`
`REVLIMID® (lenalidomide)
`5 mg, 10 mg, 15 mg and 25 mg capsules
`
`2
`3 WARNINGS:
`
`1. POTENTIAL FOR HUMAN BIRTH DEFECTS
`4
`
`2. HEMATOLOGIC TOXICITY (NEUTROPENIA AND
`5
`THROMBOCYTOPENIA)
`6
`
` 3. DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM
`7
`
`
`
`8
`
`
`POTENTIAL FOR HUMAN BIRTH DEFECTS
`9
`
`
`
`
`10 WARNING: POTENTIAL FOR HUMAN BIRTH DEFECTS
`
`11 LENALIDOMIDE IS AN ANALOGUE OF THALIDOMIDE. THALIDOMIDE IS
`12 A KNOWN HUMAN TERATOGEN THAT CAUSES SEVERE LIFE
`13 THREATENING HUMAN BIRTH DEFECTS. IF LENALIDOMIDE IS TAKEN
`14 DURING PREGNANCY, IT MAY CAUSE BIRTH DEFECTS OR DEATH TO AN
`15 UNBORN BABY. FEMALES SHOULD BE ADVISED TO AVOID PREGNANCY
`16 WHILE TAKING REVLIMID® (lenalidomide).
`
`17
`
`
`
` Special Prescribing Requirements
`
`18 BECAUSE OF THIS POTENTIAL TOXICITY AND TO AVOID FETAL
`19 EXPOSURE TO REVLIMID® (lenalidomide), REVLIMID® (lenalidomide) IS
`20 ONLY AVAILABLE UNDER A SPECIAL RESTRICTED DISTRIBUTION
`PROGRAM. THIS PROGRAM IS CALLED "RevAssist®." UNDER THIS
`21
`PROGRAM, ONLY PRESCRIBERS AND PHARMACISTS REGISTERED WITH
`22
`
`23 THE PROGRAM CAN PRESCRIBE AND DISPENSE THE PRODUCT. IN
`24 ADDITION, REVLIMID® (lenalidomide) MUST ONLY BE DISPENSED TO
`PATIENTS WHO ARE REGISTERED AND MEET ALL THE CONDITIONS OF
`25
`26 THE RevAssist® PROGRAM.
`
`PLEASE SEE THE FOLLOWING INFORMATION FOR PRESCRIBERS,
`27
`FEMALE PATIENTS, AND MALE PATIENTS ABOUT THIS RESTRICTED
`
`28
`29 DISTRIBUTION PROGRAM.
`
`
`30 RevAssist® PROGRAM DESCRIPTION
`
`31
`
`
`
` Prescribers
`
`32 REVLIMID® (lenalidomide) can be prescribed only by licensed prescribers who are
`
` registered in the RevAssist® program and understand the potential risk of teratogenicity if
`33
`lenalidomide is used during pregnancy.
`34
`
`1
`
`
`
`
`35
`36
`37
`38
`39
`40
`41
`42
`43
`44
`45
`46
`47
`
`48
`49
`50
`51
`52
`53
`
`54
`55
`56
`57
`
`58
`59
`60
`61
`62
`63
`64
`65
`
`66
`67
`
`68
`69
`
`70
`71
`72
`73
`
`74
`
`Effective contraception must be used by female patients of childbearing potential for at
`least 4 weeks before beginning REVLIMID® (lenalidomide) therapy, during
`REVLIMID® (lenalidomide) therapy, during dose interruptions and for 4 weeks
`following discontinuation of REVLIMID® (lenalidomide) therapy. Reliable contraception
`is indicated even where there has been a history of infertility, unless due to hysterectomy
`or because the patient has been postmenopausal naturally for at least 24 consecutive
`months. Two reliable forms of contraception must be used simultaneously unless
`continuous abstinence from heterosexual sexual contact is the chosen method. Females of
`childbearing potential should be referred to a qualified provider of contraceptive
`methods, if needed. Sexually mature females who have not undergone a hysterectomy,
`have not had a bilateral oophorectomy or who have not been postmenopausal naturally
`for at least 24 consecutive months (i.e., who have had menses at some time in the
`preceding 24 consecutive months) are considered to be females of childbearing potential.
`
`Before prescribing REVLIMID® (lenalidomide), females of childbearing potential
`should have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL). The first test
`should be performed within 10-14 days, and the second test within 24 hours prior to
`prescribing REVLIMID® (lenalidomide). A prescription for REVLIMID® (lenalidomide)
`for a female of childbearing potential must not be issued by the prescriber until negative
`pregnancy tests have been verified by the prescriber.
