Revlimid
Lenalidomide · Capsule · Oral
Uses
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) ] .
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 of 28 day cycle Return to at least 30,000/mcL Resume REVLIMID at 5 mg daily for Days 1 to 21 of 28-day cycle. Do not dose below 5 mg daily for Day 1 to 21 of 28 day cycle Absolute Neutrophil counts (ANC) Neutropenia in MM When Neutrophils Recommended Course Fall below 500/mcL Interrupt REVLIMID treatment, follow CBC weekly Return to at least 500/mcL Resume REVLIMID at next lower dose, continuously for Days 1-28 of repeated 28-day cycle If at 5 mg daily dose, For a subsequent drop below 500/mcL Interrupt REVLIMID treatment. Do not dose below 5 mg daily for Days 1 to 21 of 28-day cycle Return to at least 500/mcL Resume REVLIMID at 5 mg daily for Days 1 to 21 of 28-day cycle. Do not dose below 5 mg daily for Days 1 to 21 of 28-day cycle 2.2 Recommended Dosage for Myelodysplastic Syndromes The recommended starting dose of REVLIMID is 10 mg daily. Treatment is continued or modified based upon clinical and laboratory findings. Continue treatment until disease progression or unacceptable toxicity.
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 ).
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 )].
Warnings and precautions
• Increased Mortality: serious and fatal cardiac adverse reactions occurred in patients with CLL treated with REVLIMID ( 5.5 ).
• Second Primary Malignancies (SPM): Higher incidences of SPM were observed in controlled trials of patients with MM receiving REVLIMID ( 5.6 ).
• Increased Mortality: Observed in patients with MM when pembrolizumab was added to dexamethasone and a thalidomide analogue ( 5.7 ).
• Hepatotoxicity: Hepatic failure including fatalities; monitor liver function. Stop REVLIMID and evaluate if hepatotoxicity is suspected ( 5.8 ).
• Severe Cutaneous Reactions: Discontinue REVLIMID for severe reactions ( 5.9 ).
• Tumor lysis syndrome (TLS) including fatalities: Monitor patients at risk of TLS (i.e., those with high tumor burden) and take appropriate precautions ( 5.10 ).
• Tumor flare reaction: Serious tumor flare reactions, including fatal reactions, have occurred during investigational use of REVLIMID for chronic lymphocytic leukemia and lymphoma ( 5.11 ).
• 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 ( 5.12 ).
• Early mortality in MCL: Higher rate of early deaths have occurred in patients with MCL ( 5.14 ).
• Hypersensitivity: Monitor patients for potential hypersensitivity. Discontinue REVLIMID for angioedema and anaphylaxis ( 5.15 ). 5.1 Embryo-Fetal Toxicity REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes life-threatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1) ]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. REVLIMID is only available through the Lenalidomide REMS program [see Warnings and Precautions (5.2) ] . Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles or every 2 weeks in females with irregular menstrual cycles [see Use in Specific Populations (8.3) ] . Males Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm and for up to 4 weeks after discontinuing REVLIMID [see Use in Specific Populations (8.3) ]. Blood Donation Patients must not donate blood during treatment with REVLIMID and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID. 5.2 Lenalidomide REMS Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1) ] , REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the Lenalidomide REMS program. Required components of the Lenalidomide REMS program include the following:
• Prescribers must be certified with the Lenalidomide REMS program by enrolling and complying with the REMS requirements.
• Patients must sign a Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3) ] and males must comply with contraception requirements [see Use in Specific Populations (8.3) ] .
• Pharmacies must be certified with the Lenalidomide REMS program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements. Further information about the Lenalidomide REMS program is available at www.lenalidomiderems.com or by telephone at 1-888-423-5436. 5.3 Hematologic Toxicity REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medication that may increase risk of bleeding. Patients taking REVLIMID should have their complete blood counts assessed periodically as described below [see Dosage and Administration (2.1 , 2.2 , 2.3) ] . Monitor complete blood counts (CBC) in patients taking REVLIMID in combination with dexamethasone or as REVLIMID maintenance therapy for MM every 7 days (weekly) for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every 28 days (4 weeks) thereafter. A dose interruption and/or dose reduction may be required [see Dosage and Administration (2.1) ] . In the MM maintenance therapy trials, Grade 3 or 4 neutropenia was reported in up to 59% of REVLIMID-treated patients and Grade 3 or 4 thrombocytopenia in up to 38% of REVLIMID-treated patients [see Adverse Reactions (6.1) ] .
