Empliciti

• •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.
• •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.

• •With lenalidomide and dexamethasone: 10 mg/kg administered intravenously every week for the first two cycles and every 2 weeks thereafter until disease progression or unacceptable toxicity.
  2.1 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:

  • •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.
  • •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.

  Table 1:   Recommended Dosing Schedule of EMPLICITI in Combination with Lenalidomide and Dexamethasone

  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
• •With pomalidomide and dexamethasone: 10 mg/kg administered intravenously every week for the first two cycles and 20 mg/kg every 4 weeks thereafter until disease progression or unacceptable toxicity.
  2.2 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:

  • •
    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.
  • •
    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.

  Table 2:   Recommended Dosing Schedule of EMPLICITI in Combination with Pomalidomide and Dexamethasone

  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
• •Premedicate with dexamethasone, diphenhydramine, ranitidine and acetaminophen.
  2.3 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:

  • •H1 blocker: diphenhydramine (25 to 50 mg orally or intravenously) or equivalent H1 blocker.
  • •H2 blocker: ranitidine (50 mg intravenously or 150 mg orally) or equivalent H2 blocker.
  • •Acetaminophen (650 to 1000 mg orally).

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: Embryo-fetal toxicity in combination with lenalidomide and dexamethasone or pomalidomide and dexamethasone.

• •Infusion reactions: Premedication is required. Interrupt EMPLICITI for Grade 2 or higher and permanently discontinue for severe infusion reaction.
  2.2 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:

  • •
    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.
  • •
    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.

  Table 2:   Recommended Dosing Schedule of EMPLICITI in Combination with Pomalidomide and Dexamethasone

  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
  2.3 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:

  • •H1 blocker: diphenhydramine (25 to 50 mg orally or intravenously) or equivalent H1 blocker.
  • •H2 blocker: ranitidine (50 mg intravenously or 150 mg orally) or equivalent H2 blocker.
  • •Acetaminophen (650 to 1000 mg orally).
  ,
  2.4 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.
  ,
  5.1 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: Monitor for fever and other signs of infection and treat promptly.
  5.2 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 (SPM): Higher incidences of SPM were observed in a controlled clinical trial of patients with multiple myeloma receiving EMPLICITI.
  5.3 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: Monitor liver function and stop EMPLICITI if hepatotoxicity is suspected.
  5.4 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 can interfere with assays used to monitor M-protein. This interference can impact the determination of complete response.
  5.5 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.