Sarclisa 1400 mg solution for injection

Isatuximab is indicated:

- in combination with pomalidomide and dexamethasone, for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on the last therapy.

- in combination with carfilzomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy (see section 5.1).

- in combination with bortezomib, lenalidomide, and dexamethasone, for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

- in combination with bortezomib, lenalidomide, and dexamethasone, for the induction treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.

Treatment with isatuximab should be prescribed by a specialist in the treatment of malignancies.

Isatuximab subcutaneous should be administered by a healthcare professional. For the first dose only, immediate access to medical support should be available to manage systemic administration reactions (SARs) if they occur (see section 4.4).

Once the cycle 1 is completed, subsequent subcutaneous injections may be administered at the patient's home by a healthcare professional, as deemed appropriate, provided there were no SAR in the previous cycle.

Premedication

Prevention of systemic administration reaction

Premedication should be used prior to the subcutaneous administration with the following medicinal products to reduce the risk and severity of systemic administration reactions (SAR) (see section 4.4):

• Dexamethasone 40 mg (or 20 mg for patients ≥75 years of age): when administered in combination with isatuximab and pomalidomide,

Dexamethasone 20 mg: when administered in combination with isatuximab and carfilzomib.

Dexamethasone 20 mg: when administered in combination with isatuximab, bortezomib, and lenalidomide.

• Montelukast 10 mg oral (or equivalent), at cycle 1 only.

• Acetaminophen 650 mg to 1000 mg oral (or equivalent).

• Diphenhydramine 25 mg to 50 mg intravenous or oral (or equivalent [e.g., cetirizine, promethazine, dexchlorpheniramine]). The intravenous use of diphenhydramine is preferred for at least the first 4 administrations of isatuximab subcutaneous.

The above recommended dose of dexamethasone corresponds to the total dose to be administered only once before the isatuximab subcutaneous administration, as part of the premedication and of the backbone treatment, before isatuximab and pomalidomide, before isatuximab and carfilzomib, and before isatuximab, bortezomib, and lenalidomide administration.

The recommended premedication agents should be administered 15 ‒ 60 minutes prior to starting an isatuximab subcutaneous administration. Patients who do not experience a SAR upon their first 4 administrations of isatuximab subcutaneous may have their need for subsequent premedication reconsidered.

Management of neutropenia

Dose delay or omission of isatuximab subcutaneous, and the use of colony-stimulating factors (e.g. G-CSF) according to local guidelines may be required to allow recovery of blood cell counts in the event of haematological toxicity (see section 4.4).

Prevention of infection

Antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) should be considered during treatment (see section 4.4).

Posology

The recommended dose of isatuximab subcutaneous is 1400 mg administered as subcutaneous injection with CirCLIQ On-Body Delivery System (OBDS) or with a syringe and infusion set for manual administration. Isatuximab subcutaneous is administered in combination with pomalidomide and dexamethasone (Isa-SC + Pd) or in combination with carfilzomib and dexamethasone (Isa-SC + Kd), or in combination with bortezomib, lenalidomide, and dexamethasone (Isa-SC + VRd).

Patients may start treatment using intravenous or subcutaneous isatuximab. Patients currently receiving intravenous isatuximab may switch to subcutaneous isatuximab, at any time during their treatment, once cycle 1 is completed.

Isatuximab subcutaneous (SC) dosing schedules are provided in Tables 1, 2 and 3.

Table 1: Dosing schedule in combination with pomalidomide and dexamethasone or in combination with carfilzomib and dexamethasone

Each treatment cycle consists of a 28-day period. Treatment is repeated until disease progression or unacceptable toxicity.

Table 2: Dosing schedule in combination with bortezomib, lenalidomide, and dexamethasone for patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT)

Each treatment cycle consists of a 42-day period from cycle 1 to 4, and of a 28-day period from cycle 5. Treatment is repeated until disease progression or unacceptable toxicity.

Table 3: Dosing schedule in combination with bortezomib, lenalidomide, and dexamethasone for patients with NDMM who are eligible for ASCT

Each treatment cycle consists of a 42-day period.

Missed dose

The administration schedule must be carefully followed. If a planned dose of isatuximab is missed, administer the dose as soon as possible and adjust the treatment schedule accordingly, maintaining the treatment interval.

Dose adjustments

Dose reduction of isatuximab subcutaneous is not permitted. Dose delay or omission may be required. In case of Grade 3 or 4 neutropenia, or febrile neutropenia and/or neutropenic infection, see "Management of neutropenia" above. If patients experience systemic administration reactions or injection site reactions, see table 4 below for dose adjustment (see section 4.4).

Table 4: Isatuximab subcutaneous dose adjustments for SARs and ISRs

NCI-CTCAE v5.0

^* In case isatuximab subcutaneous administration using CirCLIQ OBDS needs to be paused, please refer to the OBDS instructions for use.

Special populations

Elderly

No dose adjustment is recommended in elderly patients (see sections 4.4, 4.8, and 5.2).

Patients with renal impairment

No dose adjustment of isatuximab is needed in patients with mild, moderate, severe, or end-stage renal impaired function (see section 5.2).

Patients with hepatic impairment

No dose adjustment is recommended in patients with mild hepatic impairment. Limited data are available in patients with moderate hepatic impairment and no data are available in patients with severe hepatic impairment, however, there is no evidence to suggest that dose adjustment is required in these patients (see section 5.2).

Paediatric population

The safety and effectiveness of isatuximab subcutaneous in children aged below 18 years of age have not been established. No data with isatuximab subcutaneous are available. Currently available data with intravenous formulation are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology for isatuximab can be made.

Method of administration

Sarclisa 1400 mg subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified. It is important to check the vial labels to ensure that the appropriate formulation (intravenous or subcutaneous formulation) and dose is being given to the patient as prescribed.

Sarclisa 1400 mg is for abdominal subcutaneous administration only, with CirCLIQ On-Body Delivery System (OBDS) or with a syringe and infusion set for manual administration. Refer to section 6.6 for isatuximab subcutaneous preparation and administration.

• Sarclisa 1400 mg is only for abdominal subcutaneous administration. Data are only available with an injection performed into the abdomen.

• Rotate the site of each subcutaneous administration.

• Do not inject other medications in the area where isatuximab subcutaneous is injected.

• Do not inject into areas where the skin is injured, tender, red, hot, has scars, or is excessively hairy.

Administration with CirCLIQ On-Body Delivery System

• Refer to the Instructions for Use for CirCLIQ OBDS provided with the device for full preparation and administration information.

Administration with syringe and infusion set for manual administration

Prepare injection site and insert needle

• Wipe injection site with an alcohol swab and allow it to dry.

• Avoid injecting within 5 cm around the belly button. Remove protective needle cover.

• Pinch skin at the injection site on the abdomen. It is important to pinch enough skin to inject under the skin and not into the muscle.

• Insert needle at a 45-degree angle with a quick, dart-like motion.

Note: Try to limit needle and syringe movement during the injection. If needed, secure the subcutaneous infusion set in place with a bandage.

Inject 10 mL of Sarclisa 1400 mg subcutaneously into the abdomen, over approximately 6 minutes.

Pause or slow down delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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.

Systemic administration reactions (SARs)

In clinical trials with subcutaneous isatuximab (N = 522), SARs occurred in 16 patients (3.1%); 14 patients (2.7%) experienced only one episode. An SAR occurred at first administration in 10 patients (1.9%). They were mostly low grades (Grade 1 or 2) and resolved at the most within 3 days. The reported symptoms of SARs (all below 1%) were mainly pyrexia, dyspnoea, and sinus tachycardia. There was one Grade 3 episode of SAR in one patient that experienced hypertension and dyspnoea. In case of Grade ≥2 SARs, administration adjustments should be considered (see sections 4.2 and 4.8).

To decrease the risk and severity of SARs, patients should be pre-medicated prior to isatuximab subcutaneous administration with montelukast (at cycle 1 only), acetaminophen, diphenhydramine or equivalent; dexamethasone is to be used as both premedication and anti-myeloma treatment (see section 4.2).

Neutropenia

Neutropenia was reported in clinical trials with isatuximab subcutaneous or intravenous in combination therapies. With isatuximab subcutaneous combination therapies, a higher incidence of Grade 3 ‒ 4 neutropenia reported as laboratory abnormality was observed in patients with body weight ≤50 kg compared to patients with a higher body weight, with however similar incidences of neutropenic complications (see section 4.8).

Complete blood cell counts should be monitored periodically during treatment. Antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) can be considered during treatment (see section 4.2). Patients with neutropenia should be monitored for signs of infection. No dose reductions of isatuximab subcutaneous are recommended. Isatuximab subcutaneous 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).

Infections

Infections were reported in clinical trials with isatuximab subcutaneous or intravenous in combination therapies, with an incidence of 66.4% of patients, including Grade ≥3 infections reported in 29.9% of patients. Upper respiratory tract infection, pneumonia, and bronchitis were the most frequently reported infections (see section 4.8).

Patients receiving isatuximab subcutaneous should be closely monitored for signs of infection and appropriate standard therapy instituted. Antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) should be considered during treatment (see section 4.2).

Second primary malignancies

Second primary malignancies (SPMs) were reported in clinical trials with isatuximab subcutaneous or intravenous in combination therapies (see section 4.8).

The overall incidence of SPMs in isatuximab-exposed patients (subcutaneous and intravenous formulations) is 5.4%. Monitor patients for the development of second primary malignancies and initiate treatment as indicated.