`
`Male Patients: It is not known whether lenalidomide is present in the semen of patients
`
`receiving the drug. Therefore, males receiving REVLIMID® (lenalidomide) must always
`use a latex condom during any sexual contact with females of childbearing potential even
`if they have undergone a successful vasectomy.
`
`Once treatment has started and during dose interruptions, pregnancy testing for
`females of childbearing 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 pregnancy test or in her menstrual
`bleeding. REVLIMID® (lenalidomide) treatment must be discontinued during this
`evaluation.
`
`Pregnancy test results should be verified by the prescriber and the pharmacist prior to
`dispensing any prescription.
`
` If pregnancy does occur during REVLIMID® (lenalidomide) treatment, REVLIMID®
`
`(lenalidomide) must be discontinued immediately.
`
`
`
` Any suspected fetal exposure to REVLIMID® (lenalidomide) should be reported to the
`
`FDA via the MedWatch number at 1-800-FDA-1088 and also to Celgene Corporation at
`1-888-423-5436. The patient should be referred to an obstetrician/gynecologist
`experienced in reproductive toxicity for further evaluation and counseling.
`
`Female Patients
`
`2
`
`
`
`
`75
`76
`77
`
`78
`
`79
`80
`81
`
`82
`83
`
`84
`85
`86
`87
`88
`89
`90
`
`91
`92
`93
`94
`
`95
`96
`
`97
`98
`
`99
`
`100
`101
`
`102
`
`103
`104
`105
`
`106
`107
`
`REVLIMID® (lenalidomide) should be used in females of childbearing potential only
`when the patient MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is
`unable to become pregnant while on lenalidomide therapy):
`
`
`y
`
`
`y
`
`
`y
`
`
`y
`
`
`y
`
`
`y
`
`
`y
`
`she understands and can reliably carry out instructions.
`
`she is capable of complying with the mandatory contraceptive measures, pregnancy
`testing, patient registration, and patient survey as described in the RevAssist®
`
`program.
`
`she has received and understands both oral and written warnings of the potential risks
`of taking lenalidomide during pregnancy and of exposing a fetus to the drug.
`
`she has received both oral and written warnings of the risk of possible contraception
`failure and of the need to use two reliable forms of contraception simultaneously,
`unless continuous abstinence from heterosexual sexual contact is the chosen method.
`Sexually mature females who have not undergone a hysterectomy or who have not
`been postmenopausal for at least 24 consecutive months (i.e., who have had menses at
`some time in the preceding 24 consecutive months), or had a bilateral oophorectomy
`are considered to be females of childbearing potential.
`
`she acknowledges, in writing, her understanding of these warnings and of the need for
`using two reliable methods of contraception for 4 weeks prior to beginning
`lenalidomide therapy, during lenalidomide therapy, during dose interruptions and for
`4 weeks after discontinuation of lenalidomide therapy.
`
`she has had two negative pregnancy tests with a sensitivity of at least 50 mIU/mL,
`within 10-14 days and 24 hours prior to beginning therapy.
`
`if the patient is between 12 and 18 years of age, her parent or legal guardian must
`
`have read the educational materials and agreed to ensure compliance with the above.
`
`Male Patients
`
`REVLIMID® (lenalidomide) should be used in sexually active males when the PATIENT
`MEETS ALL OF THE FOLLOWING CONDITIONS:
`
`y he understands and can reliably carry out instructions.
`
`
`y he is capable of complying with the mandatory contraceptive measures that are
`
`appropriate for men, patient registration, and patient survey as described in the
`RevAssist® program.
`
`y he has received and understands both oral and written warnings of the potential risks
`
`of taking lenalidomide and exposing a fetus to the drug.
`
`3
`
`
`
`
`108
`109
`110
`111
`
`112
`113
`114
`115
`116
`117
`118
`
`119
`120
`
`121
`
`122
`123
`124
`125
`126
`127
`128
`129
`130
`
`131
`
`132
`133
`134
`135
`136
`137
`138
`139
`140
`141
`
`142
`143
`144
`
`145
`
`y he has received both oral and written warnings of the risk of possible contraception
`
`failure and that it is unknown whether lenalidomide is present in semen. He has been
`instructed that he must always use a latex condom during any sexual contact with
` females of childbearing potential, even if he has undergone a successful vasectomy.
