Empliciti
(elotuzumab)Dosage & Administration
Empliciti Prescribing Information
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- EMPLICITI is indicated in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one to three prior therapies.
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- EMPLICITI is 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.
Recommended Dosing when EMPLICITI Is Used in Combination with Lenalidomide and Dexamethasone
The recommended dosage of EMPLICITI is 10 mg/kg administered intravenously every week for the first two cycles (28-day cycle) and every 2 weeks thereafter in conjunction with the recommended dosing of lenalidomide and low-dose dexamethasone as described below. Continue treatment until disease progression or unacceptable toxicity.
Refer to the dexamethasone and lenalidomide prescribing information for additional information.
Administer premedications before each dose of EMPLICITI [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
Administer dexamethasone as follows:
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- On days that EMPLICITI is administered, give dexamethasone 28 mg orally between 3 and 24 hours before EMPLICITI plus 8 mg intravenously between 45 and 90 minutes before EMPLICITI.
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- On days that EMPLICITI is not administered but a dose of dexamethasone is scheduled (Days 8 and 22 of cycle 3 and all subsequent cycles), give 40 mg orally.
The recommended dosing is presented in Table 1.
| Cycle | 28-Day Cycles 1 and 2 | 28-Day Cycles 3+ | ||||||
|---|---|---|---|---|---|---|---|---|
| * Premedicate with the following 45 to 90 minutes prior to EMPLICITI infusion: 8 mg intravenous dexamethasone, H1 blocker: diphenhydramine (25 to 50 mg orally or intravenously) or equivalent; H2 blocker: ranitidine (50 mg intravenously) or equivalent; acetaminophen (650 to 1000 mg orally). † Oral dexamethasone (28 mg) taken between 3 and 24 hours before EMPLICITI infusion. ** Intravenous dexamethasone 45-90 minutes before EMPLICITI infusion. | ||||||||
Day of Cycle | 1 | 8 | 15 | 22 | 1 | 8 | 15 | 22 |
Premedication* | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ||
EMPLICITI (mg/kg) intravenously | 10 | 10 | 10 | 10 | 10 | 10 | ||
Lenalidomide (25 mg) orally | Days 1-21 | Days 1-21 | ||||||
Dexamethasone† (mg) orally | 28 | 28 | 28 | 28 | 28 | 40 | 28 | 40 |
Dexamethasone** (mg) intravenously | 8 | 8 | 8 | 8 | 8 | 8 | ||
Day of Cycle | 1 | 8 | 15 | 22 | 1 | 8 | 15 | 22 |
Recommended Dosing when EMPLICITI Is Used in Combination with Pomalidomide and Dexamethasone
The recommended dosage of EMPLICITI is 10 mg/kg administered intravenously every week for the first two cycles (28-day cycle). Starting at cycle 3 (28-day cycle), administer EMPLICITI 20 mg/kg intravenously every 4 weeks. Administer EMPLICITI in conjunction with pomalidomide and low-dose dexamethasone as described below (Table 2). Continue treatment until disease progression or unacceptable toxicity.
Refer to the dexamethasone and pomalidomide prescribing information for additional information.
Administer premedications before each dose of EMPLICITI [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
Administer dexamethasone as follows:
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- On days that EMPLICITI is administered, for patients 75 years or younger give dexamethasone 28 mg orally between 3 and 24 hours before EMPLICITI plus 8 mg intravenously between 45 and 90 minutes before EMPLICITI and for patients older than 75 years give dexamethasone 8 mg orally between 3 and 24 hours before EMPLICITI plus 8 mg intravenously between 45 and 90 minutes before EMPLICITI.
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- On days that EMPLICITI is not administered but a dose of dexamethasone is scheduled (Days 8, 15 and 22 of cycle 3 and all subsequent cycles), give 40 mg orally to patients 75 years or younger and 20 mg orally to patients older than 75 years.
The recommended dosing is presented in Table 2.
