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Empliciti

Generic Name: Elotuzumab
Class: Antineoplastic Agents
Chemical Name: Disulfide with human-mouse HuLuc63 κ-chain, anti-(human protein CS1) (human-mouse HuLuc63 heavy chain), immunoglobulin G1dimer
Molecular Formula: C6476H9982N1714O2016S42
CAS Number: 915296-00-3

Introduction

Antineoplastic agent; recombinant humanized monoclonal antibody that is an antagonist of signaling lymphocytic activation molecule (SLAM) family member 7 (SLAMF7);1 6 also referred as an anti-CS1 (anti-CD2 subset 1) monoclonal antibody.2 10 11 12 16

Uses for Empliciti

Multiple Myeloma

Used in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in patients who have received 1–3 prior therapies1 2 14 (designated an orphan drug by FDA for treatment of this cancer3 ).

Empliciti Dosage and Administration

General

  • Consult respective manufacturers' labelings for information on dosage and method of administration of other antineoplastic agents used in combination regimens.1

Premedication for Infusion-related Reactions

  • Administer acetaminophen 650 mg to 1 g orally 45–90 minutes before each elotuzumab infusion.1

  • Administer a histamine H2-receptor antagonist (e.g., ranitidine 50 mg IV or 150 mg orally or equivalent) 45–90 minutes before each elotuzumab infusion.1

  • Administer a histamine H1-receptor antagonist (e.g., diphenhydramine hydrochloride 25–50 mg or equivalent IV or orally) 45–90 minutes before each elotuzumab infusion.1

  • Administer dexamethasone phosphate 8 mg IV 45–90 minutes before each elotuzumab infusion.1

Restricted Distribution Program

  • Available only through select specialty distributors.4 Consult the Empliciti website for specific availability information (http://www.emplicitihcp.com/ordering).4

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Administer drug via an infusion pump and through a sterile, nonpyrogenic, low-protein-binding 0.2- to 1.2-µm inline filter.1

Elotuzumab lyophilized powder for injection must be reconstituted and diluted prior to administration.1 Complete infusion within 24 hours of reconstitution.1

Do not admix with or administer as an IV infusion with any other drug.1

Discard any unused portion of the reconstituted or diluted solutions since vials of elotuzumab lyophilized powder for injection contain no preservatives and are intended for single use only.1

Reconstitution

Manufacturer recommends using a 15- to 18-gauge needle for preparation.1

To reconstitute elotuzumab lyophilized powder, add 13 mL of sterile water for injection to a vial containing 300 mg of the drug or add 17 mL to a vial containing 400 mg of the drug to provide a solution containing 25 mg/mL.1

Slight back pressure may occur when injecting diluent into vial.1

Swirl upright vial and then invert several times to aid dissolution; the lyophilized powder should dissolve in <10 minutes.1 Do not shake or vigorously agitate reconstituted solution.1 Do not remove contents of the reconstituted vials until all solids have completely dissolved and the solution has been allowed to stand for 5–10 minutes.1

Reconstituted solution should be colorless to slightly yellow, clear to slightly opalescent, and free of visible particulates.1

Dilution

Dilute appropriate dose in a PVC or non-PVC (polyolefin) infusion bag containing 230 mL of 0.9% sodium chloride or 5% dextrose injection.1

May adjust volume of 0.9% sodium chloride or 5% dextrose injection to avoid >5 mL of fluid per kg of patient weight.1

Rate of Administration

Day 1 of cycle 1 (initial dose): Infuse at initial rate of 0.5 mL/minute; if infusion-related events do not occur, infusion rate may be doubled every 30 minutes to a maximum rate of 2 mL/minute.1

Day 8 of cycle 1 (second dose): Infuse at initial rate of 1 mL/minute; if infusion-related events do not occur within 30 minutes, infusion rate may be increased to 2 mL/minute.1

Subsequent doses: Infuse at rate of 2 mL/minute.1

Maximum infusion rate should not exceed 2 mL/minute; however, patients who received 4 cycles of elotuzumab may receive the drug at a maximum infusion rate of 5 mL/minute.1

For severe infusion-related reactions, permanent discontinuance of elotuzumab may be necessary.1