Tumour lysis syndrome

Cases of tumour lysis syndrome (TLS) have been reported in patients who received regimens containing isatuximab administered intravenously. 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). This interference with the indirect Coombs test may persist for at least 6 months after the last administration of isatuximab. To avoid potential problems with RBC transfusion, patients being treated with isatuximab should have blood type and screen tests performed prior to the first administration. Phenotyping may be considered prior to starting isatuximab treatment as per local practice. If treatment with isatuximab 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).

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. This interference may persist for at least 6 months after the last administration of isatuximab. In patients with persistent very good partial response, where interference is suspected, consider using a validated isatuximab-specific IFE assay (Sebia Hydrashift) to remove isatuximab interference and specifically visualize any remaining serum M protein, to facilitate determination of complete response (see section 4.5).

Educational materials

All prescribers who intend to prescribe isatuximab as well as healthcare professionals at blood banks/transfusion centres must ensure they have received and are familiar with the healthcare professional educational material prepared for the management of the risk of interference with serological testing. Prescribers must explain to the patients that isatuximab may affect the results of their serological testing for at least 6 months after their last dose of isatuximab. This is also explained in the patient card that prescribers must give to patients at time of the first dose of Sarclisa. The patients must be instructed to carry the card during treatment and for at least 6 months after the treatment has ended and to share it with their healthcare team.

Elderly

Data are limited in the population ≥85 years old (see section 4.8).

Body weight >120 kg

There is a potential for reduced efficacy with isatuximab subcutaneous in patients with a body weight >120 kg, due to the effect of body weight on exposure (see section 5.2).

The pharmacokinetics of subcutaneous isatuximab, and concomitant pomalidomide, carfilzomib, bortezomib, and lenalidomide are not expected to be influenced by their co-administration, as it was shown with intravenous isatuximab.

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). This interference may persist for at least 6 months after the last administration of isatuximab. 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 may interfere with accurate response classification based on International Myeloma Working Group (IMWG) criteria (see section 4.4). This interference may persist for at least 6 months after the last administration of isatuximab. Because of this interference, Hydrashift assay was routinely used in IRAKLIA and IZALCO clinical studies for efficacy assessment to determine the complete response in patients with IgG kappa myeloma protein.

In patients with persistent very good partial response, where interference is suspected, consider using a validated isatuximab-specific IFE assay (Sebia Hydrashift) to remove isatuximab interference and specifically visualize any remaining serum M protein, to facilitate determination of complete response (see section 4.4).

Women of childbearing potential/Contraception

Women of childbearing potential treated with isatuximab should use effective contraception during treatment and for 7 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 breast-feeding 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).

Isatuximab has minor to moderate influence on the ability to drive and use machines. Fatigue and dizziness have been reported in patients taking isatuximab and this should be taken into account when driving or using machines.

Summary of the safety profile

The most frequent adverse reactions with isatuximab subcutaneous or intravenous in combination therapies (N = 2656) were infusion-related reactions (27.5%), diarrhoea (27.2%), neutropenia (25.1%), upper respiratory tract infection (23%), pneumonia (22%), and fatigue (20.7%). The most frequent serious adverse reaction was pneumonia (16.5%). Definitive study treatment discontinuation because of adverse reactions was reported in 10.2% of patients (due to pneumonia in 1.1% of patients). Adverse reactions with a fatal outcome during treatment were reported in 5.9% of patients (due to pneumonia in 1.9% of patients).

The safety profile of isatuximab 1400 mg subcutaneous (N = 522) in combination therapies was overall consistent with the known safety profile of isatuximab 10 mg/kg intravenous (N = 2134) in monotherapy or in combination therapies. Differences were observed in systemic administration reactions with a lower incidence reported with isatuximab subcutaneous (3.1%) versus isatuximab intravenous (33.5%). Injection site reactions associated with isatuximab subcutaneous administration were reported in 1.48% of injections (11.9% of patients), all Grade ≤2.

Tabulated list of adverse reactions

Adverse reactions are described by frequency category. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10 000 to <1/1000); 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 in clinical studies (see section 5.1) and post-market settings.

Isatuximab in combination with pomalidomide and dexamethasone (Isa-Pd)

The Table 5 reports the pooled safety data from 827 patients with relapsed and/or refractory multiple myeloma (RRMM) treated with isatuximab subcutaneous 1400 mg (307 patients) or with isatuximab intravenous 10 mg/kg (520 patients). Data include patients from IRAKLIA (EFC15951), TCD15484, ICARIA-MM (EFC14335) and TCD14079 studies.

Table 5: Adverse reactions reported in patients with multiple myeloma treated with isatuximab subcutaneous or intravenous formulation in combination with pomalidomide and dexamethasone

^a The term pneumonia is a grouping of terms.

^b Based on second primary malignancies reported during study treatment period and during post-treatment period.

^c Haematology laboratory values were recorded as TEAEs only if they led to treatment discontinuation and/or dose modification and/or fulfilled a serious criterion. The term neutropenia is a grouping of neutropenia and neutrophil count decrease.

^d Based on post-marketing experience with intravenous isatuximab.

^e See “Description of selected adverse reactions”.

^f Based on isatuximab intravenous arms of isatuximab SC and IV clinical studies (N = 520).

^g Based on isatuximab subcutaneous arms of isatuximab SC clinical studies (N = 307).

MedDRA 27.00

Isatuximab in combination with carfilzomib and dexamethasone (Isa-Kd)

The Table 6 reports the pooled safety data from 251 patients with RRMM treated with isatuximab subcutaneous 1400 mg or with isatuximab intravenous 10 mg/kg. Data include patients from IZALCO (ACT17453) and IKEMA (EFC15246) studies.

Table 6: Adverse reactions reported in patients with multiple myeloma treated with isatuximab subcutaneous or intravenous formulation in combination with carfilzomib and dexamethasone

^a The term pneumonia is a grouping of terms.

^b Based on second primary malignancies reported during study treatment period and during post-treatment period.

^c Haematology laboratory values were recorded as TEAEs only if they led to treatment discontinuation and/or dose modification and/or fulfilled a serious criterion. The term neutropenia is a grouping of neutropenia and neutrophil count decrease.

^d Based on post-marketing experience with intravenous isatuximab.

^e See “Description of selected adverse reactions”.

^f Based on isatuximab intravenous clinical study (N = 177).

^g Based on isatuximab subcutaneous clinical study (N = 74).

MedDRA 27.0

Isatuximab in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd)

The Table 7 reports the pooled safety data from 904 patients with NDMM eligible or not for autologous stem cell transplantation, treated with isatuximab subcutaneous 1400 mg (141 patients) or with isatuximab intravenous 10 mg/kg (763 patients). Data include patients from IsaSoCut (IIT17756), GMMG-HD8 (IIT17041), IMROZ, TCD13983 and GMMG-HD7 (IIT15403) studies.

Table 7: Adverse reactions reported in patients with multiple myeloma treated with isatuximab subcutaneous or intravenous formulation in combination with bortezomib, lenalidomide, and dexamethasone

^a The term pneumonia is a grouping of terms.

^b Based on second primary malignancies reported during study treatment period and during post-treatment period.

^c The term neutropenia is a grouping of neutropenia and neutrophil count decrease.

^d Based on post-marketing adverse reactions experience with intravenous isatuximab

^e See “Description of selected adverse reactions”.

^f Based on isatuximab intravenous arms of isatuximab SC and IV clinical studies (N = 763).

^g Based on isatuximab subcutaneous arms of isatuximab SC clinical studies (N = 141).

MedDRA 27.0

Description of selected adverse reactions

Systemic administration reactions (SARs)

In clinical trials (IRAKLIA, IZALCO, IsaSoCut, GMMG-HD8, and TCD15484, N = 522), SARs related to isatuximab subcutaneous were reported in 3.1% of patients. SARs occurred at the first administration in 1.9% of patients and at subsequent administrations in 1.3% of patients. For patients who experienced SARs, SARs occurred from the day of the administration (42.1% of patients) to 3 days after the administration (15.8% of patients). Grade 1 SARs were reported in 1.9% of patients, Grade 2 in 1.0%, and Grade 3 in 0.2%. No Grade 4 or 5 SARs were reported. All SARs resolved, within 1 day in 42.1% of patients, within 2 days in 15.8% of patients, and within at least 3 days in 42.1% of patients. No isatuximab SC administrations were interrupted or permanently discontinued due to SARs (see section 4.4).

In multiple myeloma clinical trials with intravenous isatuximab, anaphylactic reactions have been reported in association with infusion reactions in 0.3% of patients. In the postmarketing setting, fatal cases of anaphylactic reactions have been reported with intravenous isatuximab.

Injection site reactions (ISRs)

In clinical trials (IRAKLIA, IZALCO, IsaSoCut, GMMG-HD8 and TCD15484, N = 522), injection site reactions (ISRs) with isatuximab subcutaneous administration were reported in 11.9% (10% Grade 1 and 1.9% Grade 2) of patients and in 1.48% of injections (154 episodes out of 10 422 injections). No grade 3, 4, or 5 ISRs were reported. The ISRs occurred the day of the administration in 85.9% of patients. All ISRs resolved, 74.3% of them resolved on the same day. With Isa-SC + Pd and Isa-SC + Kd, 5% of patients experienced symptoms of ISR (not collected in Isa-VRd studies). The most frequent (>1%) symptoms of ISR were injection site erythema (3.4%), injection site swelling (1.8%), and injection site pain (1.6%).

