SARCLISA Concentrate solution for injection Ref.[10339] Active ingredients: Isatuximab

5.1 Infusion-Related Reactions

Infusion-related reactions have been observed in 39% of patients treated with SARCLISA [see Adverse Reactions (6.1)]. All infusion-related reactions started during the first SARCLISA infusion and resolved on the same day in 98% of the cases. The most common symptoms of an infusion-related reaction included dyspnea, cough, chills, and nausea. The most common severe signs and symptoms included hypertension and dyspnea [see Adverse Reactions (6.1)].

To decrease the risk and severity of infusion-related reactions, premedicate patients prior to SARCLISA infusion with acetaminophen, H2 antagonists, diphenhydramine, or equivalent; dexamethasone [see Dosage and Administration (2.2)]. Monitor vital signs frequently during the entire SARCLISA infusion. For patients with grade 1 or 2 reactions, interrupt SARCLISA infusion and provide appropriate medical support. If symptoms improve, restart SARCLISA infusion at half of the initial infusion rate, with supportive care as needed, and closely monitor patients. If symptoms do not recur after 30 minutes, the infusion rate may be increased to the initial rate, and then increased incrementally, as shown in Table 2 [see Dosage and Administration (2.5)]. In case symptoms do not improve or recur after interruption, permanently discontinue SARCLISA and institute appropriate management. Permanently discontinue SARCLISA therapy if a grade 3 or higher infusion-related reaction occurs and institute appropriate medical management.

5.2 Neutropenia

SARCLISA may cause neutropenia. Neutropenia (reported as laboratory abnormality) occurred in 96% of patients and grade 3-4 neutropenia occurred in 85% of patients treated with SARCLISA, pomalidomide, and dexamethasone (Isa-Pd). Febrile neutropenia occurred in 12% of patients and neutropenic infections, defined as infection with concurrent grade ≥3 neutropenia, occurred in 25% of patients treated with Isa-Pd. The most frequent neutropenic infections included those of upper respiratory tract (10%), lower respiratory tract (9%), and urinary tract (3%) [see Adverse Reactions (6.1)].

Monitor complete blood cell counts periodically during treatment. Consider the use of antibiotics and antiviral prophylaxis during treatment. Monitor patients with neutropenia for signs of infection. In case of grade 4 neutropenia delay SARCLISA dose until neutrophil count recovery to at least 1.0 × 10⁹/L, and provide supportive care with growth factors, according to institutional guidelines. No dose reductions of SARCLISA are recommended.

5.3 Second Primary Malignancies

Second primary malignancies were reported in 3.9% of patients in the SARCLISA, pomalidomide and dexamethasone (Isa-Pd) arm and in 0.7% of patients in the pomalidomide and dexamethasone (Pd) arm, and consisted of skin squamous cell carcinoma (2.6% of patients in the Isa-Pd arm and in 0.7% of patients in the Pd arm), breast angiosarcoma (0.7% of patients in the Isa-Pd arm) and myelodysplastic syndrome (0.7% of patients in the Isa-Pd arm). With the exception of the patient with myelodysplastic syndrome, patients were able to continue SARCLISA treatment. Monitor patients for the development of second primary malignancies, as per International Myeloma Working Group (IMWG) guidelines.

5.4 Laboratory Test Interference

Interference with Serological Testing (Indirect Antiglobulin Test)

SARCLISA binds to CD38 on red blood cells (RBCs) and may result in a false positive indirect antiglobulin test (indirect Coombs test). In ICARIA-multiple myeloma (MM), the indirect antiglobulin test was positive during SARCLISA treatment in 67.7% of the tested patients. In patients with a positive indirect antiglobulin test, blood transfusions were administered without evidence of hemolysis. ABO/RhD typing was not affected by SARCLISA treatment. Before the first SARCLISA infusion, conduct blood type and screen tests on SARCLISA-treated patients. Consider phenotyping prior to starting SARCLISA treatment. If treatment with SARCLISA has already started, inform the blood bank that the patient is receiving SARCLISA and SARCLISA interference with blood compatibility testing can be resolved using dithiothreitol-treated RBCs. If an emergency transfusion is required, non–cross-matched ABO/RhD-compatible RBCs can be given as per local blood bank practices [see Drug Interactions (7.1)].

Interference with Serum Protein Electrophoresis and Immunofixation Tests

SARCLISA is an IgG kappa monoclonal antibody that can be incidentally detected on both serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the accuracy of the determination of complete response in some patients with IgG kappa myeloma protein [see Drug Interactions (7.1)].