For grade 2 or greater infusion-related reactions, interrupt the infusion until the reaction resolves to grade 1 or less.1 Upon resumption, reduce the rate to 0.5 mL/minute; if infusion-related events do not occur, infusion rate may be increased in increments of 0.5 mL/minute every 30 minutes to the rate at which the infusion-related reaction occurred.1 If no further infusion-related events occur, increase the infusion rate as tolerated in increments and intervals appropriate for the treatment cycle dose (as described above).1 If infusion-related reactions recur, interrupt the infusion and do not restart on the same day.1

Dosage

Adults

Multiple Myeloma
IV

Cycles 1 and 2: 10 mg/kg once weekly (days 1, 8, 15, and 22) in combination with lenalidomide 25 mg orally once daily on days 1–21 and dexamethasone 28 mg orally on days 1, 8, 15, and 22.1

Cycle 3 and onward: 10 mg/kg every 2 weeks (days 1 and 15) in combination with lenalidomide 25 mg orally once daily on days 1–21 and dexamethasone 28 mg orally on days 1 and 15 and 40 mg orally on days 8 and 22.1

On days that elotuzumab is scheduled, give 8-mg IV dexamethasone phosphate premedication (45–90 minutes prior to the elotuzumab infusion) in addition to the 28-mg oral dexamethasone dose (3–24 hours prior to administration of elotuzumab).1 (See Premedication for Infusion-related Reactions under Dosage and Administration.)

Repeat elotuzumab in combination with lenalidomide and dexamethasone every 28 days; continue therapy until disease progression or unacceptable toxicity occurs.1

Dosage Modification
IV

If one drug in the combination regimen is delayed, interrupted, or discontinued, therapy with the other drugs may be continued; however, consider the risk of infusion-related reactions if elotuzumab is continued without dexamethasone.1

Special Populations

Hepatic Impairment

No specific dosage recommendations.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No special dosage recommendations.1 (See Geriatric Use under Cautions.)

Cautions for Empliciti

Contraindications

  • No known contraindications.1

Warnings/Precautions

Combination Therapy

When used in combination with lenalidomide and dexamethasone, cautions, precautions, and contraindications of all 3 drugs must be considered.1

Infusion-related Effects

Infusion-related reactions (e.g., pyrexia, chills, hypertension, bradycardia, hypotension) reported;1 2 generally occur more frequently during first infusion.1

To minimize incidence of infusion-related reactions, premedicate with acetaminophen, a histamine H2-receptor antagonist, histamine H1-receptor antagonist, and dexamethasone.1 (See Premedication for Infusion-related Reactions under Dosage and Administration.)

Interrupt the infusion, reduce infusion rate, and provide appropriate treatment and supportive care as clinically indicated depending on the severity.1 (See Rate of Administration under Dosage and Administration.)

If infusion-related reaction occurs, monitor vital signs every 30 minutes for 2 hours following end of the infusion.1

Infectious Complications

Infections (e.g., opportunistic infections, fungal infections, herpes zoster), sometimes fatal or requiring discontinuance of therapy, reported.1 2

Monitor for signs and symptoms of infection.1 If an infection develops, promptly initiate anti-infective therapy.1

Development of Second Primary Malignancy

Second primary malignancies reported.1 In pivotal study in patients with relapsed or refractory multiple myeloma, solid tumors and skin cancer occurred more frequently in patients receiving elotuzumab in combination with lenalidomide and dexamethasone compared with those receiving lenalidomide and dexamethasone alone; however, the incidence of hematologic malignancies was similar between both treatment groups.1

Monitor for development of second primary malignancies.1

Hepatic Effects

Liver function test abnormalities, sometimes requiring permanent discontinuance, reported.1

Periodically monitor liver function tests.1 If grade 3 or greater elevations in ALT or AST occur, interrupt therapy until complete resolution; resumption of elotuzumab therapy may be considered.1

Interference with Serum Protein Electrophoresis and Immunofixation Assays

Elotuzumab may be detected on serum protein electrophoresis (SPEP) and immunofixation (IFE) assays, particularly in patients with IgA, IgM, IgD, or lambda light chain-restricted endogenous monoclonal immunoglobulins (M-protein).1