In IZALCO, the incidence of ISR (8.1% of patients) was similar with CirCLIQ OBDS administration (0.86% of CirCLIQ OBDS injections) and manual administration (1.34% of manual injections).

In IRAKLIA, of the 12 patients (4.6% of patients, 55 administrations) with at least one Sarclisa subcutaneous administration performed at home, 1 ISR was reported. The ISR was a single grade 1 episode that resolved within the same day.

Infections

In clinical studies of isatuximab intravenous and subcutaneous formulations (N = 2656), the most commonly reported infections were upper respiratory tract infection (23.0%), pneumonia (22.0%), and bronchitis (11.0%). Grade ≥3 infections were reported in 29.9% of patients including 16.6% Grade ≥3 pneumonia). Serious infections were reported in 29.0% of patients. The most frequent serious infection was pneumonia (16.5%). Discontinuations from treatment due to infection were reported in 4.0% of patients. Fatal infections were reported in 3.4% of patients. Neutropenic complications have been observed in 9.0% of patients, including 2.5% of febrile neutropenia and 7.2% of neutropenic infections.

Second primary malignancies

In clinical trials of isatuximab intravenous and subcutaneous formulations (N = 2656), second primary malignancies (SPMs) were reported in 144 patients (5.4%), with a rate of 3.0 per 100 person-years. SPM were skin cancer in 89 patients (3.4%), solid tumours other than skin cancer in 52 patients (2.0%), and haematological malignancy in 8 patients (0.3%). The most frequently reported SPMs were basal cell carcinoma and squamous cell carcinoma of skin (1.5% and 1.6% of patients, respectively). In studies that collected this information (N = 2518), permanent full treatment discontinuation due to SPM occurred in 26 patients (1.0%).

Cardiac failure

In clinical trials of isatuximab intravenous and subcutaneous formulations (N = 2656), cardiac failure was reported in 38 patients (1.4%). In patients receiving intravenous or subcutaneous isatuximab in combination with carfilzomib and dexamethasone (IZALCO and IKEMA), 10 cases (4.0%) of cardiac failure with 5 serious cases (2.0%) were reported. In patients receiving intravenous isatuximab in IKEMA (Isa-IV +Kd vs Kd), cardiac failure was reported in 7.3% of patients with the Isa-IV + Kd arm and in 6.6% of patients with the Kd arm. Serious cardiac failure was observed in 4.0% of patients in the Isa-IV + Kd arm and in 3.3% of patients in the Kd arm (see the Summary of Product Characteristics of carfilzomib).

Haematology laboratory values

Table 8: Haematology laboratory abnormalities during the on-treatment period in patients receiving Isa-SC + Pd or Isa-IV + Pd

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.

CTCAE version: 5

Table 9: Haematology laboratory abnormalities during the on-treatment period in patients receiving Isa-SC + Kd or Isa-IV+ Kd

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.

CTCAE version: 5

Table 10: Haematology laboratory abnormalities during the on-treatment period in patients receiving Isa-SC + VRd or Isa-IV + VRd

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.

CTCAE version: 5

Elderly patients

Of the total number of patients in clinical studies of isatuximab subcutaneous and intravenous (N = 2656), 43.8% (1165 patients) were less than 65, 41.4% (1099 patients) were 65 ‒ 74, and 14.8% (392 patients) were 75 or older. Differences in safety were observed between older versus younger age groups. Grade ≥3 TEAEs were reported in 69.0% of patients less than 65, 80.2% of patients 65 ‒ 74 and 78.8% of patients 75 or older. Grade ≥3 neutropenia occurred at a higher frequency in older patients with incidences of 19.4% in patients less than 65, 24.8% in patients 65 – 74, and 28.6% in patients 75 or older. Grade ≥3 infection occurred at a higher frequency in older patients with incidences of 24.2% in patients less than 65, 34.2% in patients 65 – 74, and 34.7% in patients 75 or older. Grade 5 TEAEs were reported in 5.2% of patients less than 65, 7.1% of patients 65 ‒ 74, and 10.5% of patients 75 or older. Serious TEAEs were reported in 45.5% of patients less than 65, 56.6% of patients 65 ‒ 74, and 59.9% of patients 75 or older. TEAEs leading to definitive treatment discontinuation were reported in 6.0% of patients less than 65, 12.3% of patients 65 ‒ 74, and 13.0% of patients 75 or older.

In Newly Diagnosed Multiple Myeloma studies (N = 904), Grade 5 TEAEs were reported in 1.8% of patients less than 65, in 6.4% of patients 65 ‒ 74, and in 11.8% of patients 75 or older.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity to isatuximab.

Anti-drug antibodies (ADA) were uncommonly reported after subcutaneous isatuximab administrations (4.9% in studies in RRMM and 15.9% in studies in NDMM). In the small subgroup of ADA positive patients, there was no evident effect of ADA on isatuximab pharmacokinetics, safety, or efficacy.

Paediatric population

The safety of isatuximab in children has not been established. No data are available with subcutaneous isatuximab.

In a phase 2 single-arm study conducted with intravenous isatuximab in 67 paediatric patients with relapsed or refractory acute lymphoblastic leukaemia or acute myeloid leukaemia, all evaluable for safety, Grade ≥3 TEAEs was reported in 79.1% of patients. The most common Grade ≥3 TEAEs occurring in >10% of patients included febrile neutropenia (41.8%), septic shock (11.9%), and stomatitis (10.4%). The addition of intravenous isatuximab to standard chemotherapies did not modify the expected safety profile observed with standard chemotherapies in this paediatric population and was consistent with isatuximab safety profile for adults with multiple myeloma in ICARIA-MM and IKEMA studies (see section 4.2).

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 Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Signs and symptoms

There has been no experience of overdose of isatuximab in clinical studies. Doses of subcutaneous isatuximab up to 1400 mg have been administered in clinical studies.

Management

There is no known specific antidote for isatuximab overdose. In the event of overdose, monitor the patients for signs or symptoms of adverse reactions and take all appropriate measures immediately.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates, ATC code: L01FC02.

Mechanism of action

Isatuximab is an IgG1-derived monoclonal antibody that binds to a specific extracellular epitope of CD38 receptor. CD38 is a transmembrane glycoprotein that is highly expressed on multiple myeloma cells.

In vitro, isatuximab acts through IgG Fc-dependent mechanisms including antibody dependent cell mediated cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), and complement dependent cytotoxicity (CDC). Furthermore, isatuximab can also trigger tumour cell death by induction of apoptosis via an Fc-independent mechanism.

In vitro, isatuximab blocks the enzymatic activity of CD38 which catalyses the synthesis and hydrolysis of cyclic ADP-ribose (cADPR), a calcium mobilizing agent. Isatuximab inhibits the cADPR production from extracellular nicotinamide adenine dinucleotide (NAD) in multiple myeloma cells.

In vitro, isatuximab can activate NK cells in the absence of CD38 positive target tumour cells.

In vivo, a decrease in absolute counts of total CD16⁺ and CD56⁺ NK cells, CD19⁺ B-cells, CD4⁺ T- cells and T_REG (CD3⁺, CD4⁺, CD25⁺, CD127^-) was observed in peripheral blood of patients treated with isatuximab monotherapy with intravenous formulation in multiple myeloma patients. In addition, isatuximab induced clonal expansion of the T-cell receptor repertoire indicating an adaptive immune response.

The combination of isatuximab and pomalidomide in vitro enhances cell lysis of CD38 expressing multiple myeloma cells by effector cells (ADCC), and by direct tumour cell killing compared to that of isatuximab alone. In vivo animal experiments using a human multiple myeloma xenograft model in mice demonstrated that the combination of isatuximab and pomalidomide results in enhanced antitumour activity compared to the activity of isatuximab or pomalidomide alone.

Clinical efficacy and safety

Clinical experience of isatuximab subcutaneous

Relapsed and/or refractory multiple myeloma

IRAKLIA (EFC15951, Isa-SC + Pd vs Isa-IV + Pd)

IRAKLIA is a multicentre, multinational, randomised, open-label, 2-arm, non-inferiority phase 3 study in patients with relapsed and/or refractory multiple myeloma (RMMM). This study compared the efficacy, pharmacokinetics, and safety of isatuximab 1400 mg administered subcutaneously versus isatuximab as a 10 mg/kg intravenous infusion, in combination with pomalidomide and dexamethasone (Isa-SC + Pd versus Isa-IV + Pd).

Patients had received at least one prior therapy including lenalidomide and a proteasome inhibitor with disease progression on or within 60 days after the end of the lenalidomide therapy.

A total of 531 patients were randomized in a 1:1 ratio to receive either isatuximab 1400 mg fixed dose as subcutaneous administration with CirCLIQ OBDS (Isa-SC + Pd arm, 263 patients) or isatuximab as a 10 mg/kg intravenous infusion (Isa-IV + Pd arm, 268 patients), in combination with pomalidomide and dexamethasone. From Cycle 6 onwards, a home administration, by a healthcare professional, was proposed to the patients in Isa-SC arm on Day 15. The decision to propose at home administration on Day 15 was based on the absence of a systemic administration reaction at Cycle 4 and Cycle 5, the haematology test at Day 1 of each corresponding cycle and the investigator's judgement. Twelve (12) patients out of 202 enrolled in countries allowing it, received at least one at home administration by a healthcare professional and the total number of injections with CirCLIQ OBDS at home was 55. Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity. In both treatment arms, isatuximab was administered weekly in the first cycle and every two weeks thereafter. Pomalidomide 4 mg was taken orally once daily from day 1 to day 21 of each 28-day cycle. Dexamethasone orally 40 mg (20 mg for patients ≥75 years of age) was given on days 1, 8, 15, and 22 of each 28-day cycle.