| Cycle | 28-Day Cycles 1 and 2 | 28-Day Cycles 3+ | ||||||
|---|---|---|---|---|---|---|---|---|
| * Premedicate with the following 45 to 90 minutes prior to EMPLICITI infusion: 8 mg intravenous dexamethasone, H1 blocker: diphenhydramine (25 to 50 mg orally or intravenously) or equivalent; H2 blocker: ranitidine (50 mg intravenously) or equivalent; acetaminophen (650 to 1000 mg orally). † Oral dexamethasone taken between 3 and 24 hours before EMPLICITI infusion. ** Intravenous dexamethasone 45-90 minutes before EMPLICITI infusion. | ||||||||
Day of Cycle | 1 | 8 | 15 | 22 | 1 | 8 | 15 | 22 |
Premedication* | ✓ | ✓ | ✓ | ✓ | ✓ | |||
EMPLICITI (mg/kg) intravenously | 10 | 10 | 10 | 10 | 20 | |||
Pomalidomide (4 mg) orally | Days 1-21 | Days 1-21 | ||||||
Dexamethasone† (mg) orally ≤75 years old | 28 | 28 | 28 | 28 | 28 | 40 | 40 | 40 |
Dexamethasone† (mg) orally >75 years old | 8 | 8 | 8 | 8 | 8 | 20 | 20 | 20 |
Dexamethasone** (mg) intravenously | 8 | 8 | 8 | 8 | 8 | |||
Premedication
Dexamethasone
When EMPLICITI is used in combination with lenalidomide or pomalidomide and dexamethasone, divide dexamethasone into an oral and intravenous dose and administer as shown in Table 1 and Table 2 [see Dosage and Administration (2.1, 2.2)].
Other Medications
In addition to dexamethasone, complete administration of the following medications 45 to 90 minutes prior to EMPLICITI infusion:
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- H1 blocker: diphenhydramine (25 to 50 mg orally or intravenously) or equivalent H1 blocker.
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- H2 blocker: ranitidine (50 mg intravenously or 150 mg orally) or equivalent H2 blocker.
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- Acetaminophen (650 to 1000 mg orally).
Dose Modifications
If the dose of one drug in the regimen is delayed, interrupted, or discontinued, the treatment with the other drugs may continue as scheduled. However, if dexamethasone is delayed or discontinued, base the decision whether to administer EMPLICITI on clinical judgment (i.e., risk of hypersensitivity).
If a Grade 2 or higher infusion reaction occurs during EMPLICITI administration, interrupt the infusion and institute appropriate medical and supportive measures. Upon resolution to Grade 1 or lower, restart EMPLICITI at 0.5 mL per minute and gradually increase at a rate of 0.5 mL per minute every 30 minutes as tolerated to the rate at which the infusion reaction occurred. Resume the escalation regimen if there is no recurrence of the infusion reaction (see Table 3 and Table 4).
In patients who experience an infusion reaction, monitor vital signs every 30 minutes for 2 hours after the end of the EMPLICITI infusion. If the infusion reaction recurs, stop the EMPLICITI infusion and do not restart on that day [see Warnings and Precautions (5.1)]. Severe infusion reactions may require permanent discontinuation of EMPLICITI therapy and emergency treatment.
Dose delays and modifications for dexamethasone, pomalidomide and lenalidomide should be performed as recommended in their Prescribing Information.
Administration
Administer the entire EMPLICITI infusion with an infusion set and a sterile, nonpyrogenic, low-protein-binding filter (with a pore size of 0.2 to 1.2 micrometer) using an automated infusion pump.
Initiate EMPLICITI infusion at a rate of 0.5 mL per minute for 10 mg/kg dose. The infusion rate may be increased in a stepwise fashion as described in Table 3 if no infusion reactions develop. The maximum infusion rate should not exceed 5 mL per minute.
| Cycle 1, Dose 1 | Cycle 1, Dose 2 | Cycle 1, Dose 3 and 4 and All Subsequent Cycles | ||
|---|---|---|---|---|
Time Interval | Rate | Time Interval | Rate | Rate |
0-30 min | 0.5 mL/min | 0-30 min | 3 mL/min | |
30-60 min | 1 mL/min | 30 min or more | 4 mL/min | 5 mL/min |
60 min or more | 2 mL/min | - | - | |
Initiate EMPLICITI infusion rate at 3 mL per minute for 20 mg/kg dose. The infusion rate may be increased in a stepwise fashion as described in Table 4 if no infusion reactions develop. The maximum infusion rate should not exceed 5 mL per minute.
Patients who have escalated to 5 mL/min at 10 mg/kg dose must decrease the rate to 3 mL/min at the first infusion at 20 mg/kg.
Dose 1 | Dose 2 and all subsequent doses | |
Time Interval | Rate | Rate |
0-30 min | 3 mL/min | |
30 min or more | 4 mL/min | 5 mL/min |
Adjust the infusion rate following a Grade 2 or higher infusion reaction [see Dosage and Administration (2.4)].
Do not mix EMPLICITI with, or administer as an infusion with, other medicinal products. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of EMPLICITI with other agents.
Reconstitution and Preparation
Calculation of Dose
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- Calculate the dose (mg) and determine the number of vials needed for the 10 mg/kg and 20 mg/kg dosage based on patient weight.
