SARCLISA Concentrate for solution for infusion Ref.[50841] Active ingredients: Isatuximab

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.

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 symptoms included 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 (see section 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 reaction¹ 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 reaction¹ 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 in 6 patients (3.9%) treated with Isa-Pd and in 1 patient (0.7%) treated with Pd, and included skin cancer in 4 patients treated with IsaPd and in 1 patient treated with Pd (see section 4.8). Patients continued treatment after resection of the skin cancer. In IKEMA, 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 3.6%. 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-protein signal. 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).

Isatuximab has no impact on the pharmacokinetics of pomalidomide or carfilzomib, or vice versa.

Interference with serological testing

Because CD38 protein is expressed on the surface of red blood cells, isatuximab, an anti-CD38 antibody, may interfere with blood bank serologic tests with potential false positive reactions in indirect antiglobulin tests (indirect Coombs tests), antibody detection (screening) tests, antibody identification panels, and antihuman globulin (AHG) crossmatches in patients treated with isatuximab (see section 4.4). The interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt isatuximab binding or other locally validated methods. Since the Kell Blood group system is also sensitive to DTT treatment, Kell-negative units should be supplied after ruling out or identifying alloantibodies using DTT-treated RBCs.

Interference with Serum Protein Electrophoresis and Immunofixation Tests

Isatuximab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M-protein), and could interfere with accurate response classification based on International Myeloma Working Group (IMWG) criteria (see section 4.4). In patients with persistent very good partial response, where isatuximab interference is suspected, consider using a validated isatuximab-specific IFE assay to distinguish isatuximab from any remaining endogenous M protein in the patient’s serum, to facilitate determination of a complete response.

Women of childbearing potential/Contraception

Women of childbearing potential treated with isatuximab should use effective contraception during treatment and for 5 months after cessation of treatment.

Pregnancy

There are no available data on isatuximab use in pregnant women. Animal reproduction toxicity studies have not been conducted with isatuximab. Immunoglobulin G1 monoclonal antibodies are known to cross the placenta after the first trimester of pregnancy. The use of isatuximab in pregnant women is not recommended.

Breast-feeding

It is unknown whether isatuximab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards; however, a risk to the breast-fed child cannot be excluded during this short period just after birth. For this specific period, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from isatuximab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Afterwards, isatuximab could be used during breastfeeding if clinically needed.

Fertility

No human and animal data are available to determine potential effects of isatuximab on fertility in males and females (see section 5.3).

For other medicinal products that are administered with isatuximab, refer to the respective current summary of product characteristics.

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

Summary of the safety profile

In ICARIA-MM, the most frequent adverse reactions (>20%) are neutropenia (46.7%), infusion reactions (38.2%), pneumonia (30.9%), upper respiratory tract infection (28.3%), diarrhoea (25.7%) and bronchitis (23.7%). Serious adverse reactions occurred in 61.8% of patients receiving Isa-Pd. The most frequent serious adverse reactions are pneumonia (25.7%) and febrile neutropenia (6.6%). Permanent discontinuation of treatment because of adverse reactions was reported in 7.2% of patients treated with Isa-Pd. Adverse reactions with a fatal outcome during treatment were reported in 7.9% of patients treated with Isa-Pd (those occurring in more than 1% of patients were pneumonia occurring in 1.3% of patients and other infections occurring in 2.0% of patients).

In IKEMA, the most frequent adverse reactions (≥20%) are infusion reactions (45.8%), hypertension (36.7%), diarrhoea (36.2%), upper respiratory tract infection (36.2%), pneumonia (28.8%), fatigue (28.2%), dyspnoea (27.7%), insomnia (23.7%), bronchitis (22.6%), and back pain (22.0%). Serious adverse reactions occurred in 59.3% of patients receiving Isa-Kd. The most frequent serious adverse reaction is pneumonia (21.5%). Permanent discontinuation of treatment because of adverse reactions was reported in 8.5% of patients treated with Isa-Kd. Adverse reactions with a fatal outcome during treatment were reported in 3.4% of patients treated with Isa-Kd (those occurring in more than 1% of patients were pneumonia and cardiac failure both occurring in 1.1% of patients).

Tabulated list of adverse reactions

Adverse reactions are described using the NCI Common Toxicity Criteria, the COSTART and the MedDRA terms. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); “frequency not known (cannot be estimated from available data)”. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

The adverse reactions were reported from the 152 patients who received Isa-Pd with a median duration of exposure of 41 weeks in ICARIA-MM study (see section 5.1).

Table 3^a. Adverse reactions reported in patients with multiple myeloma treated with isatuximab in combination with pomalidomide and dexamethasone (ICARIA-MM):

^a Only TEAEs are reported in Table 3. The haematology laboratory values are reported in Table 5.
^b The term pneumonia is a grouping of the following terms: atypical pneumonia, bronchopulmonary aspergillosis, pneumonia, pneumonia haemophilus, pneumonia influenzal, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, pneumonia bacterial, haemophilus infection, lung infection, pneumonia fungal
and pneumocystis jirovecii pneumonia.
^c See “Description of selected adverse reactions”.
^d Haematology laboratory values were recorded as TEAEs only if they led to treatment discontinuation and/or dose modification or fulfilled a serious criterion.
^e Based on multiple myeloma clinical trials.
^* No grade 4

The adverse reactions were reported from the 177 patients who received Isa-Kd with a median duration of exposure of 80.0 weeks in IKEMA study (see section 5.1).