Overall, demographic and disease characteristics at baseline were similar between the two treatment arms. The median patient age was 66 years (range 31 ‒ 86), 17.9% of patients were ≥75 years; 69.4% of patients were White, 20.9% Asian, and 4.2% Black or African American; The proportion of patients with renal impairment (eGFR <60 mL/min/1.73 m²) was 32% in the Isa-SC+ Pd arm and 23% in the Isa-IV+ Pd arm. The International Staging System (ISS) stage at study entry was I in 59.3%, II in 26.6% and III in 12.1% of patients. Overall, 20.5% of patients had high-risk chromosomal abnormalities at study entry; del(17p), t(4;14), t(14;16), and chromosomal 1q21 abnormality were present in 10%, 9.6%, 2.1% and 35.6% of patients, respectively. The median body weight was 72 kg (range: 36 to 161), with 32% of patients with a weight ≤65 kg, 44.1% with a weight >65 kg to ≤85 kg, and 23.9% with a weight >85 kg.

The median number of prior lines of therapy was 2 (range 1 ‒ 8) and 30% of patients had received 1 prior line of therapy. All patients except 1 received a prior proteasome inhibitor and prior lenalidomide, and 56% of patients received prior stem cell transplantation. Patients were previously exposed to daratumumab in 14.1% of patients in Isa-SC + Pd arm vs 10.8% in Isa-IV + Pd arm. The majority of patients (83.6%) were refractory to lenalidomide, 50% to a proteasome inhibitor, and 44% to both an immunomodulator and a proteasome inhibitor.

The median duration of treatment with isatuximab was 34 weeks in both treatment arms. Full dose administration with CirCLIQ OBDS was obtained in 99.9% of injections (5140 of 5145 injections). The median duration of the injection with CirCLIQ OBDS was 13 minutes and the majority (97.9%) was completed in ≤20 minutes.

IRAKLIA was designed to demonstrate non-inferiority of treatment with isatuximab subcutaneous 1400 mg versus isatuximab intravenous based on the co-primary efficacy endpoints Overall Response Rate (ORR) and the pharmacokinetic endpoint of C_trough at steady state (corresponding to predose at Cycle 6 Day 1) (see section 5.2).

ORR results were assessed by an Independent Review Committee, based on central laboratory data for M-protein and central radiologic imaging review using the International Myeloma Working Group (IMWG) criteria.

At median follow-up time of 12 months, the results show that isatuximab 1400 mg administered subcutaneously in combination with Pd is non-inferior to isatuximab 10 mg/kg administered intravenously in combination with Pd in terms of ORR and C_trough at steady state (see section 5.2). For ORR, the noninferiority was met since the lower limit of the 95% CI of the relative risk of 1.008 [95% CI: 0.903 to 1.126] was greater than the non-inferiority margin of 0.839.

ORR was 71.1% in the isatuximab subcutaneous arm and 70.5% in the isatuximab intravenous arm.

Efficacy results are presented in Table 11.

Table 11 *: Efficacy of isatuximab subcutaneous versus isatuximab intravenous in combination with pomalidomide and dexamethasone in the treatment of multiple myeloma (IRAKLIA)

* Cut-off date: 06 Nov 2024. Median follow-up time:12 months

^a sCR, CR, VGPR, and PR were evaluated by the Independent Review Committee (IRC) using the IMWG response criteria.

^b Estimated using Clopper-Pearson method.

^c Estimated using Farrington-Manning method. The non-inferiority was met if lower limit of 95% CI is greater or equal to 0.839.

Patient satisfaction was assessed using the Patient Experience and Satisfaction Questionnaire (PESQ). In the ITT population, the incidence of patients who responded as satisfied or as very satisfied with the injection method used to administer isatuximab (item-8 of the PESQ), was 70% in the Isa-SC + Pd arm and 53.4% in the Isa-IV + Pd arm with an adjusted relative risk of 1.304 (95% CI: 1.136 to 1.496). Due to the open-label design of the study, a bias cannot be ruled out.

IZALCO (ACT17453, Isa-SC + Kd)

IZALCO study investigated patient preference (key secondary endpoint) between manual administration with a syringe and OBDS administration of isatuximab subcutaneous 1400 mg. A total of 74 participants were randomized in a 3:1 ratio to receive subcutaneous isatuximab 1 400 mg manually or via OBDS. After the first 3 cycles, the delivery method was switched for each participant (from OBDS to manual, and vice versa) for 3 additional cycles. At Cycle 7, each participant chose their preferred method of administration for the rest of the study. Among the 47 patients evaluable for administration preference at cycle 6, 74.5% (95% CI: 59.65% ‒ 86.1%) preferred CirCLIQ OBDS administration (1-sided p-value: 0.0004, statistically significant against the null hypothesis of a ≤50% preference rate).

Clinical experience of isatuximab intravenous

Relapsed and/or refractory multiple myeloma

ICARIA-MM (EFC14335, Isa-IV + Pd vs Pd)

The efficacy and safety of isatuximab in combination with pomalidomide and dexamethasone were evaluated in ICARIA-MM (EFC14335), a multicentre, multinational, randomised, open-label, 2-arm, phase III study in patients with relapsed and/or refractory multiple myeloma. Patients had received at least two prior therapies including lenalidomide and a proteasome inhibitor with disease progression on or within 60 days after the end of the previous therapy. Patients with primary refractory disease were excluded.

A total of 307 patients were randomised in a 1:1 ratio to receive either isatuximab in combination with pomalidomide and dexamethasone (Isa-Pd, 154 patients) or pomalidomide and dexamethasone (Pd, 153 patients). Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity. Isatuximab 10 mg/kg was administered as an I.V. infusion weekly in the first cycle and every two weeks thereafter. Pomalidomide 4 mg was taken orally once daily from day 1 to day 21 of each 28-day cycle. Dexamethasone (oral/intravenous) 40 mg (20 mg for patients ≥75 years of age) was given on days 1, 8, 15 and 22 for each 28-day cycle.

Overall, demographic and disease characteristics at baseline were similar between the two treatment groups, with some minor imbalances. The median patient age was 67 years (range 36 ‒ 86), 19.9% of patients were ≥75 years. ECOG PS was 0 in 35.7% of patients in the isatuximab arm and 45.1% in the comparator arm, 1 in 53.9% in the isatuximab arm and 44.4% in the comparator arm, and 2 in 10.4% in the isatuximab arm and 10.5% in the comparator arm, 10.4% of patients in the isatuximab arm versus 10.5% in the comparator arm entered the study with a history of COPD or asthma, and 38.6% versus 33.3% of patients with renal impairment (creatinine clearance <60 mL/min/1.73 m²) were included in the isatuximab arm versus the comparator arm , respectively. The International Staging System (ISS) stage at study entry was I in 37.5% (41.6% in the isatuximab arm and 33.3% in the comparator arm), II in 35.5% (34.4% in the isatuximab arm and 36.6% in the comparator arm) and III in 25.1% (22.1% in the isatuximab arm and 28.1% in the comparator arm) of patients. Overall, 19.5% of patients (15.6% in the isatuximab arm and 23.5% in the comparator arm) had high-risk chromosomal abnormalities at study entry; del(17p), t(4;14) and t(14;16) were present in 12.1% (9.1% in the isatuximab arm and 15.0% in the comparator arm), 8.5% (7.8% in the isatuximab arm and 9.2% in the comparator arm) and 1.6% (0.6% in the isatuximab arm and 2.6% in the comparator arm) of patients, respectively.

The median number of prior lines of therapy was 3 (range 2 ‒ 11). All patients received a prior proteasome inhibitor, all patients received prior lenalidomide, and 56.4% of patients received prior stem cell transplantation. The majority of patients (92.5%) were refractory to lenalidomide, 75.9% to a proteasome inhibitor, and 72.6% to both an immunomodulatory and a proteasome inhibitor, and 59% of patients were refractory to lenalidomide at last line of therapy.

The median duration of treatment was 41.0 weeks for the Isa-Pd group compared to 24.0 weeks for the Pd group.

Progression-free survival (PFS) was the primary efficacy endpoint of ICARIA-MM. The improvement in PFS represented a 40.4% reduction in the risk of disease progression or death in patients treated with Isa-Pd.

Efficacy results are presented in Table 12 and Kaplan-Meier curves for PFS and OS are provided in Figures 1 and 2:

Table 12: Efficacy of isatuximab in combination with pomalidomide and dexamethasone versus pomalidomide and dexamethasone in the treatment of multiple myeloma (intent-to-treat analysis)

^a PFS results were assessed by an Independent Response Committee based on central laboratory data for M-protein and central radiologic imaging review using the International Myeloma Working Group (IMWG) criteria.

^b Patients without progressive disease or death before the analysis cut-off or the date of initiation of further anti-myeloma treatment were censored at the date of the last valid disease assessment not showing disease progression performed prior to initiation of a further anti-myeloma treatment (if any) or the analysis cut-off date, whichever came first.

^c Stratified on age (<75 years versus ≥75 years) and number of previous lines of therapy (2 or 3 versus >3) according to IRT.

