Isatuximab

SARCLISA 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.

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.

SARCLISA should be administered by a healthcare professional, in an environment where resuscitation facilities are available. Pre-medication Prevention of infusion reaction Pre-medication should be used prior to SARCLISA infusion with the following medicinal products to reduce the risk and severity of infusion reactions: • Dexamethasone 40 mg oral or intravenous (or 20 mg oral or intravenous for patients ≥75 years of age): when administered in combination with isatuximab and pomalidomide.

• Dexamethasone 20 mg (intravenous on the days of isatuximab and/or carfilzomib infusions, and oral on the other days): when administered in combination with isatuximab and carfilzomib. • Dexamethasone 20 mg (intravenous on the days of isatuximab infusion, and oral on the other days): when administered in combination with isatuximab, bortezomib, and lenalidomide.

• Montelukast 10 mg oral (or equivalent), at least at cycle 1. • Acetaminophen 650 mg to 1000 mg oral (or equivalent). g. g. omeprazole, esomeprazole). , cetirizine, promethazine, dexchlorpheniramine]). The intravenous use is preferred for at least the first 4 infusions.

The above recommended dose of dexamethasone (oral or intravenous) corresponds to the total dose to be administered only once before the infusion, as part of the premedication and 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 a SARCLISA infusion. Patients who do not experience an infusion reaction upon their first 4 administrations of SARCLISA may have their need for subsequent premedication reconsidered.

g. G-CSF) should be considered to mitigate the risk of neutropenia. 4). 4). Posology The recommended dose of SARCLISA is 10 mg/kg body weight administered as an intravenous infusion in combination with pomalidomide and dexamethasone (Isa-Pd) or in combination with carfilzomib and dexamethasone (Isa-Kd), or in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd).

SARCLISA dosing schedules are provided in Tables 1, 2 and 3.

Table 1:

SARCLISA dosing schedule in combination with pomalidomide and dexamethasone or in combination with carfilzomib and dexamethasone Cycles Dosing schedule Cycle 1 (28-day cycle) Days 1, 8, 15 and 22 (weekly) Cycle 2 and beyond (28-day cycles) Days 1, 15 (every 2 weeks) Each treatment cycle consists of a 28-day period.

Treatment is repeated until disease progression or unacceptable toxicity.

Table 2:

SARCLISA 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) (IMROZ) Cycles Dosing schedule Cycle 1 (42-day cycle) Days 1, 8, 15, 22, and 29 Cycles 2 to 4 (42-day cycles) Days 1, 15, and 29 (every 2 weeks) Cycles 5 to 17 (28-day cycles) Days 1 and 15 (every 2 weeks) Cycles 18 and beyond (28-day cycles) Days 1 (every 4 weeks) 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:

SARCLISA dosing schedule in combination with bortezomib, lenalidomide, and dexamethasone for patients with NDMM who are eligible for ASCT (GMMG-HD7) Cycles Dosing schedule Induction treatment Cycle 1 (42-day cycle) Days 1, 8, 15, 22 and 29 Cycles 2 to 3 (42-day cycles) Days 1, 15 and 29 (every 2 weeks) Stop for intensification treatment (high dose chemotherapy and ASCT) followed by SOC maintenance treatment Each treatment cycle consists of a 42-day period.

1 and the respective current summary of product characteristics. Missed dose The administration schedule must be carefully followed. If a planned dose of SARCLISA is missed, administer the dose as soon as possible and adjust the treatment schedule accordingly, maintaining the treatment interval.

Dose adjustments No dose reduction of SARCLISA is recommended. Administration adjustments should be made if patients experience infusion reactions (see “Method of administration” below), or in case of Grade 3 or 4 neutropenia, or febrile neutropenia and/or neutropenic infection (see “Management of neutropenia” above).

For other medicinal products that are administered with SARCLISA, the respective current summary of product characteristics should be considered. Special populations Elderly Based on population pharmacokinetic analysis, no dose adjustment is recommended in elderly patients.

2). 5 times upper limit of normal (ULN) or aspartate amino transferase (AST) >ULN). 5 to 3 times ULN and any AST) and severe (total bilirubin >3 […]

7%). 8% of patients receiving Isa-Pd. 6%). 2% of patients treated with Isa-Pd. 0% of patients). 0%). 3% of patients receiving Isa-Kd. 5%). 5% of patients treated with Isa-Kd. 1% of patients). 1%). 7% of patients receiving Isa-VRd. 7%, including Covid-19 pneumonia).

5% of patients. 8% of patients treated with Isa-VRd. 4%). 2% of patients receiving Isa-VRd. 1%). 3% of patients). Permanent discontinuation of treatment because of adverse reactions was reported in 3% of patients treated with Isa- VRd. Tabulated list of adverse reactions Adverse reactions are described using the NCI Common Toxicity Criteria, the COSTART and the MedDRA terms.

Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

1) and post-market settings. 0% a The term pneumonia is a grouping of the following terms: atypical pneumonia, bronchopulmonary aspergillosis, pneumonia, pneumonia haemophilus, pneumonia influenza, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, pneumonia bacterial, haemophilus infection, lung infection, pneumonia fungal and pneumocystis jirovecii pneumonia.

b See “Description of selected adverse reactions”. c Based on second primary malignancies reported during study treatment period and during post- treatment period. d Based on post-marketing experience, anaphylactic reactions including fatal cases have been reported.

9% Upper […]

1.

and 7 WARNINGS and PRECAUTIONS, General). 3 Pharmacokinetics, Geriatrics). No dose adjustment is recommended in patients with mild hepatic impairment. 3 Pharmacokinetics, Hepatic Insufficiency). 3 Pharmacokinetics, Renal Insufficiency).

SARCLISA (isatuximab for injection) Page 8 of 54 Internal Temporary interruption or definitive discontinuation of Sarclisa treatment may be required for infusion-related reactions (IRRs) or neutropenia; no dose reduction of Sarclisa is recommended (Table 3).

03 criteria definition Administration adjustment Infusion-related reactions (IRRs) Mild (Grade 1): Infusion interruption or intervention not indicated • Continue Sarclisa infusion per the judgment of the physician with close direct monitoring of the patient’s clinical status.

• Sarclisa infusion may be stopped at any time if deemed necessary. , antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated for ≤24 hours • Stop Sarclisa infusion. • Give additional medication with diphenhydramine 25 mg IV (or equivalent) and/or IV methylprednisolone 100 mg (or equivalent) as needed.

• If symptoms improve to Grade ≤1, 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 4.

• If symptoms do not resolve rapidly or do not improve to Grade ≤1 after interruption of Sarclisa infusion, persist or worsen despite appropriate medications, or require hospitalization or are life-threatening, treatment with Sarclisa should be permanently discontinued and additional supportive therapy should be administered, as needed.

, not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae Grade 4: life-threatening consequences; urgent intervention indicated • Stop Sarclisa infusion.

• Give additional medication with diphenhydramine 25 mg IV (or equivalent) and/ or IV methylprednisolone 100 mg (or equivalent) and/or epinephrine as needed. • Discontinue Sarclisa treatment. 0 x 109/L. g. G- CSF) should be considered, according to local guidelines (see 7 Warnings And Precautions).

NSAIDs: nonsteroidal anti-inflammatory drugs For dosage adjustment information concerning medicinal products given in combination with Sarclisa, consult the corresponding Product Monographs (see 17 Supporting Product Monographs). 3 Reconstitution The preparation of the infusion solution must be done under aseptic conditions.

2 Recommended Dose and Dosage Adjustment). More than one Sarclisa concentrate vial may be necessary to obtain the required dose for the patient. • Vials of Sarclisa concentrate should be visually inspected before dilution to ensure they do not contain any particles and are not discoloured.

9% sodium chloride or dextrose 5% solution. • The infusion bag must be made of polyolefins (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) with di (2-ethylhexyl) phthalate (DEHP) or ethyl vinyl acetate (EVA). • Gently mix the diluted solution by inverting the bag.

Do not shake. 4 Administration • The infusion solution must be administered by intravenous infusion using an IV tubing infusion set (in polyethylene [PE], polyvinyl chloride [PVC] with or without di (2-ethylhexyl) phthalate [DEHP], polybutadiene [PBD] or polyurethane [PU]) with an in-line filter (polyethersulfone [PES], polysulfone or nylon).

• The infusion solution should be administered for a period of time that will depend on the infusion rate (see Infusion Rates). • Prepared Sarclisa infusion solution should be used within 48 hours when stored at 2°C - 8°C, followed by 8 hours (including the infusion time) at room temperature.

• No protection from light is required for the prepared infusion bag in a standard artificial light environment. SARCLISA (isatuximab for injection) Page 10 of 54 Internal • Do not infuse Sarclisa solution concomitantly in the same intravenous line with other agents.

• On the days where both Sarclisa and carfilzomib are administered, administer dexamethasone first, followed by Sarclisa infusion, then followed by carfilzomib infusion. Infusion Rates Following dilution, the Sarclisa infusion should be administered intravenously at the infusion rates presented in Table 4 below.

Incremental escalation of the infusion rate should be considered only in the absence […]

SARCLISA 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.

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.

SARCLISA should be administered by a healthcare professional, in an environment where resuscitation facilities are available. Premedication 3 Prevention of infusion reaction Premedication should be used prior to SARCLISA infusion with the following medicinal products to reduce the risk and severity of infusion reactions: • Dexamethasone 40 mg oral or intravenous (or 20 mg oral or intravenous for patients ≥ 75 years of age): when administered in combination with isatuximab and pomalidomide, Dexamethasone 20 mg (intravenous on the days of isatuximab and/or carfilzomib infusions, and oral on the other days): when administered in combination with isatuximab and carfilzomib.