Presence of elotuzumab on SPEP and IFE assays may result in misinterpretation of tumor response in patients with IgG kappa M-protein.1 15

Immunogenicity

Antibodies to elotuzumab, including neutralizing antibodies to the drug, reported.1 2 10

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women.1 Animal reproduction studies not performed to date.1

Because elotuzumab is administered in combination with lenalidomide and dexamethasone, contraindications of lenalidomide must be considered.1 5

Lactation

Not known whether distributed into human milk.1 Discontinue nursing.1

Effects of the drug on nursing infants or on human milk production are unknown.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

In pivotal study in patients with relapsed or refractory multiple myeloma, 57% of patients were ≥65 years of age.1 No overall differences in safety or efficacy relative to younger patients.1

Hepatic Impairment

Systemic exposure not affected by mild hepatic impairment.1 6

Not studied in patients with moderate to severe hepatic impairment.1

Renal Impairment

Systemic exposure not affected by severe renal impairment (Clcr <30 mL/minute) or end-stage renal disease requiring dialysis.1 6 13

Common Adverse Effects

Fatigue,1 2 diarrhea,1 2 pyrexia,1 2 constipation,1 2 cough,1 2 peripheral neuropathy,1 nasopharyngitis,1 2 upper respiratory tract infection,1 loss of appetite,1 pneumonia,1 extremity pain,1 headache,1 vomiting,1 weight loss,1 lymphopenia,1 cataracts,1 oropharyngeal pain,1 lymphopenia,1 leukopenia,1 thrombocytopenia,1 2 hypoalbuminemia,1 elevated alkaline phosphatase concentrations,1 hyperglycemia,1 hypocalcemia,1 decreased serum bicarbonate concentrations,1 hyperkalemia.1

Interactions for Empliciti

No formal drug interaction studies to date.1

Empliciti Pharmacokinetics

Absorption

Bioavailability

AUC is more than dose proportional over the dose range of 0.5–20 mg/kg.1 6 10

Following administration of elotuzumab 10 mg/kg IV once weekly for two 28-day cycles followed by 10 mg/kg IV every 2 weeks thereafter, plasma concentrations increase for approximately 8 weeks after initiation of elotuzumab and steady-state concentrations are reached by 2–4 weeks following initiation of administration every 2 weeks.6

Special Populations

Mild hepatic impairment: Systemic exposure similar to that in patients with normal hepatic function.1 6

Moderate to severe hepatic impairment: Pharmacokinetics not studied.1

Severe renal impairment (Clcr <30 mL/minute) or end-stage renal disease requiring dialysis: Systemic exposure similar to that in patients with normal renal function.1 6 13

Distribution

Extent

Not known whether distributed into human milk.1

Elimination

Within about 3 months (geometric mean: 82.4 days) following discontinuance of combination therapy with elotuzumab, lenalidomide, and dexamethasone, elotuzumab concentrations are predicted to decline by approximately 97% from peak steady-state values.1 17

Special Populations

Age (over range of 25–88 years), gender, race, baseline LDH concentrations, and albumin concentrations do not substantially affect pharmacokinetics.1 6 17

Stability

Storage

Parenteral

Powder for Injection

Unreconstituted drug: 2–8°C in original carton to protect from light; do not freeze.1

Diluted infusion solution: 2–8°C for up to 24 hours (including infusion time) and protected from light; ≤8 hours of the total 24 hours may be at 20–25°C under room light.1

Compatibility

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

Parenteral

Solution Compatibility

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Actions

  • An IgG1 kappa immunoglobulin that binds specifically to signaling lymphocytic activation molecule (SLAM) family member 7 (SLAMF7) (expressed on the surface of normal and malignant plasma cells and natural killer [NK] cells) and directly activates NK cells via the SLAMF7 pathway,1 9 11 16 triggering a host immune response causing lysis of myeloma cells.1 11 12 16

  • Mechanism of cell lysis is thought to involve antibody-dependent cell-mediated cytotoxicity (ADCC).1 11 12 16

  • Concomitant use of elotuzumab and lenalidomide enhances activation of NK cells compared with either drug alone.1 12

  • Increased antitumor activity with elotuzumab in combination with lenalidomide demonstrated in vitro and in vivo.1 12