^d sCR, CR, VGPR and PR were evaluated by the IRC using the IMWG response criteria.

^e Estimated using Clopper-Pearson method.

^f The duration of response was determined for patients who achieved a response of ≥PR (93 patients in the isatuximab arm and 54 patients in the comparator arm). Kaplan-Meier estimates of duration of response.

^g CI for Kaplan-Meier estimates are calculated with log-log transformation of survival function and methods of Brookmeyer and Crowley.

* Cut-off date of 11-Oct-2018. Median follow-up time = 11.60 months. HR <1 favours Isa-Pd arm.

NR: not reached

In patients with high-risk cytogenetics (central laboratory assessment), median PFS was 7.49 (95% CI: 2.628 to NC) in the Isa-Pd group and 3.745 (95% CI: 2.793 to 7.885) in the Pd group (HR = 0.655; 95% CI: 0.334 to 1.283). PFS improvements in the Isa-Pd group were also observed in patients ≥75 years (HR = 0.479; 95% CI: 0.242 to 0.946), with ISS stage III at study entry (HR = 0.635; 95% CI: 0.363 to 1.110), with baseline creatinine clearance <60 mL/min/1.73 m² (HR = 0.502; 95% CI: 0.297 to 0.847), with >3 prior lines of therapy (HR = 0.590; 95% CI: 0.356 to 0.977), in patients refractory to prior therapy with lenalidomide (HR = 0.593; 95% CI: 0.431 to 0.816) or proteasome inhibitor (HR = 0.578; 95% CI: 0.405 to 0.824) and in those refractory to lenalidomide at the last line before to the study entry (HR = 0.601; 95% CI: 0.436 to 0.828).

Insufficient data is available to conclude on the efficacy of Isa-Pd in patients previously treated with daratumumab (1 patient in the isatuximab arm and no patient in the comparator arm).

The median time to first response in responders was 35 days in the Isa-Pd group versus 58 days in the Pd group. At a median follow-up time of 52.44 months, final median overall survival was 24.57 months in the Isa-Pd group and 17.71 months in the Pd group (HR = 0.776; 95% CI: 0.594 to 1.015).

Figure 1: Kaplan-Meier Curves of PFS – ITT population – ICARIA-MM (assessment by the IRC)

Figure 2: Kaplan-Meier Curves of OS – ITT population – ICARIA-MM

Cut-off date = 07 February 2023

In the ICARIA-MM (EFC14335) study, a weight-based volume was used for isatuximab infusion. The fixed volume infusion method as described in section 4.2 was evaluated in study TCD14079 Part B and pharmacokinetics simulations confirmed minimal differences between the pharmacokinetics following injection applying a volume based on patient weight and a fixed volume of 250 mL (see section 5.2). In study TCD14079 part B, there were no new safety signals or differences in efficacy and safety as compared to ICARIA-MM.

IKEMA (EFC15246, Isa-IV + Kd vs Kd)

The efficacy and safety of isatuximab in combination with carfilzomib and dexamethasone were evaluated in IKEMA (EFC15246), a multicentre, multinational, randomized, open-label, 2-arm, phase III study in patients with relapsed and/or refractory multiple myeloma. Patients had received one to three prior therapies. Patients with primary refractory disease, who had previously been treated with carfilzomib, or who were refractory to previous anti-CD38 monoclonal antibody treatment were excluded.

A total of 302 patients were randomized in a 3:2 ratio to receive either isatuximab in combination with carfilzomib and dexamethasone (Isa-Kd, 179 patients) or carfilzomib and dexamethasone (Kd, 123 patients). Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity. Isatuximab 10 mg/kg was administered as an I.V. infusion weekly in the first cycle and every two weeks thereafter. Carfilzomib was administered as an I.V. infusion at the dose of 20 mg/m² on days 1 and 2; 56 mg/m² on days 8, 9, 15 and 16 of cycle 1; and at the dose of 56 mg/m² on days 1, 2, 8, 9, 15 and 16 for subsequent cycles of each 28-day cycle. Dexamethasone (IV on the days of isatuximab and/ or carfilzomib infusions, and per os (PO) on the other days) 20 mg was given on days 1, 2, 8, 9, 15, 16, 22 and 23 for each 28-day cycle.

Overall, demographic and disease characteristics at baseline were similar between the two treatment groups. The median patient age was 64 years (range 33 ‒ 90), 8.9% of patients were ≥75 years. ECOG PS was 0 in 53.1% of patients in the Isa-Kd group and 59.3% in the Kd group, 1 in 40.8% in the Isa-Kd group and 36.6% in the Kd group, and 2 in 5.6% in the Isa-Kd group and 4.1% in the Kd group, and 3 in 0.6% in the Isa-Kd group and 0% in the Kd group. The proportion of patients with renal impairment (eGFR< 60 mL/min/1.73 m²) was 24.0% in the Isa-Kd group versus 14.6% in the Kd group. The International Staging System (ISS) stage at study entry was I in 53.0%, II in 31.1%, and III in 15.2% of patients. The Revised-ISS (R-ISS) stage at study entry was I in 25.8%, II in 59.6%, and III in 7.9% of patients. Overall, 24.2% of patients had high-risk chromosomal abnormalities at study entry; del(17p), t(4;14), t(14;16) were present in 11.3%, 13.9% and 2.0% of patients, respectively. In addition, gain(1q21) was present in 42.1% of patients.

The median number of prior lines of therapy was 2 (range 1 – 4) with 44.4% of patients who received 1 prior line of therapy. Overall, 89.7% of patients received prior proteasome inhibitors, 78.1% received prior immunomodulators (including 43.4% who received prior lenalidomide), and 61.3% received prior stem cell transplantation. Overall, 33.1% of patients were refractory to prior proteasome inhibitors, 45.0% were refractory to prior immunomodulators (including 32.8% refractory to lenalidomide), and 20.5% were refractory to both a proteasome inhibitor and an immunomodulator.

The median duration of treatment was 80.0 weeks for the Isa-Kd group compared to 61.4 weeks for the Kd group.

Progression-free survival (PFS) was the primary efficacy endpoint of IKEMA. With a median follow-up time of 20.73 months, the primary analysis of PFS showed a statistically significant improvement in PFS represented by a 46.9% reduction in the risk of disease progression or death in patients treated with Isa-Kd compared to patients treated with Kd.

Efficacy results are presented in Table 13 and Kaplan-Meier curves for PFS and OS are provided in the Figures 3 and 4:

Table 13: Efficacy of isatuximab in combination with carfilzomib and dexamethasone versus carfilzomib and dexamethasone in the treatment of multiple myeloma (intent-to-treat analysis)

^a PFS results were assessed by an Independent Response Committee based on central laboratory data for M-protein and central radiologic imaging review using the International Myeloma Working Group (IMWG) criteria.

^b Stratified on number of previous lines of therapy (1 versus > 1) and R-ISS (I or II versus III versus not classified) according to IRT.

^c sCR, CR, VGPR, and PR were evaluated by the IRC using the IMWG response criteria.

^d Estimated using Clopper-Pearson method.

^e Nominal p-value.

^f CR to be tested with final analysis.

^g Based on a sensitivity level of 10^-5 by NGS in ITT population.

^h Based on Responders in the ITT population. Kaplan-Meier estimates of duration of response.

ⁱ CI for Kaplan-Meier estimates are calculated with log-log transformation of survival function and methods of Brookmeyer and Crowley.

* Cut-off date of 7 February 2020. Median follow-up time = 20.73 months. HR <1 favours Isa-Kd arm.

NR: not reached.

PFS improvements in the Isa-Kd group were observed in patients with high -risk cytogenetics (central laboratory assessment, HR = 0.724; 95% CI: 0.361 to 1.451), with gain (1q21) chromosomal abnormality (HR = 0.569; 95% CI: 0.330 to 0.981), ≥ 65 years (HR = 0.429; 95% CI: 0.248 to 0.742), with baseline eGFR (MDRD) < 60 mL/min/1.73 m² (HR = 0.273; 95% CI: 0.113 to 0.660), with >1 prior line of therapy (HR = 0.479; 95% CI: 0.294 to 0.778), with ISS stage III at study entry (HR = 0.650; 95% CI: 0.295 to 1.434), and in patients refractory to prior therapy with lenalidomide (HR = 0.598; 95% CI: 0.339 to 1.055).

In the sensitivity analysis without censoring for further anti-myeloma therapy, the median PFS was not reached (NR) in the Isa-Kd group versus 19.0 months (95% CI: 15.38 to NR) in the Kd group (HR = 0.572; 99% CI: 0.354 to 0.925, p = 0.0025).

Insufficient data is available to conclude on the efficacy of Isa-Kd in patients previously treated with daratumumab (1 patient in the isatuximab arm and no patient in the comparator arm).

The median time to first response was 1.08 months in the Isa-Kd group and 1.12 months in the Kd group. The median time to next anti-myeloma treatment was 43.99 months in the Isa-Kd group and 25.00 months in the Kd group (HR = 0.583; 95% CI: 0.429 to 0.792).

Figure 3: Kaplan-Meier Curves of PFS – ITT population – IKEMA (assessment by the IRC)

Cut-off date = 07 February 2020.

