reaction in 45.4% of patients. Neutropenic complications have been observed in 30.3% of patients, including 11.8% of febrile neutropenia and 25.0% of neutropenic infections. In patients treated with Isa-Kd, neutropenia occurred as a laboratory abnormality in 54.8% of patients and as an adverse reaction (1) in 4.5% of patients, with Grade 3-4 neutropenia reported as a laboratory abnormality in 19.2% of patients (with 17.5% Grade 3 and 1.7% Grade 4) and as an adverse reaction in 4.0% of patients. Neutropenic complications have been observed in 2.8% of patients, including 1.1% of febrile neutropenia and 1.7% of neutropenic infections (see section 4.8). Complete blood cell counts should be monitored periodically during treatment. Patients with neutropenia should be monitored for signs of infection. No dose reductions of SARCLISA are recommended. SARCLISA dose delays and the use of colony-stimulating factors (e.g. G-CSF) should be considered to mitigate the risk of neutropenia (see section 4.2).

(1)Haematology laboratory values were recorded as adverse reactions only if they led to treatment discontinuation and/or dose modification and/or fulfilled a serious criterion.

Infection
A higher incidence of infections including grade ≥ 3 infections, mainly pneumonia, upper respiratory tract infection and bronchitis, occurred with SARCLISA (see section 4.8). Patients receiving SARCLISA should be closely monitored for signs of infection and appropriate standard therapy instituted.
Antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) can be considered during treatment (see sections 4.2 and 4.8).

Second primary malignancies
In ICARIA-MM, second primary malignancies (SPMs) were reported at a median follow-up time of 52.44 months in 10 patients (6.6%) treated with Isa-Pd and in 3 patients (2%) treated with Pd. SPM  were skin cancer in 6 patients treated with Isa-Pd and in 3 patients treated with Pd, solid tumours other than skin cancer in 3 patients treated with Isa-Pd (one patient also had a skin cancer), and haematological malignancy (myelodysplastic syndrome) in 1 patient treated with Isa-Pd (see section 4.8). Patients continued treatment after resection of the new malignancy, except two patients treated with Isa-Pd. One patient developed metastatic melanoma and the other developed myelodysplastic syndrome. The overall benefit of Isa-Pd remains favourable (see section 5.1). In ongoing IKEMA study, at a median follow-up time of 20.73 months, SPMs were reported in 13 patients (7.3%) treated with Isa-Kd and in 6 patients (4.9%) treated with Kd. SPMs were skin cancers in 9 patients (5.1%) treated with Isa-Kd and in 3 patients (2.5%) treated with Kd, and were solid tumours other than skin cancer in 5 patients (2.8%) treated with Isa-Kd and in 4 patients (3.3%) treated with Kd. One patient (0.6%) in the Isa-Kd group and one patient (0.8%) in the Kd group had both skin cancer and solid tumours other than skin cancer (see section 4.8). Patients with skin cancer continued treatment after resection of the skin cancer. Solid tumours other than skin cancer were diagnosed within 3 months after treatment initiation in 3 patients (1.7%) treated with Isa-Kd and in 2 patients (1.6%) treated with Kd. The overall incidence of SPMs in all the SARCLISA-exposed patients is 4.1%. Physicians should carefully evaluate patients before and during treatment as per IMWG guidelines for occurrence of SPM and initiate treatment as indicated.

Tumour lysis syndrome
Cases of tumour lysis syndrome (TLS) have been reported in patients who received isatuximab. Patients should be monitored closely and appropriate precautions taken.

Interference with serological testing (indirect antiglobulin test)
Isatuximab binds to CD38 on red blood cells (RBCs) and may result in a false positive indirect antiglobulin test (indirect Coombs test). To avoid potential problems with RBC transfusion, patients being treated with SARCLISA should have blood type and screen tests performed prior to the first infusion. Phenotyping may be considered prior to starting SARCLISA treatment as per local practice.
If treatment with SARCLISA has already started, the blood bank should be informed. Patients should be monitored for theoretical risk of haemolysis. If an emergency transfusion is required, non- cross- matched ABO/Rh-compatible RBCs can be given as per local blood bank practices (see section 4.5). There is currently no available information with regards to how long the interference with the indirect Coombs test may persist after the last infusion of SARCLISA. Based on the half-life of isatuximab, it is anticipated that isatuximab mediated positive indirect Coombs test may persist for approximately 6 months after the last infusion.

Interference with determination of complete response
Isatuximab is an IgG kappa monoclonal antibody that could be detected on both serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein (see section 4.5). This interference can impact the accuracy of the determination of complete response in some patients with IgG kappa myeloma protein. Twenty-two patients in the Isa-Pd arm who met Very Good Partial Response (VGPR) criteria with only residual immunofixation-positivity were tested for interference. Serum samples from these patients were tested by mass spectrometry to separate isatuximab signal from the myeloma M-proteinsignal. In the Isa-Kd arm, out of the 27 patients identified with potential interference and tested by mass spectrometry at the sensitivity level of the immunofixation test (25 mg/dL), 15 non-Complete Response (non-CR) patients as per Independent Response Committee (IRC) showed no detectable residual myeloma M-protein. Among these 15 patients, 11 patients had plasma cell <5% in bone marrow. This indicates that 11 additional patients out of the 179 Isa-Kd patients (6.1%) could have CR as best response leading to a potential CR rate of 45.8% (see section 4.5).

Elderly
Data are limited in the elderly population ≥ 85 years old (see section 4.2).





Effects on Driving

4.7      Effects on ability to drive and use machines

SARCLISA has no or negligible influence on the ability to drive and use machines.