`
`
`y he acknowledges, in writing, his understanding of these warnings and of the need to
`
`use a latex condom during any sexual contact with females of childbearing potential,
`even if he has undergone a successful vasectomy. Females of childbearing potential
`are considered to be sexually mature females who have not undergone a
`hysterectomy, have not had a bilateral oophorectomy or who have not been
`postmenopausal for at least 24 consecutive months (i.e., who have had menses at any
`time in the preceding 24 consecutive months).
`
`
`y
`
`if the patient is between 12 and 18 years of age, his parent or legal guardian must
` have read the educational materials and agreed to ensure compliance with the above.
`
`
`HEMATOLOGIC TOXICITY (NEUTROPENIA AND THROMBOCYTOPENIA)
`
`This drug is associated with significant neutropenia and thrombocytopenia. Eighty
`percent of patients with del 5q myelodysplastic syndromes had to have a dose
`delay/reduction during the major study. Thirty-four percent of patients had to have
`a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of
`patients enrolled in the study. Patients on therapy for del 5q myelodysplastic
`syndromes should have their complete blood counts monitored weekly for the first 8
`weeks of therapy and at least monthly thereafter. Patients may require dose
`interruption and/or reduction. Patients may require use of blood product support
`and/or growth factors. (See DOSAGE AND ADMINISTRATION)
`
`
`
`DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM
`
`This drug has demonstrated a significantly increased risk of deep venous
`thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple
`myeloma who were treated with REVLIMID® (lenalidomide) combination therapy.
`Patients and physicians are advised to be observant for the signs and symptoms of
`thromboembolism. Patients should be instructed to seek medical care if they develop
`symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not
`known whether prophylactic anticoagulation or antiplatelet therapy prescribed in
`conjunction with REVLIMID® (lenalidomide) may lessen the potential for venous
`thromboembolic events. The decision to take prophylactic measures should be done
`carefully after an assessment of an individual patient’s underlying risk factors.
`
` You can get the information about REVLIMID® (lenalidomide) and the RevAssist®
`
`program on the internet at www.REVLIMID.com or by calling the manufacturer’s
`toll free number 1-888-423-5436.
`
`
`
`4
`
`
`
`
`146 DESCRIPTION
`
`147 REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent
`148 with antiangiogenic and antineoplastic properties. The chemical name is 3-(4-amino-1
`oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical
`149
`
`150
` structure:
`151
`
`
`
` Chemical Structure of Lenalidomide
`O O
`H
`N
`
`N
`
`O
`
`152
`153
`
`154
`155
`
`
`
`NH2
`
`3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione
`
`The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is
`259.3.
`
`
`
`156
`Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic
`157
`solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in
`
`158
`organic solvents and low pH solutions. Solubility was significantly lower in less acidic
`159
`buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon
`160
`atom and can exist as the optically active forms S(-) and R(+), and is produced as a
`
`161
`racemic mixture with a net optical rotation of zero.
`162 REVLIMID® (lenalidomide) is available in 5 mg, 10 mg, 15 mg and 25 mg capsules for
`163
`oral administration. Each capsule contains lenalidomide as the active ingredient and the
`164
`following inactive ingredients: lactose anhydrous, microcrystalline cellulose,
`165
`croscarmellose sodium, and magnesium stearate. The 5 mg and 25 mg capsule shell
`166
`contains gelatin, titanium dioxide and black ink. The 10 mg capsule shell contains
`167
`gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink. The 15 mg
`168
`capsule shell contains gelatin, FD&C blue #2, titanium dioxide and black ink.
`169 CLINICAL PHARMACOLOGY
`
`170 Mechanism of Action
`
`The mechanism of action of lenalidomide remains to be fully characterized.
`171
`Lenalidomide possesses antineoplastic, immunomodulatory and antiangiogenic
`172
`properties. Lenalidomide inhibited the secretion of pro-inflammatory cytokines and
`173
`increased the secretion of antiinflammatory cytokines from peripheral blood mononuclear
`174
`cells. Lenalidomide inhibited cell proliferation with varying effectiveness (IC50s) in
`175
` some but not all cell lines. Of cell lines tested, lenalidomide was effective in inhibiting
`176
`growth of Namalwa cells (a human B cell lymphoma cell line with a deletion of one
`177
`chromosome 5) but was much less effective in inhibiting growth of KG-1 cells (human
`178
`179 myeloblastic cell line, also with a deletion of one chromosome 5) and other cell lines
`180 without chromosome 5 deletions. Lenalidomide inhibited the growth of multiple
`
`
`
`5
`
`
`
`
`181 myeloma cells from patients, as well as MM.1S cells (a human multiple myeloma cell
`182
`line), by inducing cell cycle arrest and apoptosis.