Figure 4: Kaplan-Meier Curves of OS – ITT population – IKEMA

Cut-off date = 07 February 2023

Among patients with eGFR (MDRD) <50 mL/min/1.73 m² at baseline, complete renal response (≥60 mL/min/1.73 m² at ≥1 postbaseline assessment) was observed for 52.0% (13/25) of patients in the Isa-Kd group and 30.8% (4/13) in the Kd group. Sustained complete renal response (≥60 days) occurred in 32.0% (8/25) of patients in the Isa-Kd group and in 7.7% (1/13) in the Kd group. In the 4 patients in the Isa-Kd group and the 3 patients in the Kd group with severe renal impairment at baseline (eGFR (MDRD) >15 to <30 mL/min/1.73 m²), minimal renal response (≥30 to <60 mL/min/1.73 m² at ≥1 postbaseline assessment) was observed for 100% of patients in the Isa-Kd group and 33.3% of patients in the Kd group.

At a median follow-up time of 43.96 months, final PFS analysis showed a median PFS of 35.65 months for Isa-Kd group compared to 19.15 months for Kd group, with a hazard ratio of 0.576 (95.4% CI: 0.418 to 0.792). Final complete response, determined using a validated isatuximab-specific IFE assay (Sebia Hydrashift) (see section 4.5), was 44.1% in Isa-Kd group compared to 28.5% in Kd group, with odds ratio 2.094 (95% CI: 1.259 to 3.482, descriptive p = 0.0021). In 26.3% of patients in Isa-Kd group, both MRD negativity and CR were met compared to 12.2% in Kd group, with odds ratio 2.571 (95% CI: 1.354 to 4.882, descriptive p = 0.0015).

At a median follow-up time of 56.61 months, median overall survival was not reached in the Isa-Kd group (95% CI: 52.172 to NR) and was 50.60 months in Kd group (95% CI: 38.932 to NR) (HR = 0.855; 95% CI: 0.608 to 1.202).

Newly diagnosed multiple myeloma

IMROZ (EFC12522, Isa-IV + VRd vs VRd)

The efficacy and safety of isatuximab in combination with bortezomib, lenalidomide, and dexamethasone were evaluated in IMROZ (EFC12522), a multicentre, international, randomized, open-label, 2-arm, phase III study in patients with newly diagnosed multiple myeloma (NDMM) who are not eligible for stem cell transplantation. Patients over the age of 80 years were excluded, as well as patients with comorbidities that do not allow transplant procedures in patients with NDMM, based on investigator's medical assessment (e.g., lung or coronary heart disease).

A total of 446 patients were randomized in a 3:2 ratio to receive either isatuximab in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd, 265 patients) or bortezomib, lenalidomide, and dexamethasone (VRd, 181 patients) administered in both groups during 4 cycles of 42-day for the induction period. After completion of cycle 4, patients entered the continuous treatment period starting from cycle 5, 28-day cycles administered up to disease progression or unacceptable toxicity. During the continuous treatment period, patients of the Isa-VRd group received isatuximab in combination with lenalidomide, and dexamethasone (Isa-Rd), and patients in the VRd group received lenalidomide, and dexamethasone (Rd).

During the induction period (cycle 1 to 4, 42-day cycles), isatuximab 10 mg/kg was administered as an I.V. infusion on day 1, 8, 15, 22, and 29, in the first cycle and on day 1, 15, and 29, from cycle 2 to 4. Bortezomib was administered subcutaneously at the dose of 1.3 mg/m² on days 1, 4, 8, 11, 22, 25, 29, and 32 of each cycle. Lenalidomide was administered per os at the dose of 25 mg/day from day 1 to 14 and from day 22 to 35 of each cycle. Dexamethasone (I.V. on the days of isatuximab infusions, and PO on the other days) 20 mg/day was given on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 of each cycle, and administered on days 1, 4, 8, 11, 15, 22, 25, 29, and 32 of each cycle for patients ≥75 years old.

During the continuous treatment period (from cycle 5, 28-day cycles), isatuximab 10 mg/kg was administered as an I.V. infusion on day 1 and 15 from cycle 5 to 17, and on day 1 from cycle 18. Lenalidomide was administered per os at the dose of 25 mg/day from day 1 to 21 of each cycle. Dexamethasone (I.V. on the days of isatuximab infusions, and PO on the other days) 20 mg/day was given on days 1, 8, 15, and 22 of each cycle.

Overall, demographic and disease characteristics at baseline were similar between the two treatment groups. The median patient age was 72 years (range 60 ‒ 80), 26% of patients were ≥75 years. ECOG PS was 0 in 46.4% of patients in the Isa-VRd group and 43.6% in the VRd group, 1 in 42.3% in the Isa-VRd group and 45.9% in the VRd group, and 2 in 10.9% in the Isa-VRd group and 10.5% in the VRd group, and 3 in 0.4% in the Isa-VRd group and 0% in the VRd group. The proportion of patients with renal impairment (eGFR<60 mL/min/1.73m²) was 24.9% in the Isa-VRd group versus 34.3% in the VRd group. The Revised International Staging System (R-ISS) stage at study entry was I in 24.9%, II in 61.5%, and III in 10.2% of patients. Overall, 15.1% of patients had high-risk chromosomal abnormalities at study entry; del(17p), t(4;14), and t(14;16) were present in 5.7%, 7.9% and 1.9% of patients, respectively. In addition, 1q21+ was present in 35.8% of patients.

The median duration of treatment was 53.2 months for the Isa-VRd group compared to 31.3 months for the VRd group.

Progression-free survival (PFS) was the primary efficacy endpoint of IMROZ. With a median follow-up time of 59.73 months, the pre-planned second interim analysis of PFS showed a statistically significant improvement in PFS representing a 40.4% reduction in the risk of disease progression or death in patients treated with Isa-VRd compared to patients treated with VRd.

Efficacy results are presented in Table 14 and Kaplan-Meier curves for PFS are provided in Figure 5:

Table 14 *: Efficacy of isatuximab in combination with bortezomib, lenalidomide, and dexamethasone versus bortezomib, lenalidomide, and dexamethasone in the treatment of newly diagnosed multiple myeloma, transplant ineligible patients (intent-to-treat analysis)

^a PFS results were assessed by an Independent Response Committee based on central laboratory data for M-protein and central radiologic imaging review using the International Myeloma Working Group (IMWG) criteria.

^b Stratified by age (<70 years vs ≥70 years) and Revised International Staging System (R-ISS) stage (I or II vs. III or not classified) according to IRT

^c Estimated using Clopper-Pearson method.

^d Based on a sensitivity level of 10^-5 by NGS in ITT population.

^e sCR, CR, VGPR, and PR were evaluated by the IRC using the IMWG response criteria. Results should be interpreted descriptively.

* Cut-off date of 26 September 2023. Median follow-up time = 59.73 months.

NR: not reached

PFS improvement in the Isa-VRd group was confirmed by the sensitivity analyses and was observed across most subgroups of patients, including patients with 1q21+ chromosomal abnormality (HR = 0.407; 95% CI: 0.253 to 0.653), ≥70 years (HR = 0.671; 95% CI: 0.463 to 0.972), with baseline eGFR (MDRD) <60 mL/min/1.73 m² (HR = 0.63; 95% CI: 0.371 to 1.068), and with ECOG PS>1 (HR = 0.606; 95% CI: (0.246 to 1.493).

NGS MRD negativity (10^-5 sensitivity threshold) was reached in 58.1% of patients in the Isa-VRd group with a median time to first NGS MRD negativity of 196.5 days (range: 87-1834). In the VRd group, NGS MRD negativity (10^-5 sensitivity threshold) was reached in 43.6% of patients with a median time to first NGS MRD negativity of 197.0 days (range: 107 ‒ 1512). Sustained NGS MRD negativity rate for at least 12 months occurred in 46.8% of patients in the Isa-VRd group and in 24.3% in the VRd group.

The median time to progression was not reached in the Isa-VRd group and was 59.70 months (95% CI: 48.164 to NR) in the VRd group (HR = 0.414; 95% CI: 0.286 to 0.598). The median duration of response was not reached in the Isa-VRd group and was 58.25 months (95% CI: 44.583 to NR) in the VRd group. The median time to first response was 1.51 months in the Isa-VRd group and 1.48 months in the VRd group. In the Isa-VRd group, 52.1% of patients discontinued the study treatment, 14.3% due to disease progression. In the VRd group, 75.7% of patients discontinued the study treatment, 37% due to disease progression. The median time to next anti-myeloma treatment was not reached in the Isa-VRd group and was 63.57 months in the VRd group (HR = 0.376; 95% CI: 0.265 to 0.534). Median overall survival was not reached for either treatment group. Based on the descriptive analysis of overall survival data, 26% of patients in the Isa-VRd group and 32.6% of patients in the VRd group had died (HR = 0.776; 99.97% CI: 0.407 to 1.48).

Figure 5: Kaplan-Meier Curves of PFS – ITT population – IMROZ (assessment by the IRC)

Cut-off date = 26-September-2023.

GMMG-HD7 (IIT15403, Isa-IV +VRd vs VRd)

The efficacy and safety of isatuximab in combination with bortezomib, lenalidomide, and dexamethasone were evaluated in GMMG-HD7, a prospective, randomized, open-label, 2-arm, phase III study performed by the German-Speaking Myeloma Multicenter Group (GMMG), in patients with newly diagnosed multiple myeloma who are eligible for stem cell transplantation. Patient eligibility for ASCT was mainly assessed based on the patients age (≤70 years old) or comorbidities which could prevent the patient from receiving high dose therapies with autologous transplant. The study was conducted in 2 Parts; Part 1 includes induction and intensification treatments, and Part 2 is the maintenance treatment (ongoing phase). The results from Part 1 are described.

