EMPLICITI^® (elotuzumab)

Indication(s) Important Safety Information U.S. Full Prescribing Information

INDICATIONS

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 POMALYST 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.

REVLIMID^® (lenalidomide) is a thalidomide analogue indicated for the treatment of adult patients with multiple myeloma (MM) in combination with dexamethasone (dex).

REVLIMID is indicated as maintenance therapy in adult patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT).

REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.

POMALYST^® (pomalidomide) is a thalidomide analogue indicated, in combination with dexamethasone, for adult patients with MM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

IMPORTANT SAFETY INFORMATION FOR REVLIMID, POMALYST & EMPLICITI

CONTRAINDICATIONS

Pregnancy: See Boxed WARNINGS. REVLIMID & POMALYST can cause fetal harm when administered to a pregnant female and are contraindicated in females who are pregnant. If the patient becomes pregnant while taking REVLIMID or POMALYST, the patient should be apprised of the potential risk to the fetus.

Severe Hypersensitivity Reactions: REVLIMID & POMALYST are contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis) to lenalidomide, pomalidomide, or any of the excipients.

REVLIMID, POMALYST & EMPLICITI WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity & Females of Reproductive Potential: See Boxed WARNINGS. Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID or POMALYST.

• Males: REVLIMID & POMALYST are present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID or POMALYST even if they have undergone a successful vasectomy. This protective measure must be followed for up to 4 weeks after discontinuing REVLIMID or POMALYST. Males must not donate sperm while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID, or while taking POMALYST.
• Blood Donation: Patients must not donate blood during treatment with REVLIMID or POMALYST and for 4 weeks following discontinuation of the drug, as the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID or POMALYST.

REMS Program: See Boxed WARNINGS. Prescribers and pharmacies must be certified with the respective Lenalidomide or POMALYST REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID or POMALYST. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements.

• Further information about the POMALYST REMS program is available at www.pomalystrems.com or by telephone at 1-888-423-5436.
• Further information about the Lenalidomide REMS program is available at www.lenalidomiderems.com or by telephone at 1-888-423-5436.

Hematologic Toxicity: REVLIMID & POMALYST can cause significant neutropenia and thrombocytopenia. Neutropenia, anemia, and thrombocytopenia were the most frequently reported Grade 3 or 4 adverse reactions in patients taking REVLIMID & POMALYST in clinical trials. Patients may require dose interruption and/or modification. For REVLIMID, monitor patients with neutropenia for signs of infection and advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. Monitor complete blood counts (CBC) every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. For POMALYST, monitor CBC weekly for the first 8 weeks and monthly thereafter.

Venous & Arterial Thromboembolism: See Boxed WARNINGS. Venous thromboembolic events (DVT and PE) and arterial thromboses (myocardial infarction [MI] and stroke [CVA]) are increased in patients treated with REVLIMID or POMALYST. Thromboprophylaxis is recommended and the regimen should be based on the patient’s underlying risks. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Erythropoietin-stimulating agents (ESAs) and estrogens may further increase the risk of thrombosis when used with REVLIMID and their use should be based on a benefit-risk decision.

Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single-agent REVLIMID therapy increased the risk of death as compared to single-agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID, and in patients with FL or MZL receiving REVLIMID + rituximab therapy, an increase of hematologic plus solid tumor SPM, notably AML, have been observed. In patients with MM, MDS was also observed. In patients taking REVLIMID, monitor for the development of SPM and take into account both the potential benefit of REVLIMID and risk of SPM when considering treatment. In patients receiving POMALYST as an investigational therapy outside of MM, cases of AML have been reported. In the EMPLICITI ELOQUENT-2 trial (N=635), invasive second primary malignancies (SPM) were 9% (ERd) and 6% (Rd). The rate of hematologic malignancies was the same between ERd and Rd treatment arms (1.6%). Solid tumors were reported in 3.5% (ERd) and 2.2% (Rd). Skin cancer was reported in 4.4% (ERd) and 2.8% (Rd). In the ELOQUENT-3 trial (N=115), invasive SPMs were 0% (EPd) and 1.8% (Pd). Monitor patients for the development of SPMs.

Increased Mortality With Pembrolizumab: In clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue (REVLIMID or POMALYST) plus dexamethasone resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Hepatotoxicity: Hepatic failure, including fatal cases, have occurred in patients treated with REVLIMID + dexamethasone and POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor liver function tests monthly for POMALYST, and periodically for REVLIMID. Stop REVLIMID or POMALYST upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.

In the ELOQUENT-2 trial (EMPLICITI + REVLIMID + dexamethasone vs REVLIMID + dexamethasone) (N=635), AST/ALT >3X the upper limit, total bilirubin >2X the upper limit, and alkaline phosphatase <2X the upper limit were 2.5% (EMPLICITI arm) vs 0.6% (control arm). Of 8 patients experiencing hepatotoxicity, 2 patients discontinued treatment while 6 patients had resolution and continued. Stop EMPLICITI upon ≥Grade 3 elevation of liver enzymes. Continuation of treatment may be considered after return to baseline values.