Side effects
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 events (28.8%); overall, the median time to the first dose interruption of REVLIMID was 7 weeks. The most common adverse reactions leading to dose reduction of REVLIMID in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of REVLIMID was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of REVLIMID were infection events (3.4%). In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous. Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms. Table 4: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the Rd Continuous or Rd18 Arms* Note: A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. a All treatment-emergent adverse events in at least 5% of subjects in the Rd Continuous or Rd18 Arms and at least a 2% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. b All grade 3 or 4 treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. c Serious treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm.
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.
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, lenalidomide was detected in fetal plasma and tissues; concentrations of radioactivity in fetal tissues were generally lower than those in maternal tissues. These data indicated that lenalidomide crossed the placenta. 8.2 Lactation Risk Summary There is no information regarding the presence of lenalidomide in human milk, the effects of REVLIMID on the breastfed child, or the effects of REVLIMID on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children from REVLIMID, advise women not to breastfeed during treatment with REVLIMID. 8.3 Females and Males of Reproductive Potential Pregnancy Testing REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1) ] . Verify the pregnancy status of females of reproductive potential prior to initiating REVLIMID therapy and during therapy. Advise females of reproductive potential that they must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy. Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. REVLIMID treatment must be discontinued during this evaluation.
Pregnancy
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, lenalidomide was detected in fetal plasma and tissues; concentrations of radioactivity in fetal tissues were generally lower than those in maternal tissues. These data indicated that lenalidomide crossed the placenta.
Pediatric use
8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients.
Geriatric use
8.5 Geriatric Use MM In Combination : Overall, of the 1613 patients in the NDMM study who received study treatment, 94% (1521 /1613) were 65 years of age or older, while 35% (561/1613) were over 75 years of age. The percentage of patients over age 75 was similar between study arms (Rd Continuous: 33%; Rd18: 34%; MPT: 33%). Overall, across all treatment arms, the frequency in most of the adverse reaction categories (eg, all adverse reactions, grade 3/4 adverse reactions, serious adverse reactions) was higher in older (> 75 years of age) than in younger (≤ 75 years of age) subjects. Grade 3 or 4 adverse reactions in the General Disorders and Administration Site Conditions body system were consistently reported at a higher frequency (with a difference of at least 5%) in older subjects than in younger subjects across all treatment arms. Grade 3 or 4 adverse reactions in the Infections and Infestations, Cardiac Disorders (including cardiac failure and congestive cardiac failure), Skin and Subcutaneous Tissue Disorders, and Renal and Urinary Disorders (including renal failure) body systems were also reported slightly, but consistently, more frequently (<5% difference), in older subjects than in younger subjects across all treatment arms. For other body systems (e.g., Blood and Lymphatic System Disorders, Infections and Infestations, Cardiac Disorders, Vascular Disorders), there was a less consistent trend for increased frequency of grade 3/4 adverse reactions in older vs younger subjects across all treatment arms Serious adverse reactions were generally reported at a higher frequency in the older subjects than in the younger subjects across all treatment arms. MM Maintenance Therapy : Overall, 10% (106/1018) of patients were 65 years of age or older, while no patients were over 75 years of age. Grade 3 or 4 adverse reactions were higher in the REVLIMID arm (more than 5% higher) in the patients 65 years of age or older versus younger patients. The frequency of Grade 3 or 4 adverse reactions in the Blood and Lymphatic System Disorders were higher in the REVLIMID arm (more than 5% higher) in the patients 65 years of age or older versus younger patients. There were not a sufficient number of patients 65 years of age or older in REVLIMID maintenance studies who experienced either a serious adverse reaction, or discontinued therapy due to an adverse reaction to determine whether elderly patients respond relative to safety differently from younger patients. MM After At Least One Prior Therapy : Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients. Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse reactions (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse reactions was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse reactions than the proportion of younger patients (27% vs. 16%). No differences in efficacy were observed between patients over 65 years of age and younger patients. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse reactions was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse reactions was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse reactions was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients. FL or MZL in Combination: Overall, 48% (282/590) of patients were 65 years of age or older, while 14% (82/590) of patients were over 75 years of age. The overall frequency of adverse reactions was similar in patients 65 years of age or older and younger patients for both studies pooled (98%). Grade 3 or 4 adverse reactions were higher in the REVLIMID arm (more than 5% higher) in the patients 65 years of age or older versus younger patients (71% versus 59%). The frequency of Grade 3 or 4 adverse reactions were higher in the REVLIMID arm (more than 5% higher) in the patients 65 years of age or older versus younger patients in the Blood and Lymphatic System Disorders (47% versus 40%) and Infections and Infestations (16% versus 11%). Serious adverse reactions were higher in the REVLIMID arm (more than 5% higher) in the patients 65 years of age or older versus younger patients (37% versus 18%). The frequency of serious adverse reactions were higher in the REVLIMID arm (more than 5% higher) in the patients 65 years of age or older versus younger patients in Infections and Infestations (15% versus 6%). Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function.
