Revlimid

Warnings and Precautions ( 5.1 , 5.2 ) 8/2021 Warnings and Precautions ( 5.1 , 5.11 ) 5/2022

1 INDICATIONS AND USAGE REVLIMID is a thalidomide analogue indicated for the treatment of adult patients with: • Multiple myeloma (MM), in combination with dexamethasone ( 1.1 ). • MM, as maintenance following autologous hematopoietic stem cell transplantation (auto-HSCT) ( 1.1 ). • Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities ( 1.2 ). • Mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib ( 1.3 ). • Previously treated follicular lymphoma (FL), in combination with a rituximab product ( 1.4 ). • Previously treated marginal zone lymphoma (MZL), in combination with a rituximab product ( 1.5 ). Limitations of Use: • REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials ( 1.4 ). 1.1 Multiple Myeloma REVLIMID in combination with dexamethasone is indicated for the treatment of adult patients with multiple myeloma (MM). REVLIMID is indicated as maintenance therapy in adult patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT). 1.2 Myelodysplastic Syndromes REVLIMID is indicated for the treatment of adult patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. 1.3 Mantle Cell Lymphoma REVLIMID is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. 1.4 Follicular Lymphoma REVLIMID in combination with a rituximab product, is indicated for the treatment of adult patients with previously treated follicular lymphoma (FL). 1.5 Marginal Zone Lymphoma REVLIMID in combination with a rituximab product, is indicated for the treatment of adult patients with previously treated marginal zone lymphoma (MZL). 1.6 Limitations of Use REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5) ] .

2 DOSAGE AND ADMINISTRATION • MM combination therapy: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles. ( 2.1 ). • MM maintenance therapy following auto-HSCT: 10 mg once daily continuously on Days 1-28 of repeated 28-day cycles ( 2.1 ). • MDS: 10 mg once daily ( 2.2 ). • MCL: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles ( 2.3 ). • FL or MZL: 20 mg once daily orally on Days 1-21 of repeated 28-day cycles for up to 12 cycles ( 2.4 ). • Renal impairment: Adjust starting dose based on the creatinine clearance value ( 2.6 ). • For concomitant therapy doses, see Full Prescribing Information ( 2.1 , 2.4 , 14.1 , 14.4 ). 2.1 Recommended Dosage for Multiple Myeloma REVLIMID Combination Therapy The recommended starting dose of REVLIMID is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with dexamethasone. Refer to Section 14.1 for specific dexamethasone dosing. For patients greater than 75 years old, the starting dose of dexamethasone may be reduced [see Clinical Studies (14.1) ] . Treatment should be continued until disease progression or unacceptable toxicity. In patients who are not eligible for auto-HSCT, treatment should continue until disease progression or unacceptable toxicity. For patients who are auto-HSCT-eligible, hematopoietic stem cell mobilization should occur within 4 cycles of a REVLIMID-containing therapy [see Warnings and Precautions (5.12) ]. Dose Adjustments for Hematologic Toxicities During MM Treatment Dose modification guidelines, as summarized in Table 1 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID. Table 1: Dose Adjustments for Hematologic Toxicities for MM Platelet counts Thrombocytopenia in MM When Platelets Recommended Course Days 1-21 of repeated 28-day cycle Fall below 30,000/mcL Interrupt REVLIMID treatment, follow CBC weekly Return to at least 30,000/mcL Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily For each subsequent drop below 30,000/mcL Interrupt REVLIMID treatment Return to at least 30,000/mcL Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily Absolute Neutrophil counts (ANC) Neutropenia in MM When Neutrophils Recommended Course Days 1-21 of repeated 28-day cycle Fall below 1,000/mcL Interrupt REVLIMID treatment, follow CBC weekly Return to at least 1,000/mcL and neutropenia is the only toxicity Resume REVLIMID at 25 mg daily or initial starting dose Return to at least 1,000/mcL and if other toxicity Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily For each subsequent drop below 1,000/mcL Interrupt REVLIMID treatment Return to at least 1,000/mcL Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily REVLIMID Maintenance Therapy Following Auto-HSCT Following auto-HSCT, initiate REVLIMID maintenance therapy after adequate hematologic recovery (ANC at least 1,000/mcL and/or platelet counts at least 75,000/mcL). The recommended starting dose of REVLIMID is 10 mg once daily continuously (Days 1-28 of repeated 28-day cycles) until disease progression or unacceptable toxicity. After 3 cycles of maintenance therapy, the dose can be increased to 15 mg once daily if tolerated. Dose Adjustments for Hematologic Toxicities During MM Treatment Dose modification guidelines, as summarized in Table 2 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID. Table 2: Dose Adjustments for Hematologic Toxicities for MM Platelet counts Thrombocytopenia in MM When Platelets Recommended Course Fall below 30,000/mcL Interrupt REVLIMID treatment, follow CBC weekly Return to at least 30,000/mcL Resume REVLIMID at next lower dose, continuously for Days 1-28 of repeated 28-day cycle If at the 5 mg daily dose, For a subsequent drop below 30,000/mcL Interrupt REVLIMID treatment. Do not dose below 5 mg daily for Day 1 to 21 …