A total of 662 patients were randomized in a 1:1 ratio to receive either isatuximab in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd, 331 patients) or bortezomib, lenalidomide, and dexamethasone (VRd, 331 patients), administered in both groups during 3 cycles (cycles 1 to 3) of 42 days each for the induction treatment. After cycle 3, patients were given a standard intensification treatment including ASCT. ASCT was repeated 2 ‒ 3 months after initial ASCT in patients with no CR or in high-risk patients. In Part 2, prior to the start of the maintenance treatment, patients were randomized again in a 1:1 ratio to receive either isatuximab in combination with lenalidomide or lenalidomide alone. Maintenance treatment is administered with 28-day cycles for a maximum of 3 years until disease progression or unacceptable toxicity, whichever occurred first. In both treatment arms, patients received dexamethasone for the first maintenance cycle only.

During the induction period, isatuximab 10 mg/kg was administered as an IV infusion on days 1, 8, 15, 22, and 29, in cycle 1, and on days 1, 15, and 29, from cycles 2 to 3. Bortezomib was administered subcutaneously at the dose of 1.3 mg/m² on days 1, 4, 8, 11, 22, 25, 29, and 32 of each cycle. Lenalidomide was administered orally at the dose of 25 mg/day from days 1 to 14 and from days 22 to 35 of each cycle. Dexamethasone (IV on the days of isatuximab infusions, and orally on the other days) 20 mg/day was given on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 of each cycle.

Overall, demographic and disease characteristics at baseline were similar between the treatment groups (Isa-VRd versus VRd). The median patient age was 59.5 years (range 26 ‒ 70), 23.9% of patients were ≥65 years. The proportion of patients with renal impairment (eGFR<60 mL/min/1.73m²) was 19.7% in the Isa-VRd group versus 17.7% in the VRd group. The International Staging System (ISS) stage at study entry was I in 41.4%, II in 36.9%, and III in 21.8% of patients. The Revised International Staging System (R-ISS) stage at study entry was I in 26.6%, II in 61%, and III in 8% of patients. Overall, 18.7% of patients had high-risk chromosomal abnormalities at study entry; del(17p), t(4;14), and t(14;16) were present in 8.9%, 10.1% and 2.6% of patients, respectively. In addition, 1q21+ was present in 32.9% of patients.

The median duration of induction treatment was 18 weeks for the Isa-VRd and VRd groups. The median duration of Part 1 (induction and intensification treatments) was 45.4 weeks for the Isa-VRd group and 45.1 weeks for the VRd group.

Minimal residual disease (MRD) negativity rate after induction treatment, the primary efficacy endpoint of GMMG-HD7, was 50.5% (95% CI: 44.9% to 56%) in Isa-VRd arm versus 35.6% (95% CI: 30.5% to 41.1%) in the VRd arm (odds ratio: 1.838, 95% CI: 1.346 to 2.511, p-value: 0.0001). Results showed an improvement in MRD negativity rate (NGF at 10^-5 sensitivity level), representing a 14.8% increase in the Isa-VRd arm compared to the VRd arm after induction treatment.

With a median follow-up time of 49.31 months, the analysis of PFS from the 1^st randomization showed a statistically significant improvement with a 35.7% reduction in the risk of disease progression or death in patients treated with Isa-VRd compared to patients treated with VRd during induction followed by ASCT and lenalidomide maintenance treatment (HR = 0.643; 95% CI: 0.456 to 0.907).

Efficacy results are presented in Table 15 and Kaplan-Meier curves for PFS are provided in Figure 6

Table 15: Efficacy of isatuximab in combination with bortezomib, lenalidomide, and dexamethasone versus bortezomib, lenalidomide, and dexamethasone in the treatment of newly diagnosed multiple myeloma, transplant eligible patients (intent-to-treat analysis)

^a Two-sided significance level is 0.028

^b Stratified on R-ISS (I or II vs III vs Not classified) according to IRT.

CR at the end of induction was 24.8% (95% CI: 20.2% to 29.8%) in the Isa-VRd group versus 22.1% (95% CI: 17.7% to 26.9%) in the VRd group. CR at end of intensification was 46.5% (95% CI: 41.1% to 52.1%) in the Isa-VRd group versus 37.2% (95% CI: 31.9% to 42.6%) in the VRd group.

In 18.7% of patients in the Isa-VRd group, both NGF MRD negativity (10^-5 sensitivity threshold) and CR were met at the end of induction compared to 14.5% in the VRd group. In 40.5% of patients in the Isa-VRd group, both NGF MRD negativity (10^-5 sensitivity threshold) and CR were met at the end of intensification compared to 26.6% in the VRd group.

During the induction period, 5.4% of patients discontinued the study treatment in the Isa-VRd group and 10.6% of patients in the VRd group.

With a median follow-up time of 49.31 months, 14.8% patients in the Isa-VRd arm and 12.7% patients in the VRd arm had died.

Figure 6: Kaplan-Meier Curves of PFS – ITT population – GMMG-HD7

Cut-off date = 31 January 2024

Paediatric population

The Medicines and Healthcare products Regulatory Agency (MHRA) has waived the obligation to submit the results of studies with isatuximab subcutaneous in one or more subsets of the paediatric population in the treatment of malignant neoplasms of the haematopoietic and lymphoid tissue (see section 4.2 for information on paediatric use).

Subcutaneous formulation

No dedicated studies with subcutaneous isatuximab have been conducted in paediatric patients.

Intravenous formulation

A phase 2, single-arm, study in 67 paediatric patients was conducted in 3 separate disease cohorts. Fifty-nine patients with relapsed or refractory T-acute lymphoblastic leukaemia (T-ALL, 11 patients), B-acute lymphoblastic leukaemia (B-ALL, 25 patients), and acute myeloid leukaemia (AML, 23 patients) were evaluable for efficacy. For patients with T-ALL and B-ALL, the treatment consisted of one induction cycle and one consolidation cycle. For patients with AML, the treatment consisted of up to two induction cycles. The median age was 8 years (range 17 months to 17 years). Patients were treated with isatuximab intravenous in combination with standard chemotherapies (e.g., antimetabolites, anthracyclines, and alkylating agents). At interim analysis, complete response rate (the primary efficacy endpoint, defined as complete response, CR, or complete response with incomplete peripheral recovery, CRi), did not meet the pre-specified statistical threshold in the 3 cohorts with 52.0% of B-ALL patients, 45.5% of T-ALL patients, and 60.9% of AML patients reaching complete response (CR+CRi). The study was stopped after the prespecified interim analysis.

In IRAKLIA pivotal study, isatuximab was administered subcutaneously as a flat dose of 1400 mg with the same schedule of administration as isatuximab 10 mg/kg administered intravenously, every week for 4 weeks followed by every 2 weeks. The median time to reach steady state was 22 weeks (Cycle 6) with 4.87-fold accumulation for C_trough. The mean predicted C_max (CV%) and AUC_2weeks at steady state (Cycle 6) were 594 µg/mL (45.7%) and 188,000◦µg.h/mL, respectively.

In 121 pharmacokinetics-evaluable patients in the isatuximab-SC arm, the results for the co-primary pharmacokinetic endpoint, C_trough at steady state (pre-dose at Cycle 6 day 1), showed non-inferiority of isatuximab subcutaneous 1400 mg compared to isatuximab intravenous 10 mg/kg, with a geometric mean ratio (GMR) for C_trough of 1.53 (90% CI: 1.32 ‒1.78). Also, C_trough at 4 weeks (pre-dose at Cycle 2 day 1) showed non-inferiority of subcutaneous isatuximab compared to intravenous isatuximab with a GMR of 1.30 (90% CI: 1.16 ‒ 1.47).

Interactions with concomitant medication

The pharmacokinetics of subcutaneous isatuximab, and concomitant pomalidomide, carfilzomib, bortezomib and lenalidomide are not expected to be influenced by their co-administration, as it was shown with intravenous isatuximab.

Absorption

Following subcutaneous administration, isatuximab absolute bioavailability is 75.9% with a median time to reach maximum concentration (T_max) of approximately 4 days.

Distribution

Based on the population pharmacokinetic analysis, the total volume of distribution is 5.68 L.

Metabolism

As a large protein, isatuximab is expected to be metabolized by non-saturable proteolytic catabolism processes.

Elimination

Isatuximab is eliminated by two parallel pathways, a nonlinear target-mediated pathway predominating at low concentrations, and a nonspecific linear pathway predominating at higher concentrations. In the therapeutic plasma concentrations range, the linear pathway is predominant. Isatuximab clearance decreases over time by 60% to a steady state value of 4.45 mL/h (0.107 L/day). This is associated with a terminal half-life of 40 days.

Specific populations

Age

Age had no effect on the pharmacokinetics of subcutaneous isatuximab based on the population PK analysis with 769 patients aged 31 to 86 years (17.8% of patients ≥75 years old).

Gender

The population pharmacokinetic analysis with 345 female (44.0%) and 424 male (55.1%) patients showed no clinically meaningful effect of gender on the pharmacokinetics of isatuximab.

Race

The race (Caucasian 66.4%, Asian 15.2%, Black 2.6%, other races 1.7%) had no effect on isatuximab pharmacokinetics.

