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.
For other medicinal products that are administered with isatuximab, refer to the respective current summary of product characteristics.
It is unknown whether isatuximab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards; however, a risk to the breast-fed child cannot be excluded during this short period just after birth. For this specific period, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from isatuximab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Afterwards, isatuximab could be used during breastfeeding if clinically needed.
For other medicinal products that are administered with isatuximab, refer to the respective current summary of product characteristics.
Women of childbearing potential treated with isatuximab should use effective contraception during treatment and for 5 months after cessation of treatment.
No human and animal data are available to determine potential effects of isatuximab on fertility in males and females.
For other medicinal products that are administered with isatuximab, refer to the respective current summary of product characteristics.
Isatuximab has no or negligible influence on the ability to drive and use machines.
In ICARIA-MM, the most frequent adverse reactions (>20%) are neutropenia (46.7%), infusion reactions (38.2%), pneumonia (30.9%), upper respiratory tract infection (28.3%), diarrhoea (25.7%) and bronchitis (23.7%). Serious adverse reactions occurred in 61.8% of patients receiving Isa-Pd. The most frequent serious adverse reactions are pneumonia (25.7%) and febrile neutropenia (6.6%). Permanent discontinuation of treatment because of adverse reactions was reported in 7.2% of patients treated with Isa-Pd. Adverse reactions with a fatal outcome during treatment were reported in 7.9% of patients treated with Isa-Pd (those occurring in more than 1% of patients were pneumonia occurring in 1.3% of patients and other infections occurring in 2.0% of patients).
In IKEMA, the most frequent adverse reactions (≥20%) are infusion reactions (45.8%), hypertension (36.7%), diarrhoea (36.2%), upper respiratory tract infection (36.2%), pneumonia (28.8%), fatigue (28.2%), dyspnoea (27.7%), insomnia (23.7%), bronchitis (22.6%), and back pain (22.0%). Serious adverse reactions occurred in 59.3% of patients receiving Isa-Kd. The most frequent serious adverse reaction is pneumonia (21.5%). Permanent discontinuation of treatment because of adverse reactions was reported in 8.5% of patients treated with Isa-Kd. Adverse reactions with a fatal outcome during treatment were reported in 3.4% of patients treated with Isa-Kd (those occurring in more than 1% of patients were pneumonia and cardiac failure both occurring in 1.1% of patients).
Adverse reactions are described using the NCI Common Toxicity Criteria, the COSTART and the MedDRA terms. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); “frequency not known (cannot be estimated from available data)”. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
The adverse reactions were reported from the 152 patients who received Isa-Pd with a median duration of exposure of 41 weeks in ICARIA-MM study.
Table 1a. Adverse reactions reported in patients with multiple myeloma treated with isatuximab in combination with pomalidomide and dexamethasone (ICARIA-MM):
| System Organ Class Preferred Term | Adverse reaction | Frequency | Incidence (%) (N=152) | |
|---|---|---|---|---|
| Any Grade | Grade ≥3 | |||
| Infections and infestations | Pneumoniabc | Very common | 47 (30.9) | 40 (26.3) |
| Upper respiratory tract infection* | Very common | 43 (28.3) | 5 (3.3) | |
| Bronchitis* | Very common | 36 (23.7) | 5 (3.3) | |
| Herpes zoster | Common | 7 (4.6) | 1 (0.7) | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Skin squamous cell carcinoma | Common | 4 (2.6) | 2 (1.3) |
| Blood and lymphatic system disorders | Neutropeniad | Very common | 71 (46.7) | 70 (46.1) |
| Febrile neutropenia | Very common | 18 (11.8) | 18 (11.8) | |
| Immune system disorders | Anaphylactic reactione | Uncommon | 5 (0.3%) | 5 (0.3%) |
| Metabolism and nutrition disorders | Decreased appetite* | Common | 15 (9.9) | 2 (1.3) |
| Cardiac disorders | Atrial fibrillation | Common | 7 (4.6) | 3 (2.0) |
| Respiratory, thoracic and mediastinal disorders | Dyspnoea* | Very common | 23 (15.1) | 6 (3.9) |
| Gastrointestinal disorders | Diarrhoea* | Very common | 39 (25.7) | 3 (2.0) |
| Nausea* | Very common | 23 (15.1) | 0 | |
| Vomiting* | Very common | 18 (11.8) | 2 (1.3) | |
| Investigations | Weight decreased* | Common | 10 (6.6) | 0 |
| Injury, poisoning and procedural complications | Infusion reactionc | Very common | 58 (38.2) | 4 (2.6) |
a Only TEAEs are reported in Table 1. The haematology laboratory values are reported in Table 3.
b The term pneumonia is a grouping of the following terms: atypical pneumonia, bronchopulmonary aspergillosis, pneumonia, pneumonia haemophilus, pneumonia influenzal, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, pneumonia bacterial, haemophilus infection, lung infection, pneumonia fungal
and pneumocystis jirovecii pneumonia.
c See “Description of selected adverse reactions”.
d Haematology laboratory values were recorded as TEAEs only if they led to treatment discontinuation and/or dose modification or fulfilled a serious criterion.
e Based on multiple myeloma clinical trials.