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- Determine the volume of sterile water for injection (SWFI) needed for reconstitution as shown in Table 5.
| Strength | Amount of Sterile Water for Injection, USP Required for Reconstitution | Deliverable Volume of Reconstituted EMPLICITI in the Vial | Postreconstitution Concentration |
|---|---|---|---|
| * After reconstitution, each vial contains overfill to allow for withdrawal of 12 mL (300 mg) and 16 mL (400 mg), respectively. | |||
300 mg vial | 13 mL | 12 mL* | 25 mg/mL |
400 mg vial | 17 mL | 16 mL* | 25 mg/mL |
Reconstitution
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- Aseptically reconstitute each EMPLICITI vial with a syringe of adequate size and a less than or equal to 18-gauge needle (e.g., 17-gauge). A slight back pressure may be experienced during administration of the Sterile Water for Injection, USP, which is considered normal.
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- Hold the vial upright and swirl the solution by rotating the vial to dissolve the lyophilized cake. Invert the vial a few times in order to dissolve any powder that may be present on top of the vial or the stopper. Avoid vigorous agitation. DO NOT SHAKE. The lyophilized powder should dissolve in less than 10 minutes.
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- After the remaining solids are completely dissolved, allow the reconstituted solution to stand for 5 to 10 minutes. The reconstituted preparation results in a colorless to slightly yellow, clear to slightly opalescent solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the solution if any particulate matter or discoloration is observed.
Dilution
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- Once the reconstitution is completed, withdraw the necessary volume for the calculated dose from each vial, up to a maximum of 16 mL from 400 mg vial and 12 mL from 300 mg vial.
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- Further dilute with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, into an infusion bag made of polyvinyl chloride or polyolefin. The final infusion concentration should range between 1 mg/mL and 6 mg/mL.
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- The volume of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP should be adjusted so as not to exceed 5 mL/kg of patient weight at any given dose of EMPLICITI.
Complete the EMPLICITI infusion within 24 hours of reconstitution of the EMPLICITI lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2°C to 8°C (36°F-46°F) and protected from light for up to 24 hours (a maximum of 8 hours of the total 24 hours can be at room temperature, 20°C to 25°C [68°F-77°F], and room light).
For injection: 300 mg or 400 mg of elotuzumab as a white to off-white lyophilized powder in a single-dose vial for reconstitution.
Pregnancy
Risk Summary
There are no available data on EMPLICITI use in pregnant women to inform a drug associated risk of major birth defects and miscarriage. Animal reproduction studies have not been conducted with elotuzumab.
EMPLICITI is administered in combination with lenalidomide and dexamethasone or pomalidomide and dexamethasone. Lenalidomide and pomalidomide can cause embryo-fetal harm and are contraindicated for use in pregnancy. Refer to the lenalidomide, pomalidomide and dexamethasone prescribing information for additional information. Lenalidomide and pomalidomide are only available through a REMS program.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, 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 2-4% and 15-20%, respectively.
Lactation
Risk Summary
There are no data on the presence of EMPLICITI in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child from elotuzumab administered in combination with lenalidomide and dexamethasone or pomalidomide and dexamethasone, advise lactating women not to breastfeed during treatment with EMPLICITI. Refer to the lenalidomide, pomalidomide and dexamethasone prescribing information for additional information.
Females and Males of Reproductive Potential
Pregnancy Testing
Refer to the lenalidomide and pomalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential.
When EMPLICITI is used with lenalidomide or pomalidomide, there is a risk of fetal harm, including severe life-threatening human birth defects associated with lenalidomide and pomalidomide, and the need to follow requirements regarding pregnancy avoidance, including testing.
Contraception
Females
Refer to the lenalidomide and pomalidomide labeling for contraception requirements prior to initiating treatment in females of reproductive potential.
Males
Lenalidomide and pomalidomide are present in the blood and semen of patients receiving the drug. Refer to the lenalidomide and pomalidomide full prescribing information for requirements regarding contraception and the prohibitions against blood and/or sperm donation due to presence and transmission in blood and/or semen and for additional information.
Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
Geriatric Use
Of the 646 patients across treatment groups in the ELOQUENT-2 randomized trial designed to evaluate the use of EMPLICITI in combination with lenalidomide and low-dose dexamethasone in multiple myeloma, 57% were 65 years of age or older; the number of patients 65 years or older was similar between treatment groups. No overall differences in efficacy or safety were observed between patients 65 years or older and younger patients (less than 65 years of age).
Of the 117 patients across treatment groups in the ELOQUENT-3 randomized trial designed to evaluate the use of EMPLICITI in combination with pomalidomide and low-dose dexamethasone in multiple myeloma, 62% were 65 years of age or older; the number of patients 65 years or older was similar between treatment groups. This study did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
None.