5.5 Embryo-Fetal Toxicity

Based on the mechanism of action, SARCLISA can cause fetal harm when administered to a pregnant woman. SARCLISA may cause fetal immune cell depletion and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use an effective method of contraception during treatment with SARCLISA and for at least 5 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. The combination of SARCLISA with pomalidomide is contraindicated in pregnant women because pomalidomide may cause birth defects and death of the unborn child. Refer to the pomalidomide prescribing information on use during pregnancy.

The following clinically significant adverse reactions from SARCLISA are also described in other sections of the labeling:

• Infusion-Related Reactions [see Warnings and Precautions (5.1)]
• Neutropenia [see Warnings and Precautions (5.2)]
• Second Primary Malignancies [see Warnings and Precautions (5.3)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Multiple Myeloma

The safety of SARCLISA was evaluated in ICARIA-MM, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. Patients were eligible for inclusion if they had ECOG status of 0–2, platelets ≥75,000 cells/mm ³, absolute neutrophil count ≥1 × 10⁹/L, creatinine clearance ≥30 mL/min (MDRD formula), and AST and/or ALT ≤3 × ULN. Patients received SARCLISA 10 mg/kg intravenously, weekly in the first cycle and every two weeks thereafter, in combination with pomalidomide and low dose dexamethasone (Isa-Pd) (n=152) or pomalidomide and low dose dexamethasone (Pd) (n=149) [see Clinical Studies (14)]. Among patients receiving Isa-Pd, 66% were exposed to SARCLISA for 6 months or longer and 24% were exposed for greater than 12 months or longer.

The median age of patients who received Isa-Pd was 68 years (range 36–83); 58% male, 76% white, and 14% Asian.

Serious adverse reactions occurred in 62% of patients receiving Isa-Pd. Serious adverse reactions in >5% of patients who received Isa-Pd included pneumonia (26%), upper respiratory tract infections (7%), and febrile neutropenia (7%). Fatal adverse reactions occurred in 11% of patients (those that occurred in more than 1% of patients were pneumonia and other infections [3%]).

Permanent discontinuation due to an adverse reaction (grades 1-4) occurred in 7% of patients who received Isa-Pd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Pd were infections (2.6%). In addition, SARCLISA alone was discontinued in 3% of patients due to infusion-related reactions.

Dosage interruptions due to an adverse reaction occurred in 31% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion-related reaction (28%).

The most common adverse reactions (≥20%) were neutropenia, infusion-related reactions, pneumonia, upper respiratory tract infection, and diarrhea.

Table 3 summarizes the adverse reactions in ICARIA-MM.

Table 3. Adverse Reactions (≥10%) in Patients Receiving SARCLISA, Pomalidomide, and Dexamethasone with a Difference Between Arms of ≥5% Compared to Control Arm in ICARIA-MM Trial:

CTCAE version 4.03
* Pneumonia includes atypical pneumonia, bronchopulmonary aspergillosis, pneumonia, pneumonia haemophilus, pneumonia influenzal, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, candida pneumonia, pneumonia bacterial, haemophilus infection, lung infection, pneumonia fungal, and pneumocystis jirovecii pneumonia.
^† Upper respiratory tract infection includes bronchiolitis, bronchitis, bronchitis viral, chronic sinusitis, fungal pharyngitis, influenza-like illness, laryngitis, nasopharyngitis, parainfluenzae virus infection, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tracheitis, upper respiratory tract infection, and upper
respiratory tract infection bacterial.
^‡ Dyspnea includes dyspnea, dyspnea exertional, and dyspnea at rest.

Table 4 summarizes the hematology laboratory abnormalities in ICARIA-MM.

Table 4. Treatment Emergent Hematology Laboratory Abnormalities in Patients Receiving Isa-Pd Treatment versus Pd Treatment – ICARIA-MM:

Description of Selected Adverse Reactions

Infusion-related reactions

In ICARIA-MM, infusion-related reactions (defined as adverse reactions associated with the SARCLISA infusions, with an onset typically within 24 hours from the start of the infusion) were reported in 58 patients (38%) treated with SARCLISA. All patients who experienced infusion-related reactions, experienced them during the 1st infusion of SARCLISA, with 3 patients (2%) also having infusion-related reactions at their 2nd infusion, and 2 patients (1.3%) at their 4th infusion. Grade 1 infusion-related reactions were reported in 3.9%, Grade 2 in 32%, Grade 3 in 1.3%, and Grade 4 in 1.3% of the patients. Signs and symptoms of Grade 3 or higher infusion-related reactions included dyspnea, hypertension, and bronchospasm. The incidence of infusion interruptions because of infusion-related reactions was 29.6%. The median time to infusion interruption was 55 minutes.

