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Isatuximab-irfc

Class: Antineoplastic Agents
Brands: Sarclisa

Medically reviewed by Drugs.com on March 9, 2020. Written by ASHP.

Introduction

Isatuximab-irfc is an antineoplastic agent.

Uses for Isatuximab-irfc

Isatuximab-irfc has the following uses:

Isatuximab-irfc is a CD38-directed cytolytic antibody indicated, in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

Isatuximab-irfc Dosage and Administration

General

Isatuximab-irfc is available in the following dosage form(s) and strength(s):

Injection:

  • 100 mg/5 mL (20 mg/mL) solution in single-dose vial.

  • 500 mg/25 mL (20 mg/mL) solution in single-dose vial.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration
  • Premedicate with dexamethasone, acetaminophen, H2-receptor antagonists, and diphenhydramine hydrochloride 15–60 minutes prior to start of infusion. Dexamethasone is considered to be both a premedication and a part of the combination chemotherapy regimen.

  • The recommended dosage of isatuximab-irfc is 10 mg/kg as an intravenous infusion on days 1, 8, 15, and 22 of the first 28-day cycle and on days 1 and 15 of each subsequent cycle; administer in combination with pomalidomide and dexamethasone until disease progression or unacceptable toxicity.

  • See Full Prescribing Information for instructions on preparation and administration.

Cautions for Isatuximab-irfc

Contraindications

Patients with severe hypersensitivity to isatuximab-irfc or to any of its excipients.

Warnings/Precautions

Infusion-related Reactions

Infusion-related reactions have been observed in 39% of patients treated with isatuximab-irfc. All infusion-related reactions started during the first isatuximab-irfc infusion and resolved on the same day in 98% of the cases. The most common symptoms of an infusion-related reaction included dyspnea, cough, chills, and nausea. The most common severe signs and symptoms included hypertension and dyspnea.

To decrease the risk and severity of infusion-related reactions, premedicate patients prior to isatuximab-irfc infusion with dexamethasone, acetaminophen, H2-receptor antagonists, and diphenhydramine hydrochloride; dexamethasone is considered to be both a premedication and a part of the combination chemotherapy regimen. Monitor vital signs frequently during the entire isatuximab-irfc infusion. For patients with grade 1 or 2 reactions, interrupt isatuximab-irfc infusion and provide appropriate medical support. If symptoms improve, restart isatuximab-irfc 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 (see Full Prescribing Information for infusion rates). In case symptoms do not improve or recur after interruption, permanently discontinue isatuximab-irfc and institute appropriate management. Permanently discontinue isatuximab-irfc therapy if a grade 3 or higher infusion-related reaction occurs and institute appropriate medical management.

Neutropenia

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

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

Second Primary Malignancies

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

Laboratory Test Interference

Interference with Serological Testing (Indirect Antiglobulin Test)

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

Interference with Serum Protein Electrophoresis and Immunofixation Tests

Isatuximab-irfc is an IgG kappa monoclonal antibody that can be incidentally detected on both serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the accuracy of the determination of complete response in some patients with IgG kappa myeloma protein.

Embryo-fetal Toxicity

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

Specific Populations

Pregnancy

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

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

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

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

Lactation

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

Females and Males of Reproductive Potential

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

Isatuximab-irfc can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use effective contraception during treatment and for at least 5 months after the last dose of isatuximab-irfc. Additionally, refer to the pomalidomide labeling for contraception requirements prior to initiating treatment in females of reproductive potential.

Males should refer to the pomalidomide prescribing information.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

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

Common Adverse Effects

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

The most common hematology laboratory abnormalities (in ≥80% of patients) were anemia, neutropenia, lymphopenia, and thrombocytopenia.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Isatuximab-irfc is an IgG1-derived monoclonal antibody that binds to CD38 expressed on the surface of hematopoietic and tumor cells, including multiple myeloma cells. Isatuximab-irfc induces apoptosis of tumor cells and activation of immune effector mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement dependent cytotoxicity (CDC). Isatuximab-irfc inhibits the ADP-ribosyl cyclase activity of CD38. Isatuximab-irfc can activate natural killer (NK) cells in the absence of CD38-positive target tumor cells and suppresses CD38-positive T-regulatory cells.

The combination of isatuximab-irfc and pomalidomide enhanced ADCC activity and direct tumor cell killing compared to that of isatuximab-irfc alone in vitro, and enhanced antitumor activity compared to the activity of isatuximab-irfc or pomalidomide alone in a human multiple myeloma xenograft model.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Infusion-Related Reaction

Instruct patients to immediately report any occurrence of symptoms occurring within 24 hours of start of infusion to their healthcare provider.

Neutropenia

Inform patients about the risk of neutropenia and infection during isatuximab-irfc treatment and the importance of reporting immediately any fever or symptoms of infection to their healthcare provider.

Second Primary Malignancies

Inform patients of the risk of developing second primary malignancies during treatment with isatuximab-irfc in combination with pomalidomide and low-dose dexamethasone .

Interference with Laboratory Tests

Advise patients to inform healthcare providers and transfusion center personnel that they are treated with isatuximab-irfc in case a red blood cell transfusion is planned.

Embryo-Fetal Toxicity

Advise women of the potential hazard to a fetus and to avoid becoming pregnant during treatment and for at least 5 months after the last dose of isatuximab-irfc.

Advise patients that pomalidomide has the potential to cause fetal harm and has specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Advise patients to report suspected or known pregnancies. Pomalidomide is only available through a REMS program.

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Isatuximab-irfc

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, solution, concentrate, for IV infusion only

20 mg/mL (100 and 500 mg)

Sarclisa

Sanofi-Aventis

AHFS Drug Information. © Copyright 2021, Selected Revisions March 9, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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