`
`183
`184
`
`185
`
`Lenalidomide inhibited the expression of cyclooxygenase-2 (COX-2) but not COX-1 in
`vitro.
`
`Pharmacokinetics and Drug Metabolism
`
`186 Absorption:
`
`Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration
`187
`188 with maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose.
`189 Co-administration with food does not alter the extent of absorption (AUC) but does
`190
`reduce the maximal plasma concentration (Cmax) by 36%. The pharmacokinetic
`disposition of lenalidomide is linear. Cmax and AUC increase proportionately with
`191
`192
`increases in dose. Multiple dosing at the recommended dose-regimen does not result in
`193
`drug accumulation.
`
`194
`195
`196
`197
`198
`
`199
`
`Pharmacokinetic sampling in myelodysplastic syndromes (MDS) patients was not
`performed. In multiple myeloma patients maximum plasma concentrations occurred
`between 0.5 and 4.0 hours post-dose both on Days 1 and 28. AUC and Cmax values
`increase proportionally with dose following single and multiple doses. Exposure (AUC)
`in multiple myeloma patients is 57% higher than in healthy male volunteers.
`
`Pharmacokinetic Parameters
`
`200 Distribution:
`
`201
`
`In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%.
`
`
`202 Metabolism and Excretion:
`
`203
`204
`205
`206
`
`207
`
`The metabolic profile of lenalidomide in humans has not been studied. In healthy
`volunteers, approximately two-thirds of lenalidomide is eliminated unchanged through
`urinary excretion. The process exceeds the glomerular filtration rate and therefore is
`partially or entirely active. Half-life of elimination is approximately 3 hours.
`
`Special Populations:
`
`Patients with Renal Insufficiency: The pharmacokinetics of lenalidomide were studied in
`208
`patients with renal impairment due to nonmalignant conditions. In this study, 5 patients
`209
`210 with mild renal function impairment (creatinine clearance 57-74 mL/min), 6 patients with
`211 moderate renal function impairment (creatinine clearance 33-46 mL/min), 6 patients with
`212
`severe renal function impairment (creatinine clearance 17-29 mL/min), and 6 patients
`213
`with end stage renal disease requiring dialysis were administered a single oral 25-mg
`dose of REVLIMID® (lenalidomide). As a control group comparator, 7 healthy subjects
`214
`215
`of similar age with normal renal function (creatinine clearance 83-145 mL/min) were also
`administered a single oral 25-mg dose of REVLIMID® (lenalidomide). As creatinine
`216
`
`6
`
`
`
`
`217
`218
`219
`220
`221
`222
`223
`
`clearance decreased from mild to severe impairment, half-life increased and drug
`clearance decreased linearly. Patients with moderate and severe renal impairment had a
`3-fold increase in half-life and a 66% to 75% decrease in drug clearance compared to
`healthy subjects. Patients on hemodialysis (n=6) given a single, 25-mg dose of
`lenalidomide had an approximate 4.5-fold increase in half-life and an 80% decrease in
`drug clearance compared to healthy subjects. Approximately 40% of the administered
`dose was removed from the body during a single dialysis session.
`
`224 Adjustment of the starting dose of REVLIMID® (lenalidomide) is recommended in
`225
`patients with moderate or severe renal impairment and in patients on dialysis. See
`
` 226 DOSAGE AND ADMINISTRATION.
`
`227
`228
`
`229
`230
`231
`232
`
`In multiple myeloma patients, those patients with mild renal impairment had an AUC
`56% greater than those with normal renal function.
`
`Patients with Hepatic Disease: The pharmacokinetics of lenalidomide in patients with
`hepatic impairment have not been studied.
`Age: The effects of age on the pharmacokinetics of lenalidomide have not been studied.
`Pediatric: No pharmacokinetic data are available in patients below the age of 18 years.
`
`233 Gender: The effects of gender on the pharmacokinetics of lenalidomide have not been
`234
`studied.
`
`235
`
`Race: Pharmacokinetic differences due to race have not been studied.