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.
Description
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
Mechanism of action
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 .
How supplied
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.
Storage
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.
Patient information
Advise the patient to read the FDA-approved Patient labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [see Boxed Warning and Contraindications (4.1) ]. REVLIMID is a thalidomide analogue and can cause serious birth defects or death to a developing baby [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] .
• Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy.
• Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test.
• Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use 2 different forms of contraception including at least 1 highly effective form, simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner's vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap.
• Instruct patient to immediately stop taking REVLIMID and contact her healthcare provider if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.
• Advise patient that if her healthcare provider is not available, she should call the REMS Call Center at 1-888-423-5436 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3) ].
• Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy.
• Advise male patients taking REVLIMID that they must not donate sperm and for up to 4 weeks after discontinuation of REVLIMID [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3) ] .
• All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 4 weeks following discontinuation of REVLIMID [see Warnings and Precautions (5.1) ] . Lenalidomide REMS program Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the Lenalidomide REMS program [see Warnings and Precautions (5.2) ] .
• Patients must sign a Patient-Physician agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.3) ] .
• REVLIMID is available only from pharmacies that are certified in the Lenalidomide REMS program. Provide patients with the telephone number and website for information on how to obtain the product. Pregnancy Exposure Registry Inform females there is a Pregnancy Exposure Registry that monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy and that they can contact the Pregnancy Exposure Registry by calling 1-888-423-5436 [see Use in Specific Populations (8.1) ] . Hematologic Toxicity Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [see Boxed Warning and Warnings and Precautions (5.3) ] . Venous and Arterial Thromboembolism Inform patients of the risk of thrombosis including DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation [see Boxed Warning and Warnings and Precautions (5.4) ] . Increased Mortality in Patients with CLL Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure [see Warnings and Precautions (5.5) ] . Second Primary Malignancies Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID [see Warnings and Precautions (5.6) ] . Hepatotoxicity Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.8) ] . Severe Cutaneous Reactions Inform patients of the potential risk for severe skin reactions such as SJS, TEN, and DRESS and report any signs and symptoms associated with these reactions to their healthcare provider for evaluation. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID [see Warnings and Precautions (5.9) ]. Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.10) ] . Tumor Flare Reaction Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.11) ] . Early Mortality in Patients with MCL Inform patients with MCL of the potential for early death [see Warnings and Precautions (5.14) ] . Hypersensitivity Inform patients of the potential for severe hypersensitivity reactions such as angioedema and anaphylaxis to REVLIMID. Instruct patients to contact their healthcare provider right away for signs and symptoms of these reactions. Advise patients to seek emergency medical attention for signs or symptoms of severe hypersensitivity reactions [see Warnings and Precautions (5.15) ] .
Label text from the FDA structured product label by Celgene Corporation (revised Mar 24, 2023). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Lenalidomide in 6 products
Revlimid NDC products (6)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 59572-402 | Lenalidomide 2.5 mg/1 Capsule | Celgene Corporation | NDA |
| 59572-405 | Lenalidomide 5 mg/1 Capsule | Celgene Corporation | NDA |
| 59572-410 | Lenalidomide 10 mg/1 Capsule | Celgene Corporation | NDA |
| 59572-415 | Lenalidomide 15 mg/1 Capsule | Celgene Corporation | NDA |
| 59572-420 | Lenalidomide 20 mg/1 Capsule | Celgene Corporation | NDA |
| 59572-425 | Lenalidomide 25 mg/1 Capsule | Celgene Corporation | NDA |
Frequently asked questions
What is Revlimid used for?
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…
What are the side effects of Revlimid?
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… See the full label for the complete list.
Who makes Revlimid?
Revlimid is listed by 1 labeler in the FDA NDC directory, including Celgene Corporation.