In a separate study (TCD 14079 Part B) with SARCLISA 10 mg/kg administered from a 250 mL fixed-volume infusion in combination with Pd, infusion-related reactions (all Grade 2) were reported in 40% of patients, at the first administration, the day of the infusion. Overall, the infusion-related reactions of SARCLISA 10 mg/kg administered as a 250 mL fixed-volume infusion were similar to that of SARCLISA as administered in ICARIA-MM.

Infections

In ICARIA-MM, the incidence of Grade 3 or higher infections was 43% in Isa-Pd group. Pneumonia was the most commonly reported severe infection with Grade 3 reported in 22% of patients in Isa-Pd group compared to 16% in Pd group, and Grade 4 in 3.3% of patients in Isa-Pd group compared to 2.7% in Pd group. Discontinuations from treatment due to infection were reported in 2.6% of patients in Isa-Pd group compared to 5.4% in Pd group. Fatal infections were reported in 3.3% of patients in Isa-Pd group and in 4% in Pd group.

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other isatuximab-irfc products may be misleading.

In ICARIA-MM, no patients tested positive for antidrug antibodies (ADA). Therefore, the neutralizing ADA status was not determined. Overall, across 6 clinical studies in multiple myeloma (MM) with SARCLISA single agent and combination therapies including ICARIA-MM (N=564), the incidence of treatment emergent ADAs was 2.3%. No clinically significant differences in the pharmacokinetics, safety, or efficacy of isatuximab-irfc were observed in patients with ADAs.

7.1 Laboratory Test Interference

Interference with Serological Testing

SARCLISA, an anti-CD38 antibody, may interfere with blood bank serologic tests with false positive reactions in indirect antiglobulin tests (indirect Coombs tests), antibody detection (screening) tests, antibody identification panels, and antihuman globulin crossmatches in patients treated with SARCLISA [see Warnings and Precautions (5.4)].

Interference with Serum Protein Electrophoresis and Immunofixation Tests

SARCLISA may be incidentally detected by serum protein electrophoresis and immunofixation assays used for the monitoring of M-protein and may interfere with accurate response classification based on International Myeloma Working Group (IMWG) criteria [see Warnings and Precautions (5.4)].

Risk Summary

SARCLISA can cause fetal harm when administered to a pregnant woman. The assessment of isatuximab-irfc-associated risks is based on the mechanism of action and data from target antigen CD38 knockout animal models (see Data). There are no available data on SARCLISA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction toxicity studies have not been conducted with isatuximab-irfc. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

The combination of SARCLISA and pomalidomide is contraindicated in pregnant women because pomalidomide may cause birth defects and death of the unborn child. Refer to the pomalidomide prescribing information on use during pregnancy. Pomalidomide is only available through a REMS program.

Clinical Considerations

Fetal/neonatal reactions

Immunoglobulin G1 monoclonal antibodies are known to cross the placenta. Based on its mechanism of action, SARCLISA may cause depletion of fetal CD38-positive immune cells and decreased bone density. Defer administration of live vaccines to neonates and infants exposed to SARCLISA in utero until a hematology evaluation is completed.

Data

Animal data

Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density which recovered 5 months after birth. Data from studies using CD38 knockout animal models also suggest the involvement of CD38 in regulating humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic development (frogs).

Risk Summary

There are no available data on the presence of isatuximab-irfc in human milk, milk production, or the effects on the breastfed child. Maternal immunoglobulin G is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to SARCLISA are unknown. Because of the potential for serious adverse reactions in the breastfed child from isatuximab-irfc administered in combination with pomalidomide and dexamethasone, advise lactating women not to breastfeed during treatment with SARCLISA. Refer to pomalidomide prescribing information for additional information.

Pregnancy Testing

With the combination of SARCLISA with pomalidomide, refer to the pomalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential.

Contraception

Females

SARCLISA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment and for at least 5 months after the last dose of SARCLISA. Additionally, refer to the pomalidomide labeling for contraception requirements prior to initiating treatment in females of reproductive potential.

Males

Refer to the pomalidomide prescribing information.

Safety and effectiveness in pediatric patients have not been established.

Of the total number of subjects in clinical studies of SARCLISA, 53% (306 patients) were 65 and over, while 14% (82 patients) were 75 and over. No overall differences in safety or effectiveness were observed between subjects 65 and over and younger subjects, and other reported clinical experience has not identified differences in responses between the adults 65 years and over and younger patients, but greater sensitivity of some older individuals cannot be ruled out.