`
`236 CLINICAL STUDIES
`
`237 Myelodysplastic Syndromes (MDS) with a Deletion 5q Cytogenetic Abnormality
`
`
`238
`239
`240
`241
`242
`243
`244
`
`The efficacy and safety of REVLIMID® (lenalidomide) were evaluated in patients with
`transfusion dependent anemia in Low- or Intermediate-1- risk MDS with a 5q (q31-33)
`cytogenetic abnormality in isolation or with additional cytogenetic abnormalities, at a
`dose of 10 mg once daily or 10 mg once daily for 21 days every 28 days in an open-label,
`single-arm, multi-center study. The major study was not designed nor powered to
`prospectively compare the efficacy of the 2 dosing regimens. Sequential dose reductions
`to 5 mg daily and 5 mg every other day, as well as dose delays, were allowed for toxicity.
`
`This major study enrolled 148 patients who had RBC transfusion dependent anemia.
`245
`246 RBC-transfusion dependence was defined as having received ≥ 2 units of RBCs within 8
`247
`weeks prior to study treatment. The study enrolled patients with absolute neutrophil
`counts (ANC) ≥ 500/mm3, platelet counts ≥ 50,000/mm3, serum creatinine ≤ 2.5 mg/dL,
`248
`249
`serum SGOT/AST or SGPT/ALT ≤ 3.0 x upper limit of normal (ULN), and serum direct
`250
`bilirubin ≤ 2.0 mg/dL. Granulocyte colony-stimulating factor was permitted for patients
`251 who developed neutropenia or fever in association with neutropenia. Baseline patient and
`252
`disease-related characteristics are summarized in Table 1.
`
`7
`
`
`
`
`
`
`
`
`
`
`
`
`
` 71.0
`
` 37.0, 95.0
`
`n
`(%)
`
`
`
`51
`(34.5)
`
`
`(65.5)
`97
`
`
`n
`(%)
`
`
`
`143
`(96.6)
`
`(3.4)
`5
`
`
`
`
`
`Table 1: Baseline Demographic and Disease-Related Characteristics
`
`
`
`
`
`
`
` Overall
`(N=148)
`
`
`
`
`
`
` Age (years)
` Median
`
` Min, Max
`
`Gender
`
`
`Male
`
`
`
`Female
`
`
`Race
`
`
`White
`
`
`
`Other
`
` Duration of MDS (years)
` 2.5
` Median
`
`
`
`
`
` 0.1, 20.7
` Min, Max
`
`
`
`
`
` n
` Del 5 (q31-33) Cytogenetic Abnormality
`(%)
`
`
`
`
`
`
`148
`(100.0)
`Yes
`
`
`
`
`
`
`37
` Other cytogenetic abnormalities
` (25.2)
`
`
`
`
` IPSS Score [a]
`
`
`
`
`
`
`
` n
` (%)
`55
` (37.2)
` Low (0)
`
`
`
`
`
`65
` (43.9)
` Intermediate-1 (0.5-1.0)
`
`
`
`
`
`
`
`6
`(4.1)
`Intermediate-2 (1.5-2.0)
`
`
`
`
`
`
`
`
`2
`(1.4)
`High (≥2.5)
`
`
`
`
`
`
`20
` (13.5)
` Missing
`
`
`
`
`
`
` FAB Classification [b] from central review
`
`
`n
`
`
`
`
`(%)
`77
`RA
` (52.0)
`
`
`
`
`
`
`16
` RARS
` (10.8)
`
`
`
`
`
` (20.3)
`30
` RAEB
`
`
`
`
`
` (2.0)
`3
` CMML
`
`
`
`
`
`
`
`[a] IPSS Risk Category: Low (combined score = 0), Intermediate-1 (combined score = 0.5 to 1.0),
`
`
`
`
` Intermediate-2 (combined score = 1.5 to 2.0), High (combined score ≥ 2.5); Combined score =
`
`
`
`
`
` (Marrow blast score + Karyotype score + Cytopenia score)
`
` [b] French-American-British (FAB) classification of MDS.
`
`
`The frequency of RBC-transfusion independence was assessed using criteria modified
`from the International Working Group (IWG) response criteria for MDS. RBC
`transfusion independence was defined as the absence of any RBC transfusion during any
`consecutive “rolling” 56 days (8 weeks) during the treatment period.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`253
`254
`255
`256
`
`Transfusion independence was seen in 99/148 (67%) patients (95% CI [59, 74]). The
`257
`258 median duration from the date when RBC transfusion independence was first declared
`259
`(i.e., the last day of the 56-day RBC transfusion-free period) to the date when an
`260
`additional transfusion was received after the 56-day transfusion-free period among the 99
`261
`responders was 44 weeks (range of 0 to >67 weeks).