Infusion Reactions: Infusion reactions were reported in 10% of patients treated with EMPLICITI in the ELOQUENT-2 trial [EMPLICITI + REVLIMID + dexamethasone (ERd) vs REVLIMID + dexamethasone (Rd)] and 3.3% in the ELOQUENT-3 trial [EMPLICITI + POMALYST + dexamethasone (EPd) vs POMALYST + dexamethasone (Pd)]. In the ELOQUENT-2 trial, all infusion reactions were Grade 3 or lower, with Grade 3 infusion reactions occurring in 1% of patients. The most common symptoms included fever, chills, and hypertension. Bradycardia and hypotension also developed during infusions. In the 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 the patients who experienced an infusion reaction had them during the first treatment cycle.

• If a Grade 2 or higher infusion reaction occurs, interrupt the EMPLICITI infusion and institute appropriate medical and supportive measures. If the infusion reaction recurs, stop the EMPLICITI infusion and do not restart it on that day. Severe infusion reactions may require permanent discontinuation of EMPLICITI therapy and emergency treatment.
• Premedicate with dexamethasone, H1 blocker, H2 blocker, and acetaminophen prior to EMPLICITI infusion.

Infections: In the ELOQUENT-2 trial (N=635), infections were reported in 81% of patients in the ERd arm and 74% in the Rd arm. Grade 3-4 infections were 28% (ERd) and 24% (Rd). Discontinuations due to infections were 3.5% (ERd) and 4.1% (Rd). Fatal infections were 2.5% (ERd) and 2.2% (Rd). Opportunistic infections were reported in 22% (ERd) and 13% (Rd). Fungal infections were 10% (ERd) and 5% (Rd). Herpes zoster was 14% (ERd) and 7% (Rd). In the ELOQUENT-3 trial (N=115), infections were reported in 65% of patients in both the EPd arm and the Pd arm. Grade 3-4 infections were reported in 13% (EPd) and 22% (Pd). Discontinuations due to infections were 7% (EPd) and 5% (Pd). Fatal infections were 5% (EPd) and 3.6% (Pd). Opportunistic infections were reported in 10% (EPd) and 9% (Pd). Herpes zoster was reported in 5% (EPd) and 1.8% (Pd). Monitor patients for development of infections and treat promptly.

Severe Cutaneous Reactions: Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with REVLIMID & POMALYST. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These reactions can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. Consider REVLIMID & POMALYST interruption or discontinuation for Grade 2 or 3 skin rash. Permanently discontinue REVLIMID & POMALYST for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN, or DRESS.

Tumor Lysis Syndrome (TLS): TLS may occur in patients treated with REVLIMID or POMALYST. Fatal instances of TLS have been reported during treatment with REVLIMID. Closely monitor patients at risk and take appropriate preventive approaches.

Hypersensitivity: Hypersensitivity including angioedema, anaphylaxis, and anaphylactic reactions to REVLIMID & POMALYST have been reported. Permanently discontinue REVLIMID & POMALYST for angioedema or anaphylaxis.

Dizziness & Confusional State: In patients taking POMALYST in clinical trials, 14% experienced dizziness (1% Grade 3 or 4) and 7% a confusional state (3% Grade 3 or 4). Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.

Neuropathy: In patients taking POMALYST in clinical trials, 18% experienced neuropathy (2% Grade 3 in one trial) and 12% peripheral neuropathy.

Tumor Flare Reaction (TFR): Serious tumor flare reactions, including fatal reactions, have occurred during investigational use of REVLIMID for CLL and lymphoma. Monitoring and evaluation for TFR is recommended in patients with MCL, FL, or MZL.

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (>4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection.

Thyroid Disorders: Both hypothyroidism and hyperthyroidism have been reported. Measure thyroid function before starting REVLIMID treatment and during therapy.

Early Mortality in Patients With MCL: In another MCL study, there was an increase in early deaths (within 20 weeks); 12.9% in the REVLIMID arm versus 7.1% in the control arm. Risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (≥10 x 10⁹/L).

Interference with Determination of Complete Response: EMPLICITI is a humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein.

ADVERSE REACTIONS

REVLIMID - Multiple Myeloma

• In Newly Diagnosed: The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more Grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18.
  • The most common adverse reactions reported in ≥20% (Arm Rd Continuous): diarrhea (45%), anemia (44%), neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash (26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (20%), muscle spasms (20%), and thrombocytopenia (20%).
• Maintenance Therapy Post Auto-HSCT: The most frequently reported Grade 3 or 4 reactions in ≥20% (REVLIMID arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions of lung infection and neutropenia (more than 4.5%) occurred in the REVLIMID arm.
  • The most frequently reported adverse reactions in ≥20% (REVLIMID arm) across both maintenance studies (Study 1, Study 2) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (4%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (54%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 20%).
• After at Least One Prior Therapy: The most common adverse reactions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (27% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight decreased (20% vs 15%).

