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Isatuximab-irfc

Brand name: Sarclisa
Drug class: Antineoplastic Agents
Chemical name: Immunoglobulin G1, anti-(human CD38 antigen) (human-Mus musculus monoclonal hu38SB19 heavy chain), disulfide with human-Mus musculus monoclonal hu38SB19 light chain, dimer
Molecular formula: C6456H9932N1700O2026S44 (peptide)
CAS number: 1461640-62-9

Medically reviewed by Drugs.com on Jul 12, 2021. Written by ASHP.

Introduction

Antineoplastic agent; a chimeric anti-CD38 monoclonal antibody.

Uses for Isatuximab-irfc

Multiple Myeloma

Used in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma in patients who have received ≥2 prior therapies including lenalidomide and a proteasome inhibitor (designated an orphan drug by FDA for use in multiple myeloma).

Isatuximab-irfc Dosage and Administration

General

  • Administer only in settings where emergency equipment and appropriate medical support is available. (See Infusion-related Effects under Cautions.)

  • Because neutropenia occurs frequently, periodically monitor CBCs during therapy and consider anti-infective and antiviral prophylaxis. (See Hematologic Effects under Cautions.)

  • Perform blood typing and screening prior to the first isatuximab infusion. (See Interference with Laboratory Testing under Cautions.)

Premedication for Infusion-related Reactions

Administer the following premedications 15–60 minutes prior to each isatuximab infusion :

  • Oral or IV dexamethasone 40 mg, or a reduced dosage of 20 mg for ≥75 years of age

  • Oral acetaminophen 650 mg to 1 g or equivalent

  • Histamine H2-antagonist

  • Oral or IV diphenhydramine 25–50 mg or equivalent (IV preferred for at least the first 4 doses)

Restricted Distribution

  • Obtain through designated specialty pharmacies and distributors.

Administration

IV Administration

Administer by IV infusion using a polyurethane (PU), polybutadiene (PBD), polyvinyl chloride (PVC), or polyethylene (PE) infusion set equipped with a nylon, polysulfone, or polyethersulfone (PES) 0.22-µm inline filter.

Do not infuse simultaneously through the same IV line with any other drug.

Dilution

Must be diluted prior to IV infusion.

Remove the volume of diluent equal to the total required volume of injection concentrate from a 250-mL bag of 0.9% sodium chloride injection or 5% dextrose injection. Add the required volume of injection concentrate to the diluent in the polyolefin, polypropylene, ethyl vinyl acetate, PVC with di-(2-ethylhexyl) phthalate (DEHP), or PE infusion bag. Gently invert bag to mix solution; do not shake.

Discard any unused portions of the injection concentrate or diluted solution.

Rate of Administration

An incremental escalation of the infusion rate may be considered in the absence of infusion-related reactions. (See Table 1.)

Table 1. Recommended Incremental Escalation of Isatuximab-irfc Infusion Rate.1

Infusion

Initial Infusion Rate

Incremental Escalation of Infusion Rate

First

25 mL/hour

If infusion-related reactions do not occur after 60 minutes, increase infusion rate in increments of 25 mL/hour every 30 minutes to maximum rate of 150 mL/hour

Second

50 mL/hour

If infusion-related reactions do not occur after 30 minutes, continue current infusion rate (50 mL/hour) for 30 minutes then increase in increments of 100 mL/hour every 30 minutes to maximum rate of 200 mL/hour

Subsequent

200 mL/hour

Do not exceed maximum rate of 200 mL/hour

For grade 2 or 3 infusion-related reactions, interrupt the infusion until the reaction has improved to grade 0 or 1. Upon resumption, reduce the rate by 50%; if the reaction does not recur following resumption at a reduced rate after 30 minutes, increase infusion rate to initial rate, followed by an incremental escalation of the infusion rate (see Table 1).

For grade 2 or 3 infusion-related reactions that do not improve following interruption of the infusion, persist or worsen despite appropriate symptomatic and supportive therapy, or require hospitalization, permanently discontinue therapy.

For grade 4 infusion-related reactions, permanently discontinue therapy.

Dosage

Calculate dosage based on actual body weight prior to each dose.

Consult the respective manufacturers' labelings or published protocols for information on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens.

Adults

Multiple Myeloma
IV

Cycle 1: 10 mg/kg on days 1, 8, 15, and 22 during cycle 1. Subsequent cycles: 10 mg/kg on days 1 and 15.

  • Repeat treatment cycles every 28 days.

  • Continue therapy until disease progression or unacceptable toxicity occurs.