`
`262 Ninety percent of patients who achieved a transfusion benefit did so by completion of
`263
`three months in the study.
`
`264 RBC-transfusion independence rates were unaffected by age or gender.
`
`The dose of REVLIMID® (lenalidomide) was reduced or interrupted at least once due to
`
`265
`an adverse event in 118 (79.7%) of the 148 patients; the median time to the first dose
`
`266
`reduction or interruption was 21 days (mean, 35.1 days; range, 2-253 days), and the
`
`267
`268 median duration of the first dose interruption was 22 days (mean, 28.5 days; range, 2-265
`
`269
`days). A second dose reduction or interruption due to adverse events was required in 50
`
`270
`(33.8%) of the 148 patients. The median interval between the first and second dose
`
`
`8
`
`
`
`
`reduction or interruption was 51 days (mean, 59.7 days; range, 15-205 days) and the
`271
`272 median duration of the second dose interruption was 21 days (mean, 26 days; range, 2
`273
`148 days).
`
`274 Granulocyte colony-stimulating factors were permitted for patients who developed
`275
`neutropenia or fever in association with neutropenia.
`276 Multiple Myeloma
`277
`Two randomized studies (Studies 1 and 2) were conducted to evaluate the efficacy and
`safety of REVLIMID® (lenalidomide). These multicenter, multinational, double-blind,
`278
`placebo-controlled studies compared REVLIMID® (lenalidomide) plus oral pulse high
`279
`280
`dose dexamethasone therapy to dexamethasone therapy alone, in patients with multiple
`281 myeloma who had received at least one prior treatment.
`
`282
`283
`284
`285
`286
`287
`
`288
`289
`290
`
`291
`292
`293
`294
`295
`296
`297
`
`In both studies, patients in the REVLIMID® (lenalidomide)/dexamethasone group took
`25 mg of REVLIMID® (lenalidomide) orally once daily on Days 1 to 21 and a matching
`placebo capsule once daily on Days 22 to 28 of each 28-day cycle. Patients in the
`placebo/dexamethasone group took 1 placebo capsule on Days 1 to 28 of each 28-day
`cycle. Patients in both treatment groups took 40 mg of dexamethasone orally once daily
`on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy.
`
`The dose of dexamethasone was reduced to 40 mg orally once daily on Days 1 to 4 of
`each 28-day cycle after the first 4 cycles of therapy. In both studies, treatment was to
`continue until disease progression.
`
`In both studies, dose adjustments were allowed based on clinical and laboratory findings.
`Sequential dose reductions to 15 mg daily, 10 mg daily and 5 mg daily were allowed for
`toxicity. (See DOSAGE AND ADMINISTRATION)
`Table 2 summarizes the baseline patient and disease characteristics in the two studies. In
`both studies, baseline demographic and disease-related characteristics were comparable
`between the REVLIMID® (lenalidomide)/dexamethasone and placebo/dexamethasone
`groups.
`
`9
`
`
`
`
`
`
`298
`
`299
`300
`
`
`
`Table 2: Baseline Demographic and Disease-Related Characteristics –
`
`Studies 1 and 2
`
`
`Study 1
`
`Study 2
`
`Patient Characteristics
`
`Age (years)
`Median
`
`Min, Max
`
`
`Sex
`
`Male
`
`
`Female
`
`
`Race/Ethnicity
`White
`
`Other
`ECOG Performance Status 0-1
`
