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Indications
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 ).
1.1Multiple 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).
1.2Myelodysplastic 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.
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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.
1.4Follicular Lymphoma
REVLIMID in combination with a rituximab product, is indicated for the treatment of adult patients with previously treated follicular lymphoma (FL).
1.5Marginal Zone Lymphoma
REVLIMID in combination with a rituximab product, is indicated for the treatment of adult patients with previously treated marginal zone lymphoma (MZL).
1.6Limitations 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) ] .
Contraindications
Pregnancy ( Boxed Warning , 4.1 , 5.1 , 8.1 ).
Demonstrated severe hypersensitivity to lenalidomide ( 4.2 , 5.9 , 5.15 ).
4.1Pregnancy
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) ] .
4.2Severe 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 ).
5.1Embryo-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.
5.3Hematologic 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) ] . Monitor complete blood counts (CBC) in patients taking REVLIMID for MDS weekly for the first 8 weeks and at least monthly thereafter.
Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days) [see Boxed Warning and Dosage and Administration (2.2) ] .
Monitor complete blood counts (CBC) in patients taking REVLIMID for MCL weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. Monitor complete blood counts (CBC) in patients taking REVLIMID for FL or MZL weekly for the first 3 weeks of Cycle 1 (28 days), every 2 weeks during Cycles 2-4, and then monthly thereafter.
Patients may require dose interruption and/or dose reduction. In the AUGMENT and MAGNIFY trials, Grade 3 or 4 neutropenia was reported in 50% and 33%, respectively, of patients in the REVLIMID/rituximab arm. Grade 3 or 4 thrombocytopenia was reported in 2% and 8%, respectively, of patients in the REVLIMID/rituximab arm [see Adverse Reactions (6.1) ] .
5.4Venous and Arterial Thromboembolism
Venous thromboembolic events (VTE [DVT and PE]) and arterial thromboembolic events (ATE, myocardial infarction and stroke) are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with MM after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clini
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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 ).
7.1Digoxin
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.
7.2Concomitant 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) ] .
7.3Warfarin 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.
Pregnancy and breastfeeding
8.1Pregnancy 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.
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.
6.1Clinical 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. d Preferred terms for the blood and lymphatic system disorders body system were included by medical judgment as known adverse reactions for Rd Continuous/Rd18, and have also been reported as serious. e Footnote “a” not applicable. f Footnote “b” not applicable. @ - adverse reactions in which at least one resulted in a fatal outcome. % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases). *Adverse reactions included in combined adverse reaction terms : Abdominal Pain : Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain Pneumonias : Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral Sepsis : Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis Rash : Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalized, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular Deep Vein Thrombosis : Deep vein thrombosis, venous thrombosis limb, venous thrombosis Body System Adverse Reaction All Adverse Reactions a Grade 3/4 Adverse Reactions b Rd Continuous (N = 532) Rd18 (N = 540) MPT (N = 541) Rd Continuous (N = 532) Rd18 (N = 540) MPT (N = 541) General disorders and administration site conditions Fatigue % 173 (33) 177 (33) 154 (28) 39 ( 7) 46 ( 9) 31 ( 6) Asthenia 150 (28) 123 (23) 124 (23) 41 ( 8) 33 ( 6) 32 ( 6) Pyrexia c 114 (21) 102 (19) 76 (14) 13 ( 2) 7 ( 1) 7 ( 1) Non-cardiac chest pain f 29 ( 5) 31 ( 6) 18 ( 3) <1% < 1% < 1% Gastrointestinal disorders Diarrhea 242 (45) 208 (39) 89 (16) 21 ( 4) 18 ( 3) 8 ( 1) Abdominal pain % f 109 (20) 78 (14) 60 (11) 7 ( 1) 9 ( 2) < 1% Dyspepsia f 57 (11) 28 ( 5) 36 ( 7) <1% < 1% 0
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
LENALIDOMIDE 5MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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