3 DOSAGE FORMS AND STRENGTHS Capsules: • 2.5 mg, white and blue-green opaque hard capsules imprinted "REV" on one half and "2.5 mg" on the other half in black ink • 5 mg, white opaque capsules imprinted "REV" on one half and "5 mg" on the other half in black ink • 10 mg, blue/green and pale yellow opaque capsules imprinted "REV" on one half and "10 mg" on the other half in black ink • 15 mg, powder blue and white opaque capsules imprinted "REV" on one half and "15 mg" on the other half in black ink • 20 mg, powder blue and blue-green opaque hard capsules imprinted "REV" on one half and "20 mg" on the other half in black ink • 25 mg, white opaque capsules imprinted "REV" on one half and "25 mg" on the other half in black ink Capsules: 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg ( 3 ).

4 CONTRAINDICATIONS • Pregnancy ( Boxed Warning , 4.1 , 5.1 , 8.1 ). • Demonstrated severe hypersensitivity to lenalidomide ( 4.2 , 5.9 , 5.15 ). 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide's structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning ]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus [see Warnings and Precautions (5.1 , 5.2) , Use in Special Populations (8.1 , 8.3) ] . 4.2 Severe Hypersensitivity Reactions REVLIMID is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.9 , 5.15 )].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in detail in other sections of the prescribing information: o Embryo-Fetal Toxicity [see Boxed Warning , Warnings and Precautions (5.1 , 5.2) ] o Hematologic Toxicity [see Boxed Warning , Warnings and Precautions (5.3) ] o Venous and Arterial Thromboembolism [see Boxed Warning , Warnings and Precautions (5.4) ] o Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5) ] o Second Primary Malignancies [see Warnings and Precautions (5.6) ] o Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone [see Warnings and Precautions (5.7) ] o Hepatotoxicity [see Warnings and Precautions (5.8) ] o Severe Cutaneous Reactions [see Warnings and Precautions (5.9) ] o Tumor Lysis Syndrome [see Warnings and Precautions (5.10) ] o Tumor Flare Reactions [see Warnings and Precautions (5.11) ] o Impaired Stem Cell Mobilization [see Warnings and Precautions (5.12) ] o Thyroid Disorders [see Warnings and Precautions (5.13) ] o Early Mortality in Patients with MCL [see Warnings and Precautions (5.14) ] o Hypersensitivity [see Warnings and Precautions (5.15) ] • MM: Most common adverse reactions (≥20%) include diarrhea, fatigue, anemia, constipation, neutropenia, leukopenia, peripheral edema, insomnia, muscle cramp/spasms, abdominal pain, back pain, nausea, asthenia, pyrexia, upper respiratory tract infection, bronchitis, nasopharyngitis, gastroenteritis, cough, rash, dyspnea, dizziness, decreased appetite, thrombocytopenia, and tremor ( 6.1 ). • MDS: Most common adverse reactions (>15%) include thrombocytopenia, neutropenia, diarrhea, pruritus, rash, fatigue, constipation, nausea, nasopharyngitis, arthralgia, pyrexia, back pain, peripheral edema, cough, dizziness, headache, muscle cramp, dyspnea, pharyngitis, and epistaxis ( 6.1 ). • Non-Hodgkin's Lymphoma (NHL: MCL, FL or MZL): Most common adverse reactions (≥15%) included neutropenia, thrombocytopenia, anemia, leukopenia, diarrhea, constipation, nausea, fatigue, pyrexia, cough, upper respiratory tract infection, and rash ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed MM – REVLIMID Combination Therapy: Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of REVLIMID with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7). In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. 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. In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of REVLIMID were infection ev …

7 DRUG INTERACTIONS • Digoxin: Monitor digoxin plasma levels periodically due to increased C max and AUC with concomitant REVLIMID therapy ( 7.1 ). • Concomitant use of erythropoietin stimulating agents or estrogen containing therapies with REVLIMID may increase the risk of thrombosis ( 7.2 ). 7.1 Digoxin When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin C max and AUC inf were increased by 14%. Periodically monitor digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, during administration of REVLIMID. 7.2 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID [see Warnings and Precautions (5.4) ] . 7.3 Warfarin Co-administration of multiple doses of REVLIMID (10 mg/day) with a single dose of warfarin (25 mg) had no effect on the pharmacokinetics of lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. 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.