`Disease Characteristics
`Baseline Multiple Myeloma Stage
`(Durie-Salmon)
`
`I
`II
`III
`
`Baseline Creatinine (mg/dL)
`Median
`
`
`Min, Max
`B2-microglobulin (mg/L)
`
` Median
`
` Min, Max
`
`
`Number of Prior Therapies
`No. of Prior Antimyeloma
`
`Therapies
`1
`
`
`≥ 2
`
`Types of Prior Therapies
`
`
`Stem Cell Transplantation
`Thalidomide
`Dexamethasone
`Bortezomib
`
`Melphalan
`Doxorubicin
`
`
`
`
`
`301
`
`REVLIMID/Dex
`N=170
`
`Placebo/Dex
`N=171
`
`
`REVLIMID/Dex
`N=176
`
`Placebo/Dex
`N=175
`
`
`
`
`
`
`64
`36, 86
`
`102 (60%)
` 68 (40%)
`
`134 (79%)
` 36 (21%)
`151 (89%)
`
`
`
`
`
`
`
`2%
`31%
`67%
`
`
`1.0
`0.4, 2.6
`
`3.7
`1.1, 45
`
`
`
`
`
`
`62
`37, 85
`
`101 (59%)
` 70 (41%)
`
`143 (84%)
` 28 (16%)
`163 (95%)
`
`
`
`
`
`
`
`2%
`31%
`67%
`
`
`1.0
`0.5, 2.4
`
`3.3
`1.3, 15.2
`
`
`
`
`
`
`63
`33, 84
`
`104 (59%)
` 72 (41%)
`
`172 (98%)
`
`4 (2%)
`150 (85%)
`
`
`
`
`6%
`
`28%
`
`65%
`
`
`0.9
`0.3, 2.3
`
`3.4
`1.0, 14.4
`
`
`
`
`64
`40, 82
`
`103 (59%)
` 72 (41%)
`
`
`
`
`175(100%)
`
`
`(0%)
` 0
`144 (82%)
`
`
`
`
`
`
`
`
`
`5%
`33%
`63%
`
`
`0.9
`0.5, 2.3
`
`3.3
`1.3, 25.3
`
`
`
`
`
`
`
`
`
`
`
`32%
`68%
`
`
`
`56%
`30%
`66%
`5%
`56%
`56%
`
`
`
`33%
`67%
`
`
`
`54%
`38%
`69%
`
`4%
`52%
`57%
`
`
`
`38%
`62%
`
`
`
`60%
`42%
`80%
`11%
`34%
`55%
`
`
`
`37%
`63%
`
`
`
`60%
`46%
`70%
`12%
`31%
`52%
`
`10
`
`
`
`
`The primary efficacy endpoint in both studies was time to progression (TTP). TTP was
`defined as the time from randomization to the first occurrence of progressive disease or
`death due to progressive disease.
`
`Preplanned interim analyses of both studies showed that the combination of REVLIMID®
`
`(lenalidomide)/dexamethasone was significantly superior to dexamethasone alone for
`TTP. The studies were unblinded to allow patients in the placebo/dexamethasone group
`to receive treatment with the REVLIMID® (lenalidomide)/dexamethasone combination.
`
`Table 3 summarizes TTP and response rates based on the best response assessments for
`Studies 1 and 2.
`
`
`
`Table 3: Summary of Efficacy Analysis — Studies 1 and 2
`Study 1
`Study 2
`REVLIMID/Dex
`Placebo/Dex
`REVLIMID/Dex
`Placebo/Dex
`N=170
`N=171
`N=176
`N=175
`
`
`
`
`
`302
`303
`304
`305
`306
`307
`308
`309
`310
`311
`312
`313
`314
`
`315
`
`316
`317
`318
`319
`
`
`
`
`
`
`
`
`
`
`
`
`TTP
`
`Censored
`n (%)
`
`
`115 (68)
`
`37.1
`[28, NE1]
`
`
`61 (36)
`
`19.9
`
`[16, 22]
`
`
`133 (76)
`
`
`78 (45)
`
`
`
`NE1
`
`
`20
`
` [19.9, 21.6]
`
`
`0.356 [0.257, 0.494]
`
`
`0.392 [0.274, 0.562]
`
`
`<0.0001
`
`
`
`14 (8)
`
`
`76 (44)
`
`90 (53)
`
`
`
` 1 (1)
`
`
`27 (16)
`
`28 (16)
`<0.0001
`
`5.5 [3.3, 9.1]
`
`
`
`<0.0001
`
`
`
`14 (8)
`
`76 (43)
`
`90 (51)
`
`
`
`1 (1)
`
`33 (19)
`
`34 (19)
`
`<0.0001
`
`4.3 [2.7, 7.0]
`
`
`
`
`Median TTP in weeks
`
`
`
` [95% CI]
`
`Hazard Ratio2
`
`
`[95% CI]
`
`Log-rank Test
` p-value 3
`
`Response
`
`Complete Response
`(CR) n (%)
`Partial Response
`(RR/PR) n (%)
`Overall Response
`
`n (%)
`p-value
`Odds Ratio
`
`[95% CI]
`
`
`
`
`
`
`1 NE, Not estimable due to short follow-up.
`
`2 Hazard Ratio of Revlimid/Dexamethasone to Placebo/Dexamethasone
`
`3 The p-value is based on a one-tailed unstratified log rank test.