Dexamethasone 20 mg (intravenous on the days of isatuximab infusion, and oral on the other days): when administered in combination with isatuximab, bortezomib, and lenalidomide. • Montelukast 10 mg oral (or equivalent), at least at cycle 1.

• Acetaminophen 650 mg to 1 000 mg oral (or equivalent). , omeprazole, esomeprazole). , cetirizine, promethazine, dexchlorpheniramine]). The intravenous use is preferred for at least the first 4 infusions. The above recommended dose of dexamethasone (oral or intravenous) corresponds to the total dose to be administered only once before the infusion, as part of the premedication and 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 a SARCLISA infusion. Patients who do not experience an infusion reaction upon their first 4 administrations of SARCLISA may have their need for subsequent premedication reconsidered.

g. G-CSF) should be considered to mitigate the risk of neutropenia. 4). 4). Posology The recommended dose of SARCLISA is 10 mg/kg body weight administered as an intravenous infusion in combination with pomalidomide and dexamethasone (Isa-Pd) or in combination with carfilzomib and dexamethasone (Isa-Kd), or in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd).

SARCLISA dosing schedules are provided in Tables 1, 2, and 3:

Table 1: SARCLISA dosing schedule in combination with pomalidomide and dexamethasone or in combination with carfilzomib and dexamethasone Cycles Dosing schedule Cycle 1 (28-day cycle) Days 1, 8, 15 and 22 (weekly) Cycle 2 and beyond (28-day cycle) Days 1, 15 (every 2 weeks) 4 Each treatment cycle consists of a 28-day period.

Treatment is repeated until disease progression or unacceptable toxicity.

Table 2:

SARCLISA 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) (IMROZ) Cycles Dosing schedule Cycle 1 (42-day cycle) Days 1, 8, 15, 22, and 29 Cycles 2 to 4 (42-day cycles) Days 1, 15, and 29 (every 2 weeks) Cycles 5 to 17 (28-day cycles) Days 1 and 15 (every 2 weeks) Cycles 18 and beyond (28-day cycles) Days 1 (every 4 weeks) 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:

SARCLISA dosing schedule in combination with bortezomib, lenalidomide, and dexamethasone for patients with NDMM who are eligible for ASCT (GMMG-HD7) Cycles Dosing schedule Induction treatment Cycle 1 (42-day cycle) Days 1, 8, 15, 22, and 29 Cycles 2 to 3 (42-day cycles) Days 1, 15, and 29 (every 2 weeks) Stop for intensification treatment (high dose chemotherapy and ASCT) followed by SOC maintenance treatment Each treatment cycle consists of a 42-day period.

1 and the respective current summary of product characteristics. Missed dose The administration schedule must be carefully followed. If a planned dose of SARCLISA is missed, administer the dose as soon as possible and adjust the treatment schedule accordingly, maintaining the treatment interval.

Dose adjustments No dose reduction of SARCLISA is recommended. Administration adjustments should be made if patients experience infusion reactions (see “Method of administration” below), or in case of Grade 3 or 4 neutropenia, or febrile neutropenia and/or neutropenic infection (see "Management of neutropenia" above).

For other medicinal products that are administered with SARCLISA, the respective current summary of product characteristics should be considered. 5 Special populations Elderly Based on population pharmacokinetic analysis, no dose adjustment is recommended in elderly patients.

2). 5 times upper limit of normal (ULN) or aspartate amino transferase (AST) > ULN). 5 to 3 times ULN and any AST) and severe (total […]

7 %). 8 % of patients receiving Isa-Pd. 6 %). 2 % of patients treated with Isa-Pd. 0 % of patients). 0 %). 3 % of patients receiving Isa-Kd. 5 %). 5 % of patients treated with Isa-Kd. 1 % of patients). 1%). 7% of patients receiving Isa-VRd. 7%, including Covid-19 pneumonia).

5% of patients. 8% of patients treated with Isa-VRd. 4%). 2% of patients receiving Isa-VRd. 1%). 3% of patients). Permanent discontinuation of treatment because of adverse reactions was reported in 3% of patients treated with Isa-VRd. Tabulated list of adverse reactions 11 Adverse reactions are described using the NCI Common Toxicity Criteria, the COSTART and the MedDRA terms.

Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); frequency not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

1) and post-market settings. 0 % 12 a The term pneumonia is a grouping of the following terms: atypical pneumonia, bronchopulmonary aspergillosis, pneumonia, pneumonia haemophilus, pneumonia influenza, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, pneumonia bacterial, haemophilus infection, lung infection, pneumonia fungal and pneumocystis jirovecii pneumonia.

b See “Description of selected adverse reactions”. c Based on second primary malignancies reported during study treatment period and during post-treatment period. d Based on post-marketing adverse reactions.

Table 6a:

Adverse reactions reported in patients with multiple myeloma treated with isatuximab in combination with carfilzomib and dexamethasone System Organ Class Preferred Term Adverse reaction Frequency Incidence (N = 177) Any Grade Grade ≥ 3 […]

1.