8 USE IN SPECIFIC POPULATIONS • Lactation: Advise not to breastfeed ( 8.2 ). 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy as well as female partners of male patients who are exposed to REVLIMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the REMS Call Center at 1-888-423-5436. Risk Summary Based on the mechanism of action [see Clinical Pharmacology (12.1) ] and findings from animal studies [see Data] , REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy [see Boxed Warning , Contraindications (4.1) , and Use in Specific Populations (5.1) ] . REVLIMID is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Lenalidomide caused thalidomide-type limb defects in monkey offspring. Lenalidomide crossed the placenta after administration to pregnant rabbits and pregnant rats [see Data ] . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the REMS Call Center at 1-888-423-5436. The estimated 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. The estimated background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies. Data Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats. In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide. Following daily oral administration of lenalidomide from Gestation Day 7 through Gestation Day 20 in pregnant rabbits, fetal plasma lenalidomide concentrations were approximately 20-40% of the maternal C max. Following a single oral dose to pregnant rats …

12.1 Mechanism of Action Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of lenalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. In vitro, in the presence of drug, substrate proteins (including Aiolos, Ikaros, and CK1α) are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects. Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including MM, mantle cell lymphoma, and del (5q) myelodysplastic syndromes, follicular lymphoma and marginal zone lymphoma in vitro . Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including MM. Immunomodulatory properties of lenalidomide include increased number and activation of T cells and natural killer (NK) cells leading to direct and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) via increased secretion of interleukin-2 and interferon-gamma, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In MM cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis. The combination of lenalidomide and rituximab increases ADCC and direct tumor apoptosis in follicular lymphoma cells and increases ADCC in marginal zone lymphoma cells compared to rituximab alone in vitro .

11 DESCRIPTION REVLIMID, a thalidomide analogue, is an immunomodulatory agent with antiangiogenic and antineoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2 H -isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure: 3-(4-amino-1-oxo 1,3-dihydro-2 H -isoindol-2-yl) piperidine-2,6-dione The empirical formula for lenalidomide is C 13 H 13 N 3 O 3, and the gram molecular weight is 259.3. Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero. REVLIMID is available in 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg and 25 mg capsules for oral administration. Each capsule contains lenalidomide as the active ingredient and the following inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 5 mg and 25 mg capsule shell contains gelatin, titanium dioxide and black ink. The 2.5 mg and 10 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink. The 15 mg capsule shell contains gelatin, FD&C blue #2, titanium dioxide and black ink. The 20 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink. Chemical Structure

10 OVERDOSAGE There is no specific experience in the management of REVLIMID overdose in patients with MM, MDS, MCL, FL, or MZL. In dose-ranging studies in healthy subjects, some were exposed to up to 200 mg (administered 100 mg BID) and in single-dose studies, some subjects were exposed to up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the primary reported AEs. In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied White and blue-green opaque hard capsules imprinted "REV" on one half and "2.5 mg" on the other half in black ink: 2.5 mg bottles of 28 (NDC 59572-402-28) 2.5 mg bottles of 100 (NDC 59572-402-00) White opaque capsules imprinted "REV" on one half and "5 mg" on the other half in black ink: 5 mg bottles of 28 (NDC 59572-405-28) 5 mg bottles of 100 (NDC 59572-405-00) Blue/green and pale yellow opaque capsules imprinted "REV" on one half and "10 mg" on the other half in black ink: 10 mg bottles of 28 (NDC 59572-410-28) 10 mg bottles of 100 (NDC 59572-410-00) Powder blue and white opaque capsules imprinted "REV" on one half and "15 mg" on the other half in black ink: 15 mg bottles of 21 (NDC 59572-415-21) 15 mg bottles of 100 (NDC 59572-415-00) Powder blue and blue-green opaque hard capsules imprinted "REV" on one half and "20 mg" on the other half in black ink. 20 mg bottles of 21 (NDC 59572-420-21) 20 mg bottles of 100 (NDC 59572-420-00) White opaque capsules imprinted "REV" on one half and "25 mg" on the other half in black ink: 25 mg bottles of 21 (NDC 59572-425-21) 25 mg bottles of 100 (NDC 59572-425-00) 16.2 Storage Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [See USP Controlled Room Temperature]. 16.3 Handling and Disposal Care should be exercised in the handling of REVLIMID. REVLIMID capsules should not be opened or broken. If powder from REVLIMID contacts the skin, wash the skin immediately and thoroughly with soap and water. If REVLIMID contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. 1 Dispense no more than a 28-day supply.