* No grade 4
The adverse reactions were reported from the 177 patients who received Isa-Kd with a median duration of exposure of 80.0 weeks in IKEMA study.
Table 2a. Adverse reactions reported in patients with multiple myeloma treated with isatuximab in combination with carfilzomib and dexamethasone (IKEMA):
| System Organ Class Preferred Term | Adverse reaction | Frequency | Incidence (%) (N=177) | |
|---|---|---|---|---|
| Any Grade | Grade ≥3 | |||
| Infections and infestations | Pneumoniabc | Very common | 28.8% | 20.9% |
| Upper respiratory tract infection* | Very common | 36.2% | 3.4% | |
| Bronchitis* | Very common | 22.6% | 2.3% | |
| Herpes zoster | Common | 2.3% | 0.6% | |
| Vascular disorders | Hypertension* | Very common | 36.7% | 20.3% |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Skin cancers* | Common | 5.1% | 0.6% |
| Solid tumours other than skin cancers | Common | 3.4% | 1.7% | |
| Blood and lymphatic system disorders | Neutropeniad | Common | 4.5% | 4.0% |
| Immune system disorders | Anaphylactic reactione | Uncommon | 5 (0.3%) | 5 (0.3%) |
| Respiratory, thoracic and mediastinal disorders | Dyspnoea* | Very common | 27.7% | 5.1% |
| Cough* | Very common | 19.8% | 0% | |
| Gastrointestinal disorders | Diarrhoea* | Very common | 36.2% | 2.8% |
| Vomiting* | Very common | 15.3% | 1.1% | |
| General disorders and administration site conditions | Fatigue* | Very common | 28.2% | 3.4% |
| Injury, poisoning and procedural complications | Infusion reactionc* | Very common | 45.8% | 0.6% |
a Only TEAEs are reported in Table 2. The haematology laboratory values are reported in Table 4.
b The term pneumonia is a grouping of the following terms: atypical pneumonia, pneumocystis jirovecii pneumonia, pneumonia, pneumonia influenzal, pneumonia legionella, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis.
c See “Description of selected adverse reactions”.
d Haematology laboratory values were recorded as TEAEs only if they led to treatment discontinuation and/or dose modification or fulfilled a serious criterion.
e Based on multiple myeloma clinical trials.
* No grade 4 or 5.
In ICARIA-MM, infusion reactions were reported in 58 patients (38.2%) treated with isatuximab. All patients who experienced infusion reactions, experienced them during the 1st infusion of isatuximab, with 3 patients (2.0%) also having infusion reactions at their 2nd infusion, and 2 patients (1.3%) at their 4th infusion. Grade 1 infusion reactions were reported in 3.9%, Grade 2 in 31.6%, Grade 3 in 1.3%, and Grade 4 in 1.3% of the patients. All infusion reactions were reversible and resolved the same day in 98% of the infusions. Signs and symptoms of Grade 3 or 4 infusion reactions included dyspnoea, hypertension, and bronchospasm.
The incidence of infusion interruptions because of infusion reactions was 28.9%. The median time to infusion interruption was 55 minutes.
Discontinuations from treatment due to infusion reaction were reported in 2.6% of patients in Isa-Pd group.
In IKEMA, infusion reactions were reported in 81 patients (45.8%) treated with Isa-Kd. Grade 1 infusion reactions were reported in 13.6%, Grade 2 in 31.6%, and Grade 3 in 0.6% of the patients treated with Isa-Kd. All infusion reactions were reversible and resolved the same day in 73.8% of episodes in Isa-Kd patients and in more than 2 days in 2.5% of episodes in Isa-Kd patients. Signs and symptoms of Grade 3 infusion reactions included dyspnoea and hypertension. The incidence of patients with isatuximab infusion interruptions because of infusion reactions was 29.9%. The median time to isatuximab infusion interruption was 63 minutes. Isatuximab was discontinued in 0.6% of patients due to infusion reactions.