`
`
`11
`
`
`
`
`320
`321
`322
`
`323
`324
`
`
`Figures 1 and 2 depict the Kaplan-Meier estimates of TTP in Studies 1 and 2,
`
`
` respectively.
`
`
`Figure 1:
`
`
`Kaplan-Meier Estimate of Time to Progression — Study 1
`
`
` Time to Progression (TTP), Study 1
`
`
`
` REVLIMID/Dex vs Placebo/Dex
`
`
`REVLIMID/Dex
`
`Placebo/Dex
`
`p<0.0001c
`
`125
`
`
`100
`
`
`75
`
`
`50
`
`
`25
`
`
`Proportion of Patients
`
`
`
`0
`
`0
`
`10
`
`20
`
`30
`40
`50
`
`Time To Progression (wks)
`
`Data cutoff date: 15Jul2004
`
`60
`
`70
`
`80
`
`
`325
`
`326
`
`327
`
`c p-value from log-rank test
`
`
`
`The median duration of Study 1 follow-up was 20.1 weeks.
`
`
`
`
`12
`
`
`
`
`328
`329
`
`Figure 2:
`
`
`Kaplan-Meier Estimate of Time to Progression — Study 2
`
`Time to Progression (TTP), Study 2
`
`REVLIMID/Dex vs Placebo/Dex
`
`
`REVLIMID/Dex
`
`Placebo/Dex
`
`p<0.0001c
`
`10
`
`30
`20
`Time To Progression (wks)
`
`
`Data cutoff date: 15Sep2004
`
`
`40
`
`50
`
`125
`
`100
`
`75
`
`50
`
`25
`
`Proportion of Patients
`
`0
`
`0
`
`c p-value from log-rank test
`
`330
`331
`
`332
`
`The median duration of Study 2 follow-up was 22.3 weeks.
`
`INDICATIONS AND USAGE
`
`
`
`333 REVLIMID® (lenalidomide) is indicated for the treatment of patients with transfusion
`334
`dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes
`335
`associated with a deletion 5q cytogenetic abnormality with or without additional
`336
`cytogenetic abnormalities.
`
`337 REVLIMID® (lenalidomide) in combination with dexamethasone is indicated for the
`338
`treatment of multiple myeloma patients who have received at least one prior therapy.
`
`339 CONTRAINDICATIONS
`
`340
`
`Pregnancy Category X: (See BOXED WARNINGS)
`
`341 Due to its structural similarities to thalidomide, a known human teratogen, and data from
`
`342
`an embryofetal development study showing treatment with lenalidomide produced
`343 malformations in the offspring of female monkeys who received the drug during
`344
`pregnancy, lenalidomide is contraindicated in pregnant women and women capable of
`
`becoming pregnant. (See BOXED WARNINGS.) When there is no alternative, females
`345
`346
`of childbearing potential may be treated with lenalidomide provided adequate precautions
`347
`are taken to avoid pregnancy. Females must commit either to abstain continuously from
`
`13
`
`
`
`
`heterosexual sexual intercourse or to use two methods of reliable birth control, including
`348
`at least one highly effective method (e.g., IUD, hormonal contraception, tubal ligation, or
`349
`partner’s vasectomy) and one additional effective method (e.g., latex condom,
`350
`diaphragm, or cervical cap), beginning 4 weeks prior to initiating treatment with
`351
`352 REVLIMID® (lenalidomide), during therapy with REVLIMID® (lenalidomide), during
`therapy delay, and continuing for 4 weeks following discontinuation of REVLIMID®
`353
`
`(lenalidomide) therapy. If hormonal or IUD contraception is medically contraindicated,
`354
`355
`two other effective or highly effective methods may be used.
`
`Females of childbearing potential being treated with REVLIMID® (lenalidomide) should
`356
`have pregnancy testing (sensitivity of at least 50 mIU/mL). The first test should be
`357
`performed within 10-14 days and the second test within 24 hours prior to beginning
`358
`359 REVLIMID® (lenalidomide) therapy and then weekly during the first month of
`360 REVLIMID® (lenalidomide), then monthly thereafter in women with regular menstrual
`361
`cycles or every 2 weeks in women with irregular menstrual cycles. Pregnancy testing and
`362
`counseling should be performed if a patient misses her period or if there is any
`abnormality in menstrual bleeding. If pregnancy occurs, REVLIMID® (lenalidomide)
`363
`364 must be immediately discontinued. Under these conditions, the patient should be referred
`365
`to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation
`
`and counseling.
`366
`
`367 REVLIMID® (l