  • Administer therapeutic dosage of dexamethasone (40 mg, or a reduced dosage of 20 mg for patients ≥75 years of age) 15–60 minutes prior to each infusion to minimize the risk of infusion-related effects.

  • If a dose is missed, administer dose as soon as possible. Adjust administration schedule to maintain appropriate treatment interval between doses.

Dosage Modification for Toxicity

No dosage reductions are recommended for adverse effects.

Hematologic Effects

For grade 4 neutropenia, interrupt treatment until neutrophil count recovers to ≥1000/mm3. (See Hematologic Effects under Cautions.)

Infusion-related Effects

For grade 2 or greater infusion-related reactions, reduce infusion rate or permanently discontinue therapy depending on severity of reaction, and provide appropriate symptomatic and supportive therapy. (See Rate of Administration under Dosage and Administration.)

For grade 4 infusion-related reactions, permanently discontinue therapy.

Special Populations

Hepatic Impairment

IV

Mild hepatic impairment (total bilirubin concentrations exceeding the ULN, but ≤1.5 times the ULN, or AST concentrations exceeding the ULN): No dosage adjustment required.

Renal Impairment

IV

Mild to severe renal impairment (estimated glomerular filtration rate [eGFR] <90 mL/minute per 1.73 m2): No dosage adjustment required.

Geriatric Patients

No specific dosage recommendations.

Cautions for Isatuximab-irfc

Contraindications

  • Severe hypersensitivity to isatuximab or any ingredient in the formulation.

Warnings/Precautions

Combination Therapy

When used in combination with pomalidomide and dexamethasone, consider cautions, precautions, and contraindications for these drugs in addition to those for isatuximab.

Infusion-related Effects

Severe infusion-related reactions (e.g., angioedema, bronchospasm, cardiac arrest, dyspnea, swelling, hypertension, hypotension), including life-threatening anaphylaxis, reported; generally occur during the first infusion.

Administer premedication with dexamethasone, acetaminophen, a histamine H2-antagonist, and diphenhydramine hydrochloride prior to each isatuximab infusion. (See Premedication for Infusion-related Reactions under Dosage and Administration.)

Monitor vital signs frequently during infusions of the drug. Temporary interruption followed by a reduction in the infusion rate or permanent discontinuance of the drug may be necessary depending on severity of reaction; institute appropriate treatment and supportive care as clinically indicated. (See Rate of Administration under Dosage and Administration.)

Hematologic Effects

Neutropenia, febrile neutropenia, and neutropenic infections reported in patients receiving isatuximab-irfc in combination with pomalidomide and dexamethasone. Most frequent neutropenic infections included infections of the lower respiratory tract, upper respiratory tract, and urinary tract.

Monitor CBCs periodically during treatment. If neutropenia develops, monitor for signs or symptoms of infection. Temporary interruption of therapy may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

Consider anti-infective and antiviral prophylaxis. Use of growth factors may be used to treat neutropenia as clinically indicated.

Development of Second Primary Malignancy

Second primary malignancies (i.e., squamous cell carcinoma, breast angiosarcoma, myelodysplastic syndrome) reported in patients receiving isatuximab-irfc in combination with pomalidomide and dexamethasone.

Monitor patients for development of second primary malignancies.

Interference with Laboratory Testing

Indirect Antiglobulin Test

False positive indirect antiglobulin (Coombs’) test results reported. Positive indirect antiglobulin tests following discontinuance of an anti-CD38 monoclonal antibody may persist for up to 9 months following last infusion. Determination of ABO and Rh blood type not affected.

Isatuximab may also interfere with antibody detection tests, antibody identification panels, and antihuman globulin crossmatches.

If blood typing and screening did not occur prior to initiation of isatuximab therapy, inform blood bank to use dithiothreitol-treated RBCs for blood typing and screening. Do not assume a positive indirect antiglobulin test result in a patient receiving isatuximab is a false-positive since RBC alloantibodies may be present. If immediate transfusion is required because of emergency, transfuse non-cross-matched ABO/RhD blood type-compatible RBCs according to local protocols.

Interference with Serum Protein Electrophoresis and Immunofixation Tests

Isatuximab may interfere with serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE) assays resulting in misinterpretation of tumor response in patients with IgG kappa myeloma protein.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm in humans based on mechanism of action; IgG1 monoclonal antibodies cross the placenta. Effects on the fetus may include decreased bone mineral density and CD38-positive immune cell depletion. Defer administration of live vaccines to neonates and infants exposed to isatuximab in utero until a hematology evaluation is completed.

When used in combination with pomalidomide, consider that pomalidomide is contraindicated in pregnant women.