In ICARIA-MM, the incidence of Grade 3 or higher infections was 42.8%. Pneumonia was the most commonly reported severe infection with Grade 3 reported in 21.7% of patients in the Isa-Pd group compared to 16.1% in the Pd group, and Grade 4 in 3.3% of patients in the Isa-Pd group compared to 2.7% in the Pd group. Discontinuations from treatment due to infection were reported in 2.6% of patients in the Isa-Pd group compared to 5.4% in the Pd group. Fatal infections were reported in 3.3% of patients in the Isa-Pd group and 4.0% in the Pd group. In IKEMA, the incidence of Grade 3 or higher infections was 38.4%. Pneumonia was the most commonly reported severe infection with Grade 3 reported in 15.8% of patients in the Isa-Kd group compared to 10.7% in the Kd group, and Grade 4 in 3.4% of patients in the Isa-Kd group compared to 2.5% in the Kd group. Treatment was discontinued due to infection in 2.8% of patients in the Isa-Kd group compared to 4.9% in the Kd group. Fatal infections were reported in 2.3% of patients in the Isa-Kd group and 0.8% in the Kd group.
In relapsed and refractory multiple myeloma clinical trials, herpes zoster was reported in 2.0% of patients. In ICARIA-MM, the incidence of herpes zoster was 4.6% in the Isa-Pd group compared to 0.7% in the Pd group, and in IKEMA, incidence was 2.3% in the Isa-Kd group compared to 1.6% in the Kd group.
In IKEMA, cardiac failure (including cardiac failure, cardiac failure congestive, cardiac failure acute, cardiac failure chronic, left ventricular failure, and pulmonary oedema) was reported in 7.3% of patients with the Isa-Kd group (4.0% of Grade ≥3) and in 6.6% of patients with the Kd group (4.1% of Grade ≥3). Serious cardiac failure was observed in 4.0% of patients in the Isa-Kd group and in 3.3% of patients in the Kd group. Cardiac failure with a fatal outcome during treatment was reported in 1.1% of patients in the Isa-Kd group and not reported in the Kd group (see the current prescribing information for carfilzomib).
Table 3. Haematology laboratory abnormalities in patients receiving isatuximab combined with pomalidomide and dexamethasone–versus pomalidomide and dexamethasone (ICARIA-MM):
| Laboratory parameter | Isatuximab + Pomalidomide + Dexamethasone n (%) (N=152) | Pomalidomide + Dexamethasone n (%) (N=147) | ||||
|---|---|---|---|---|---|---|
| All grades | Grade 3 | Grade 4 | All grades | Grade 3 | Grade 4 | |
| Anaemia | 151 (99.3) | 48 (31.6) | 0 | 145 (98.6) | 41 (27.9) | 0 |
| Neutropenia | 146 (96.1) | 37 (24.3) | 92 (60.5) | 137 (93.2) | 57 (38.8) | 46 (31.3) |
| Lymphopenia | 140 (92.1) | 64 (42.1) | 19 (12.5) | 137 (93.2) | 52 (35.4) | 12 (8.2) |
| Thrombocytopenia | 127 (83.6) | 22 (14.5) | 25 (16.4) | 118 (80.3) | 14 (9.5) | 22 (15.0) |
The denominator used for the percentage calculation is the number of patients with at least 1 evaluation of the laboratory test during the considered observation period.
Table 4. Haematology laboratory abnormalities in patients receiving isatuximab combined with carfilzomib and dexamethasone versus carfilzomib and dexamethasone (IKEMA):
| Laboratory parameter | Isatuximab + Carfilzomib + Dexamethasone (N=177) | Carfilzomib + Dexamethasone (N=122) | ||||
|---|---|---|---|---|---|---|
| All grades | Grade 3 | Grade 4 | All grades | Grade 3 | Grade 4 | |
| Anaemia | 99.4% | 22.0% | 0% | 99.2% | 19.7% | 0% |
| Neutropenia | 54.8% | 17.5% | 1.7% | 43.4% | 6.6% | 0.8% |
| Lymphopenia | 94.4% | 52.0% | 16.9% | 95.1% | 43.4% | 13.9% |
| Thrombocytopenia | 94.4% | 18.6% | 11.3% | 87.7% | 15.6% | 8.2% |
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.
Across 9 clinical studies in multiple myeloma (MM) with isatuximab single agent and combination therapies including ICARIA-MM and IKEMA (N=1018), the incidence of treatment emergent ADAs was 1.9%. No effect of ADAs was observed on pharmacokinetics, safety or efficacy of isatuximab.
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