POMALYST

• The most common adverse reactions for POMALYST (≥30%) included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain, and pyrexia.
• In the phase III trial, nearly all patients treated with POMALYST + low-dose dex experienced at least one adverse reaction (99%). Adverse reactions (≥15% in the POMALYST + low-dose dex arm and ≥2% higher than control) included neutropenia (51%), fatigue and asthenia (47%), upper respiratory tract infection (31%), thrombocytopenia (30%), pyrexia (27%), dyspnea (25%), diarrhea (22%), constipation (22%), back pain (20%), cough (20%), pneumonia (19%), bone pain (18%), edema peripheral (17%), peripheral neuropathy (17%), muscle spasms (15%), and nausea (15%). Grade 3 or 4 adverse reactions (≥15% in the POMALYST + low-dose dex arm and ≥1% higher than control) included neutropenia (48%), thrombocytopenia (22%), and pneumonia (16%).

EMPLICITI

• ELOQUENT-2 trial: Serious adverse reactions were 65% (ERd) and 57% (Rd). The most frequent serious adverse reactions in the ERd arm compared to the Rd arm were: pneumonia (15%, 11%), pyrexia (7%, 5%), respiratory tract infection (3.1%, 1.3%), anemia (2.8%, 1.9%), pulmonary embolism (3.1%, 2.5%), and acute renal failure (2.5%, 1.9%). The most common adverse reactions in ERd and Rd, respectively (≥20%) were fatigue (62%, 52%), diarrhea (47%, 36%), pyrexia (37%, 25%), constipation (36%, 27%), cough (34%, 19%), peripheral neuropathy (27%, 21%), nasopharyngitis (25%, 19%), upper respiratory tract infection (23%, 17%), decreased appetite (21%, 13%), and pneumonia (20%, 14%).
• ELOQUENT-3 trial: Serious adverse reactions were 70% (EPd) and 60% (Pd). The most frequent serious adverse reactions in the EPd arm compared to the Pd arm were: pneumonia (13%, 11%) and respiratory tract infection (7%, 3.6%). The most common adverse reactions in EPd arm (≥20% EPd) and Pd, respectively, were constipation (22%, 11%) and hyperglycemia (20%, 15%).

DRUG INTERACTIONS

• REVLIMID: Periodically monitor digoxin plasma levels due to increased C_max and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as ESAs or estrogen-containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin.
• POMALYST: Avoid concomitant use with strong inhibitors of CYP1A2. If concomitant use of a strong CYP1A2 inhibitor is unavoidable, reduce POMALYST dose to 2 mg.

USE IN SPECIFIC POPULATIONS

• Pregnancy: See Boxed WARNINGS for REVLIMID & POMALYST. If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There are REVLIMID and POMALYST pregnancy exposure registries that monitor pregnancy outcomes in females exposed to REVLIMID or POMALYST during pregnancy as well as female partners of male patients who are exposed to REVLIMID or POMALYST. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure of the drug to the FDA via the MedWatch program at 1-800-FDA-1088 and also to REMS Call Center at 1-888-423-5436.
• Pregnancy and EMPLICITI Use: There are no available data on EMPLICITI use in pregnant women to inform a drug-associated risk of major defects and miscarriage.
• Lactation: There is no information regarding the presence of pomalidomide, lenalidomide or elotuzumab in human milk, the effects of POMALYST, REVLIMID or EMPLICITI on the breastfed child, or the effects of POMALYST, REVLIMID or EMPLICITI on milk production. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child from POMALYST or REVLIMID, advise women not to breastfeed during treatment.
• Pediatric Use: Safety and effectiveness of REVLIMID, POMALYST or in combination with EMPLICITI have not been established in pediatric patients.
• Geriatric Use: No dose adjustment is required for POMALYST based on age. Patients >65 years of age were more likely than patients ≤65 years of age to experience pneumonia.
• Renal Impairment: Adjust the starting dose of REVLIMID based on the creatinine clearance value and for patients on dialysis. For POMALYST in patients with severe renal impairment requiring dialysis, reduce the recommended dosage to 3 mg orally daily. Take dose of POMALYST following hemodialysis on hemodialysis days.
• Hepatic Impairment: In patients with mild to moderate hepatic impairment, reduce POMALYST dosage to 3 mg orally daily and to 2 mg orally daily in patients with severe hepatic impairment.
• Smoking Tobacco: Advise patients that smoking may reduce the efficacy of POMALYST. Cigarette smoking reduces pomalidomide AUC due to CYP1A2 induction.

Please see U.S. Full Prescribing Information for REVLIMID, POMALYST, and EMPLICITI, including Boxed WARNINGS for REVLIMID and POMALYST.