Avoid pregnancy during therapy. Advise women of reproductive potential to use effective contraception during and for ≥5 months after last dose. Apprise pregnant women of potential risk to the fetus. (See Pregnancy under Warnings/Precautions: Specific Populations.)

Immunogenicity

Potential for immunogenicity. Presence of anti-isatuximab antibodies does not appear to affect pharmacokinetics, safety, or efficacy of isatuximab.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

When used in combination with pomalidomide, consider that pomalidomide is contraindicated in pregnant women.

Lactation

Not known whether isatuximab is distributed into human milk; however, human IgG is distributed into milk.

Effects of drug on nursing infants or human milk production unknown.

Discontinue breast-feeding during combination therapy with isatuximab, pomalidomide, and dexamethasone.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety or efficacy relative to younger patients; however, possibility of increased sensitivity in some older individuals cannot be ruled out.

Hepatic Impairment

Systemic exposure not altered by mild hepatic impairment.

Not studied in patients with moderate or severe hepatic impairment. (See Special Populations under Pharmacokinetics.)

Renal Impairment

Systemic exposure not altered by renal impairment. (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Neutropenia, infusion-related reactions, pneumonia, upper respiratory tract infection, diarrhea, anemia, lymphopenia, thrombocytopenia.

Interactions for Isatuximab-irfc

No formal drug interaction studies.

Pharmacokinetics of isatuximab not expected to be affected by drugs affecting CYP isoenzymes or transport systems.

Isatuximab-irfc Pharmacokinetics

Absorption

Bioavailability

Systemic exposure increases in a dose-proportional manner over a dosage range of 5–20 mg/kg every week for 4 weeks, followed by every 2 weeks.

Steady-state concentrations are achieved within a median of 8 weeks.

Special Populations

Mild hepatic impairment: No clinically important effect on systemic exposure to isatuximab.

Moderate or severe hepatic impairment: Not studied.

Renal impairment: No clinically important effect on systemic exposure to isatuximab.

Age (36–85 years), sex, and race (Caucasian, Black, Asian) do not appear to substantially affect pharmacokinetics of isatuximab.

Distribution

Extent

Human IgG crosses the placenta and distributes into milk. Not known whether isatuximab is distributed into milk.

Elimination

Metabolism

Expected to degrade into small peptides via catabolic pathways.

Clearance decreases with increasing dosage and repeated administration.

≥99% elimination of drug expected in approximately 2 months after last dose.

Stability

Storage

Parenteral

Injection Concentrate

2–8ºC in original carton to protect from light. Do not freeze or shake.

Diluted infusion solution: Administer immediately or store at 2–8ºC for up to 48 hours, followed by up to 8 hours at room temperature (including infusion time).

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Sodium chloride 0.9%

Dextrose 5% in water

Actions

  • IgG1 immunoglobulin produced from mammalian (Chinese hamster ovary) cells.

  • Binds to CD38, a transmembrane glycoprotein expressed on the surface of hematopoietic and tumor cells, including multiple myeloma cells.

  • Induces apoptosis of tumor cells and activates immune effector mechanisms (i.e., antibody-dependent cell-mediated cytotoxicity [ADCC], antibody-dependent cellular phagocytosis [ADCP], complement-dependent cytotoxicity [CDC]).

  • Suppresses CD38-positive T-regulatory cells and, in the absence of CD38-positive tumor cells, activation of natural killer (NK) cells.

Advice to Patients

  • Advise patients to read the manufacturer's patient information.

  • Risk of infusion-related reactions. Importance of immediately reporting any signs or symptoms of such reactions (e.g., shortness of breath; wheezing or difficulty breathing; swelling of the face, mouth, throat, or tongue; throat tightness; palpitations; dizziness, lightheadedness, or fainting; headache; cough; rash or itching; nausea; rhinitis or nasal congestion; chills).

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

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

  • Risk of laboratory test interference. Advise patients to inform clinicians and transfusion center personnel that they are receiving isatuximab-irfc in case a RBC transfusion is planned.

  • Risk of fetal harm. Advise women of childbearing potential of the potential hazard to a fetus and to avoid becoming pregnant during isatuximab treatment and for ≥5 months after the last dose of the drug.

  • 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.

  • Advise patients to inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

  • Advise women to inform clinicians if they are breast-feeding or plan to breast-feed.

  • Inform patients of other important precautionary information. (See Cautions.)

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.

Distribution of isatuximab is restricted. (See Restricted Distribution under Dosage and Administration.)

Isatuximab-irfc

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Concentrate, for injection, for IV infusion

20 mg/mL (100 and 500 mg)

Sarclisa

Sanofi-Aventis

AHFS DI Essentials™. © Copyright 2022, Selected Revisions July 12, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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