Advice to Patients

  • Risk of infusion-related reactions; importance of reporting signs and symptoms of such reactions (e.g., fever, chills, rash, breathing difficulty) that occur during or ≤24 hours after an infusion of the drug.1 Importance of taking premedications as directed to minimize risk of infusion-related reactions.1

  • Risk of fetal harm when used in combination with lenalidomide.1 Importance of advising women of childbearing potential and men who are partners of such women to take precautions to avoid fetal exposure to lenalidomide.1 Importance of women informing a clinician immediately if they are or plan to become pregnant.1

  • Importance of advising women to avoid breast-feeding while receiving elotuzumab.1 Importance of women informing a clinician if they plan to breast-feed.1

  • Risk of infection.1 Importance of reporting signs or symptoms of infection (e.g., cough, fever, flu-like symptoms, shortness of breath, painful rash, burning on urination).1

  • Risk of developing a second primary malignancy.1

  • Risk of hepatotoxicity and importance of periodic liver function test monitoring.1 Importance of reporting any manifestations of hepatotoxicity (e.g., jaundice, weakness, loss of appetite, fatigue, confusion, abdominal swelling, unusually colored stool).1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (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 elotuzumab is restricted.4 (See Restricted Distribution Program under Dosage and Administration.)

Elotuzumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

300 mg

Empliciti

Bristol-Myers Squibb

400 mg

Empliciti

Bristol-Myers Squibb

AHFS DI Essentials. © Copyright 2017, Selected Revisions May 15, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Bristol-Myers Squibb. Empliciti (elotuzumab) for injection prescribing information. Princeton, NJ; 2015 Nov.

2. Lonial S, Dimopoulos M, Palumbo A et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015; 373:621-31. [PubMed 26035255]

3. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2016 Jun 10.

4. Bristol-Myers Squibb. How to order empliciti. From Bristol-Myers Squibb for US Healthcare Professionals website. Accessed 2016 Jun 8.

5. Celgene. Revlimid (lenalidomide) capsules prescribing information. Summit, NJ; 2015 Feb.

6. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761035Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website.

7. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761035Orig1s000: Chemistry review(s). From FDA website.

8. Lonial S, Vij R, Harousseau JL et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012; 30:1953-9. [PubMed 22547589]

9. Guo H, Cruz-Munoz ME, Wu N et al. Immune cell inhibition by SLAMF7 is mediated by a mechanism requiring src kinases, CD45, and SHIP-1 that is defective in multiple myeloma cells. Mol Cell Biol. 2015; 35:41-51. [PubMed 25312647]

10. Zonder JA, Mohrbacher AF, Singhal S et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood. 2012; 120:552-9. [PubMed 22184404]

11. Collins SM, Bakan CE, Swartzel GD et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother. 2013; 62:1841-9. [PubMed 24162108]

12. Balasa B, Yun R, Belmar NA et al. Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-α pathways. Cancer Immunol Immunother. 2015; 64:61-73. [PubMed 25287778]

13. Berdeja J, Jagannath S, Zonder J et al. Pharmacokinetics and safety of elotuzumab combined with lenalidomide and dexamethasone in patients with multiple myeloma and various levels of renal impairment: results of a phase Ib study. Clin Lymphoma Myeloma Leuk. 2016; 16:129-38. [PubMed 26795075]

14. Richardson PG, Jagannath S, Moreau P et al. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol. 2015; 2:e516-27. [PubMed 26686406]

15. Afifi S, Michael A, Lesokhin A. Immunotherapy: A new approach to treating multiple myeloma with daratumumab and elotuzumab. Ann Pharmacother. 2016; 50:555-68. [PubMed 27083916]

16. Lonial S, Kaufman J, Laubach J et al. Elotuzumab: a novel anti-CS1 monoclonal antibody for the treatment of multiple myeloma. Expert Opin Biol Ther. 2013; 13:1731-40. [PubMed 24151843]

17. Gibiansky L, Passey C, Roy A et al. Model-based pharmacokinetic analysis of elotuzumab in patients with relapsed/refractory multiple myeloma. J Pharmacokinet Pharmacodyn. 2016; 43:243-57. [PubMed 26993283]

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