Table 4^a. Adverse reactions reported in patients with multiple myeloma treated with isatuximab in combination with carfilzomib and dexamethasone (IKEMA):

^a Only TEAEs are reported in Table 4. The haematology laboratory values are reported in Table 6.
^b The term pneumonia is a grouping of the following terms: atypical pneumonia, pneumocystis jirovecii pneumonia, pneumonia, pneumonia influenzal, pneumonia legionella, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis.
^c See “Description of selected adverse reactions”.
^d Haematology laboratory values were recorded as TEAEs only if they led to treatment discontinuation and/or dose modification or fulfilled a serious criterion.
^e Based on multiple myeloma clinical trials.
^* No grade 4 or 5.

Description of selected adverse reactions

Infusion reactions

In ICARIA-MM, infusion reactions were reported in 58 patients (38.2%) treated with SARCLISA. All patients who experienced infusion reactions, experienced them during the 1st infusion of SARCLISA, with 3 patients (2.0%) also having infusion reactions at their 2nd infusion, and 2 patients (1.3%) at their 4th infusion. Grade 1 infusion reactions were reported in 3.9%, Grade 2 in 31.6%, Grade 3 in 1.3%, and Grade 4 in 1.3% of the patients. All infusion reactions were reversible and resolved the same day in 98% of the infusions. Signs and symptoms of Grade 3 or 4 infusion reactions included dyspnoea, hypertension, and bronchospasm.

The incidence of infusion interruptions because of infusion reactions was 28.9%. The median time to infusion interruption was 55 minutes.

Discontinuations from treatment due to infusion reaction were reported in 2.6% of patients in Isa-Pd group.

In IKEMA, infusion reactions were reported in 81 patients (45.8%) treated with Isa-Kd. Grade 1 infusion reactions were reported in 13.6%, Grade 2 in 31.6%, and Grade 3 in 0.6% of the patients treated with Isa-Kd. All infusion reactions were reversible and resolved the same day in 73.8% of episodes in Isa-Kd patients and in more than 2 days in 2.5% of episodes in Isa-Kd patients. Signs and symptoms of Grade 3 infusion reactions included dyspnoea and hypertension. The incidence of patients with isatuximab infusion interruptions because of infusion reactions was 29.9%. The median time to isatuximab infusion interruption was 63 minutes. Isatuximab was discontinued in 0.6% of patients due to infusion reactions. (see sections 4.2 and 4.4).

Infections

In ICARIA-MM, the incidence of Grade 3 or higher infections was 42.8%. Pneumonia was the most commonly reported severe infection with Grade 3 reported in 21.7% of patients in the Isa-Pd group compared to 16.1% in the Pd group, and Grade 4 in 3.3% of patients in the Isa-Pd group compared to 2.7% in the Pd group. Discontinuations from treatment due to infection were reported in 2.6% of patients in the Isa-Pd group compared to 5.4% in the Pd group. Fatal infections were reported in 3.3% of patients in the Isa-Pd group and 4.0% in the Pd group. In IKEMA, the incidence of Grade 3 or higher infections was 38.4%. Pneumonia was the most commonly reported severe infection with Grade 3 reported in 15.8% of patients in the Isa-Kd group compared to 10.7% in the Kd group, and Grade 4 in 3.4% of patients in the Isa-Kd group compared to 2.5% in the Kd group. Treatment was discontinued due to infection in 2.8% of patients in the Isa-Kd group compared to 4.9% in the Kd group. Fatal infections were reported in 2.3% of patients in the Isa-Kd group and 0.8% in the Kd group. (see section 4.4).

In relapsed and refractory multiple myeloma clinical trials, herpes zoster was reported in 2.0% of patients. In ICARIA-MM, the incidence of herpes zoster was 4.6% in the Isa-Pd group compared to 0.7% in the Pd group, and in IKEMA, incidence was 2.3% in the Isa-Kd group compared to 1.6% in the Kd group.

Cardiac failure

In IKEMA, cardiac failure (including cardiac failure, cardiac failure congestive, cardiac failure acute, cardiac failure chronic, left ventricular failure, and pulmonary oedema) was reported in 7.3% of patients with the Isa-Kd group (4.0% of Grade ≥3) and in 6.6% of patients with the Kd group (4.1% of Grade ≥3). Serious cardiac failure was observed in 4.0% of patients in the Isa-Kd group and in 3.3% of patients in the Kd group. Cardiac failure with a fatal outcome during treatment was reported in 1.1% of patients in the Isa-Kd group and not reported in the Kd group (see the current prescribing information for carfilzomib).

Haematology laboratory values

Table 5. Haematology laboratory abnormalities in patients receiving isatuximab combined with pomalidomide and dexamethasone–versus pomalidomide and dexamethasone (ICARIA-MM):

The denominator used for the percentage calculation is the number of patients with at least 1 evaluation of the laboratory test during the considered observation period.

Table 6. Haematology laboratory abnormalities in patients receiving isatuximab combined with carfilzomib and dexamethasone versus carfilzomib and dexamethasone (IKEMA):

The denominator used for the percentage calculation is the number of patients with at least 1 evaluation of the laboratory test during the considered observation period.

Immunogenicity

Across 9 clinical studies in multiple myeloma (MM) with isatuximab single agent and combination therapies including ICARIA-MM and IKEMA (N=1018), the incidence of treatment emergent ADAs was 1.9%. No effect of ADAs was observed on pharmacokinetics, safety or efficacy of isatuximab.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.