Weight

The flat-dose administration of isatuximab 1400 mg subcutaneous formulation achieved adequate exposure for all body weight subgroups (18 patients below 50 kg, 91 patients below 65 kg, 68 patients above 85 kg, and 23 patients above 100 kg). A limited number of patients with a body weight >120 kg were included in the studies.

At steady state, the mean predicted Ctrough and AUC were 44% and 41% lower in the body weight group >100 kg (but still overlapping with exposures after 10 mg/kg of isatuximab IV administration in patients ≤50 kg), while the mean Ctrough and AUC were 24% and 26% higher in the body weight group ≤50 kg, compared to the patients with body weight of 51 kg –100 kg after subcutaneous administration, respectively.

The pharmacokinetic differences were not clinically relevant across body weight categories.

Hepatic impairment

No formal studies of isatuximab in patients with hepatic impairment have been conducted. Among the 769 patients included in the population PK analysis, 95 patients had mild hepatic impairment (total bilirubin 1.0 to 1.5 times upper limit of normal [ULN] or AST >ULN), and 7 patients had moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST). Mild hepatic impairment had no meaningful effect on the pharmacokinetics of subcutaneous isatuximab. The effect of moderate (total bilirubin >1.5 times to 3 times ULN and any AST) and severe hepatic impairment (total bilirubin >3 times ULN and any AST) on subcutaneous isatuximab pharmacokinetics is unknown.

However, since isatuximab is a monoclonal antibody, it is not expected to be cleared via hepatic-enzyme mediated metabolism and as such, variation in hepatic function is not expected to affect the elimination of isatuximab (see section 4.2).

Renal impairment

No formal studies of isatuximab in patients with renal impairment have been conducted.

The population pharmacokinetic analyses on 769 patients included 380 patients with mild renal impairment (eGFR ≥60 ‒ <90 mL/min/1.73 m²), 187 patients with moderate renal impairment (eGFR ≥30 ‒ <60 mL/min/1.73 m²) and 8 patients with severe renal impairment (eGFR <30 mL/min/1.73 m²).

For the intravenous formulation, a pharmacokinetics analysis on 22 patients with End-Stage Renal Disease (ESRD) including patients on dialysis (eGFR <15 mL/min/1.73 m²) showed no clinically meaningful effects of ESRD on isatuximab intravenous pharmacokinetics compared to those of normal, mild, or moderate renal function. No dose adjustment of isatuximab is needed in patients with mild, moderate, severe, or end-stage renal impaired function.

Analyses suggested no meaningful effect of mild to severe renal impairment, including ESRD, on isatuximab pharmacokinetics compared to normal renal function.

Paediatric population

Subcutaneous formulation

No dedicated studies with subcutaneous isatuximab have been conducted in paediatric patients.

Intravenous formulation

In the paediatric patient population (from 17 months to 17 years old), after the first intravenous isatuximab administration, among the 3 cohorts, the mean C_max ranged from 322 to 433 µg/mL, mean AUC_1week from 28,592 to 31,703 µg.h/mL, and after repeated intravenous isatuximab administrations over 3 weeks, cumulative mean AUC ranged from 130,862 to 148,397 µg.h/mL. Pharmacokinetics data reported in paediatric population with AML and ALL were consistent with those from adults with ALL and MM at the same intravenous isatuximab dose.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, albeit the species selected is not pharmacologically responsive and therefore the relevance for humans is not known. Genotoxicity, carcinogenic potential and toxicity to reproduction and development studies have not been performed.

Arginine hydrochloride

Histidine

Histidine hydrochloride monohydrate

Poloxamer 188

Sucrose

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Unopened vial

3 years

After vial opening (for use with the CirCLIQ OBDS device or for manual administration with a syringe)

Chemical and physical in-use stability of Sarclisa solution for subcutaneous injection has been demonstrated for 4 hours (including the injection time) at room temperature (15°C to 25°C) and ambient light.

After insertion of the vial in CirCLIQ OBDS device

Once the vial is punctured, the injection with CirCLIQ On-Body Injector should be performed as soon as possible. CirCLIQ On-Body Injector should be used at temperature 18°C to 28°C and ambient light. If the injection is not completed within 4 hours, discard the vial and the On-Body Delivery System.

After transfer of the solution to the syringe for manual administration

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of user. The syringe can be stored for up to 4 hours at 15°C to 25°C and ambient light, including the administration time. Discard after 4 hours, if not used.

Store in a refrigerator (2°C ‒ 8°C).

Unpunctured vials may be stored at room temperature (≤30 °C) for a single period of up to 24 hours. Once the vial has been taken out of the refrigerator, it must not be returned to the refrigerator (see section 6.6).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after insertion of the vial in CirCLIQ OBDS or of the solution in the syringe for manual administration, see section 6.3.

For storage conditions of the OBDS, please refer to CirCLIQ OBDS Instructions for Use.

10 mL of solution for subcutaneous injection containing 1400 mg of isatuximab in a 20 mL type I colourless clear glass vial closed with an ETFE (copolymer of ethylene and tetrafluoroethylene)-coated bromobutyl stopper. The vials are crimped with an aluminium seal with a green flip-off cap. The fill volume has been established to ensure removal of 10 mL (i.e. 10.77 mL). Pack size of one vial.

CirCLIQ On-Body Delivery System (OBDS) is packaged separately from Sarclisa 1400 mg solution for subcutaneous injection.

Preparation of the subcutaneous administration

Sarclisa should be administered by a healthcare professional.

• To prevent medication errors, check Sarclisa subcutaneous vial label to ensure it is the correct medication for subcutaneous use (vial with green cap). Do not administer Sarclisa 1400 mg solution for subcutaneous injection intravenously.

Sarclisa subcutaneous is ready to use.

Prepare and administer Sarclisa 1400 mg subcutaneously using clean technique.

• Prior to use‚ allow Sarclisa subcutaneous vial to reach room temperature for approximately 20 minutes to minimize pain during the injection. Keep the unpunctured vial in the original carton prior to use to protect from light. Do not heat. Do not shake.

Vials of Sarclisa subcutaneous should be visually inspected before use. The solution may contain a few translucent to white particles. Sarclisa subcutaneous should not be used if the solution is cloudy or discoloured, or if particles other than those described above are present.

Sarclisa subcutaneous is only for abdominal subcutaneous administration using:

• CirCLIQ On-Body Delivery System (OBDS)

OR

• 20 mL syringe and infusion set for manual administration

Preparation with CirCLIQ On-Body Delivery System

• Refer to the Instructions for Use for CirCLIQ OBDS provided with the device for full preparation and administration information.

• Once the vial is punctured, the injection with CirCLIQ OBDS On-Body Injector should be performed as soon as possible. CirCLIQ On-Body Injector should be used at temperature 18°C to 28°C and ambient light. If the injection is not completed within 4 hours, discard the vial and the On-Body Delivery System.

Preparation with syringe and infusion set for manual administration

1. Before you begin, collect your supplies:

• The syringe must be a 20 mL polypropylene syringe with Luer-fitting connector.

• The transfer needle must be made of 18G stainless steel with 5-micron filter and Luer-fitting connector.

• The subcutaneous infusion set must have 23G stainless steel needle and tubing up to 30 cm length made of polyethylene, or polyvinyl chloride, with a Luer-fitting connector.

Suitability of above materials for injection of Sarclisa subcutaneous was demonstrated in compatibility testing and clinical studies.

2. Check the expiration date

3. Remove green vial cap and wipe vial rubber stopper with an alcohol wipe and allow to air dry.

4. Attach the transfer needle and fill the syringe.

• Using the transfer needle, withdraw the full content of the Sarclisa subcutaneous vial into a 20 mL compatible syringe.

Note: if the syringe containing Sarclisa subcutaneous is not used immediately:

 o replace the transfer needle with a syringe closing cap. Label the syringe appropriately to include the drug name and route of administration per institutional standards.

 o store it for up to 4 hours at room temperature (15°C to 25°C) and ambient light, including the administration time. Discard after 4 hours, if not used.

5. Attach the subcutaneous infusion set to the syringe and set the dose.

• Prime the syringe and subcutaneous infusion set and set the dose to 10 mL.

Note: To avoid needle clogging, attach the subcutaneous infusion set to the syringe immediately prior to injection.

Administration

• Sarclisa 1400 mg is only for abdominal subcutaneous administration. Data are only available with an injection performed into the abdomen.

• Rotate the site of each subcutaneous administration.

• Do not inject other medications in the area where isatuximab subcutaneous is injected.

• Do not inject into areas where the skin is injured, tender, red, hot, has scars, or is excessively hairy.

Administration with CirCLIQ On-Body Delivery System

• Refer to the Instructions for Use for CirCLIQ OBDS provided with the device for full preparation and administration information.

Administration with syringe and infusion set for manual administration

Prepare injection site and insert needle.

• Wipe injection site with an alcohol swab and allow it to dry

• Avoid injecting within 5 cm around the belly button. Remove protective needle cover

• Pinch skin at the injection site on the abdomen. It is important to pinch enough skin to inject under the skin and not into the muscle.

• Insert needle at a 45-degree angle with a quick, dart-like motion.

Note: Try to limit needle and syringe movement during the injection. If needed, secure the subcutaneous infusion set in place with a bandage.

Inject 10 mL of Sarclisa 1400 mg subcutaneously into the abdomen, over approximately 6 minutes.

Pause or slow down delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.

Disposal

Any unused portion of solution should be discarded. All materials that have been utilized for the preparation and administration should be disposed of according to standard procedures