Infusion Reactions
EMPLICITI can cause infusion reactions. Infusion reactions were reported in 10% of patients treated with EMPLICITI in the ELOQUENT-2 trial and 3.3% in the ELOQUENT-3 trial. In the ELOQUENT-2 trial, all reports of infusion reaction were Grade 3 or lower. In the ELOQUENT-2 trial, Grade 3 infusion reactions occurred in 1% of patients. The most common symptoms of an infusion reaction included fever, chills, and hypertension. Bradycardia and hypotension also developed during infusions.
In the ELOQUENT-2 trial, 5% of patients required interruption of the administration of EMPLICITI for a median of 25 minutes due to infusion reactions, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had them during the first dose.
In the ELOQUENT-3 trial, the only infusion reaction symptom was chest discomfort (2%), which was Grade 1. All patients in the ELOQUENT-3 trial who experienced an infusion reaction had them during the first treatment cycle.
Administer premedication consisting of dexamethasone, antihistamines (H1 and H2 blockers) and acetaminophen prior to EMPLICITI infusion [see Dosage and Administration (2.3)].
Interrupt EMPLICITI infusion for Grade 2 or higher infusion reactions and institute appropriate medical management [see Dosage and Administration (2.4)].
Infections
In the ELOQUENT-2 trial (N=635), infections were reported in 81% of patients in EMPLICITI combined with lenalidomide and dexamethasone (E-Ld) arm and 74% in lenalidomide and dexamethasone (Ld). In the ELOQUENT-3 trial (N=115), infections were reported in 65% of patients in both EMPLICITI combined with pomalidomide and dexamethasone (E-Pd) arm and in pomalidomide and dexamethasone (Pd) arm. In the ELOQUENT-2 trial, Grade 3 to 4 infections were noted in 28% and 24% of E-Ld- and Ld-treated patients and in the ELOQUENT-3 trial, 13% and 22% of E-Pd- and Pd-treated patients, respectively. Discontinuations due to infections occurred in 3.5% of E-Ld-treated and 4.1% of Ld-treated patients in the ELOQUENT-2 trial and 7% of E-Pd-treated and 5% of Pd-treated patients in the ELOQUENT-3 trial. Fatal infections were reported in 2.5% and 2.2% of E-Ld- and Ld-treated patients in the ELOQUENT-2 trial and 5% and 3.6% of E-Pd- and Pd-treated patients in the ELOQUENT-3 trial.
Opportunistic infections were reported in 22% of patients in the E-Ld arm and 13% of patients in the Ld arm in the ELOQUENT-2 trial and 10% of patients in the E-Pd arm and 9% of patients in the Pd arm in the ELOQUENT-3 trial. In the ELOQUENT-2 trial, fungal infections occurred in 10% of patients in the E-Ld arm and 5% of patients in the Ld arm. Herpes zoster was reported in 14% of patients treated with E-Ld and 7% of patients treated with Ld in the ELOQUENT-2 trial and 5% of patients treated with E-Pd and 1.8% of patients treated with Pd in the ELOQUENT-3 trial.
Monitor patients for development of infections and treat promptly.
Second Primary Malignancies
In the ELOQUENT-2 trial (N=635), invasive second primary malignancies (SPM) have been observed in 9% of patients treated with E-Ld and 6% of patients treated with Ld and in the ELOQUENT-3 trial (N=115) in 1.8% of patients treated with Pd and in none of the patients treated with E-Pd. In the ELOQUENT-2 trial, the rate of hematologic malignancies were the same between E-Ld and Ld treatment arms (1.6%). Solid tumors were reported in 3.5% and 2.2% of E-Ld- and Ld-treated patients, respectively. Skin cancer was reported in 4.4% and 2.8% of patients treated with E-Ld and Ld, respectively.
Monitor patients for the development of second primary malignancies.
Hepatotoxicity
In the ELOQUENT-2 trial (N=635), elevations in liver enzymes (aspartate transaminase/alanine transaminase [AST/ALT] greater than 3 times the upper limit, total bilirubin greater than 2 times the upper limit, and alkaline phosphatase less than 2 times the upper limit) consistent with hepatotoxicity were reported in 2.5% and 0.6% of E-Ld- and Ld-treated patients. Two patients experiencing hepatotoxicity were not able to continue treatment; however, 6 out of 8 patients had resolution and were able to continue treatment. Monitor liver enzymes periodically. Stop EMPLICITI upon Grade 3 or higher elevation of liver enzymes. After return to baseline values, continuation of treatment may be considered.
Interference with Determination of Complete Response
EMPLICITI is a humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPEP) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein [see Drug Interactions (7.2)]. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein.