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`
`REVLIMID® (lenalidomide)
`5 mg, 10 mg, 15 mg and 25 mg capsules
`
`WARNINGS:
`1. POTENTIAL FOR HUMAN BIRTH DEFECTS
`2. HEMATOLOGIC TOXICITY (NEUTROPENIA AND
`THROMBOCYTOPENIA)
`3. DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM
`
`
`
`
`POTENTIAL FOR HUMAN BIRTH DEFECTS
`
`WARNING: POTENTIAL FOR HUMAN BIRTH DEFECTS
`
`LENALIDOMIDE IS AN ANALOGUE OF THALIDOMIDE. THALIDOMIDE IS
`A KNOWN HUMAN TERATOGEN THAT CAUSES SEVERE LIFE-
`THREATENING HUMAN BIRTH DEFECTS. IF LENALIDOMIDE IS TAKEN
`DURING PREGNANCY, IT MAY CAUSE BIRTH DEFECTS OR DEATH TO AN
`UNBORN BABY. FEMALES SHOULD BE ADVISED TO AVOID PREGNANCY
`WHILE TAKING REVLIMID® (lenalidomide).
`
`Special Prescribing Requirements
`
`BECAUSE OF THIS POTENTIAL TOXICITY AND TO AVOID FETAL
`EXPOSURE TO REVLIMID® (lenalidomide), REVLIMID® (lenalidomide) IS
`ONLY AVAILABLE UNDER A SPECIAL RESTRICTED DISTRIBUTION
`PROGRAM. THIS PROGRAM IS CALLED "REVASSISTSM". UNDER THIS
`PROGRAM, ONLY PRESCRIBERS AND PHARMACISTS REGISTERED WITH
`THE PROGRAM CAN PRESCRIBE AND DISPENSE THE PRODUCT. IN
`ADDITION, REVLIMID MUST ONLY BE DISPENSED TO PATIENTS WHO
`ARE REGISTERED AND MEET ALL THE CONDITIONS OF THE
`REVASSISTSM PROGRAM .
`
`PLEASE SEE THE FOLLOWING INFORMATION FOR PRESCRIBERS,
`FEMALE PATIENTS, AND MALE PATIENTS ABOUT THIS RESTRICTED
`DISTRIBUTION PROGRAM.
`
`REVASSISTSM PROGRAM DESCRIPTION
`
`Prescribers
`
`REVLIMID® (lenalidomide) can be prescribed only by licensed prescribers who are
`registered in the RevAssistSM program and understand the potential risk of teratogenicity
`if lenalidomide is used during pregnancy.
`
`1
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`

`

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`Effective contraception must be used by female patients of childbearing potential for at
`least 4 weeks before beginning REVLIMID® (lenalidomide) therapy, during
`36
`REVLIMID® (lenalidomide) therapy, during dose interruptions and for 4 weeks
`37
`following discontinuation of REVLIMID® (lenalidomide) therapy. Reliable contraception
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`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
`40
`41 months. Two reliable forms of contraception must be used simultaneously unless
`42
`continuous abstinence from heterosexual sexual contact is the chosen method. Females of
`43
`childbearing potential should be referred to a qualified provider of contraceptive
`44 methods, if needed. Sexually mature females who have not undergone a hysterectomy,
`45
`have not had a bilateral oophorectomy or who have not been postmenopausal naturally
`46
`for at least 24 consecutive months (i.e., who have had menses at some time in the
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`preceding 24 consecutive months) are considered to be females of childbearing potential.
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`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
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`females of childbearing potential should occur weekly during the first 4 weeks of use,
`59
`then pregnancy testing should be repeated every 4 weeks in females with regular
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`61 menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur
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`every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses
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`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
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`evaluation.
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`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
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`

`

`REVLIMID® (lenalidomide) should be used in females of childbearing potential only
`75
`76 when the patient MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is
`77
`unable to become pregnant while on lenalidomide therapy):
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`• 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 RevAssistSM
`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:
`
`• he understands and can reliably carry out instructions.
`
`• he is capable of complying with the mandatory contraceptive measures that are
`appropriate for men, patient registration, and patient survey as described in the
`RevAssistSM program.
`
`• he has received and understands both oral and written warnings of the potential risks
`of taking lenalidomide and exposing a fetus to the drug.
`
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`• 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.
`
`• 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).
`
`•
`
`if the patient is between 12 and 18 years of age, his parent or legal guardian must
`have read the educational material 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.
`
`
`
`
`
`4
`
`

`

`You can get the information about REVLIMID® and the RevAssistSM program on
`the internet at www.REVLIMID.com or by calling the manufacturer’s toll free
`number 1-888-423-5436.
`
`DESCRIPTION
`
`REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent
`with anti-angiogenic and anti-neoplastic 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
`structure:
`
`Chemical Structure of Lenalidomide
`O O
`
`NH
`
`N
`
`O
`
`
`
`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.
`
`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® (lenalidomide) is available in 5 mg, 10 mg, 15 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 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.
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action:
`
`The mechanism of action of lenalidomide remains to be fully characterized.
`Lenalidomide possesses anti-neoplastic, immunomodulatory and antiangiogenic
`properties. Lenalidomide inhibited the secretion of pro-inflammatory cytokines and
`increased the secretion of anti-inflammatory cytokines from peripheral blood
`mononuclear cells. Lenalidomide inhibited cell proliferation with varying effectiveness
`(IC50s) in some but not all cell lines. Of cell lines tested, lenalidomide was effective in
`
`5
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`inhibiting growth of Namalwa cells (a human B cell lymphoma cell line with a deletion
`of one chromosome 5) but was much less effective in inhibiting growth of KG-1 cells
`(human myeloblastic cell line, also with a deletion of one chromosome 5) and other cell
`lines without chromosome 5 deletions. Lenalidomide inhibited the growth of multiple
`myeloma cells from patients, as well as MM.1S cells (a human multiple myeloma cell
`line), by inducing cell cycle arrest and apoptosis.
`
`Lenalidomide inhibited the expression of cyclooxygenase-2 (COX-2) but not COX-1 in
`vitro.
`
`Pharmacokinetics and Drug Metabolism:
`
`Absorption:
`
`Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration
`with maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose.
`Co-administration with food does not alter the extent of absorption (AUC) but does
`reduce the maximal plasma concentration (Cmax) by 36%. The pharmacokinetic
`disposition of lenalidomide is linear. Cmax and AUC increase proportionately with
`increases in dose. Multiple dosing at the recommended dose-regimen does not result in
`drug accumulation.
`
`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:
`
`Distribution:
`
`In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%.
`
`Metabolism and Excretion:
`
`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 in MDS patients
`with renal dysfunction has not been determined. In multiple myeloma patients, those with
`mild renal impairment had an AUC 56% greater than those with normal renal function.
`(See PRECAUTIONS: Renal Impairment).
`
`6
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`

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`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.
`
`Gender: The effects of gender on the pharmacokinetics of lenalidomide have not been
`studied.
`
`Race: Pharmacokinetic differences due to race have not been studied.
`
`CLINICAL STUDIES
`
`Myelodysplastic Syndromes (MDS) with a Deletion 5q Cytogenetic Abnormality
`
`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.
`RBC-transfusion dependence was defined as having received ≥ 2 units of RBCs within 8
`weeks prior to study treatment. The study enrolled patients with absolute neutrophil
`counts (ANC) ≥ 500 cells/mm3, platelet counts ≥ 50,000/mm3, serum creatinine ≤ 2.5
`mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3.0 x upper limit of normal (ULN), and
`serum direct bilirubin ≤ 2.0 mg/dL. Granulocyte colony-stimulating factor was permitted
`for patients who developed neutropenia or fever in association with neutropenia. Baseline
`patient and disease-related characteristics are summarized in Table 1.
`Table 1: Baseline Demographic and Disease-Related Characteristics
` Overall
` (N=148)
`Age (years)
` Median 71.0
` Min, Max 37.0, 95.0
`Gender n (%)
` Male 51 (34.5)
` Female 97 (65.5)
`Race n (%)
` White 143 (96.6)
` Other 5 (3.4)
`Duration of MDS (years)
` Median 2.5
` Min, Max 0.1, 20.7
`Del 5 (q31-33) Cytogenetic Abnormality n (%)
` Yes 148 (100.0)
` Other cytogenetic abnormalities 37 ( 25.2)
`IPSS Score [a] n (%)
` Low (0) 55 (37.2)
` Intermediate-1 (0.5-1.0) 65 (43.9)
` Intermediate-2 (1.5-2.0) 6 ( 4.1)
` High (>=2.5) 2 ( 1.4)
` Missing 20 (13.5)
`
`7
`
`

`

`FAB Classification [b] from central review n (%)
` RA 77 (52.0)
` RARS 16 (10.8)
` RAEB 30 (20.3)
` CMML 3 ( 2.0)
`[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 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.
`
`Transfusion independence was seen in 99/148 (67%) patients (95% CI [59, 74]). The
`median duration from the date when RBC transfusion independence was first declared
`(i.e., the last day of the 56-day RBC transfusion-free period) to the date when an
`additional transfusion was received after the 56-day transfusion-free period among the 99
`responders was 44 weeks (range of 0 to >67 weeks).
`
`Ninety percent of patients who achieved a transfusion benefit did so by completion of
`three months in the study.
`
`RBC-transfusion independence rates were unaffected by age or gender.
`
`The dose of REVLIMID® (lenalidomide) was reduced or interrupted at least once due to
`an adverse event in 118 (79.7%) of the 148 patients; the median time to the first dose
`reduction or interruption was 21 days (mean, 35.1 days; range, 2-253 days), and the
`median duration of the first dose interruption was 22 days (mean, 28.5 days; range, 2-265
`days). A second dose reduction or interruption due to adverse events was required in 50
`(33.8%) of the 148 patients. The median interval between the first and second dose
`reduction or interruption was 51 days (mean, 59.7 days; range, 15-205 days) and the
`median duration of the second dose interruption was 21 days (mean, 26 days; range, 2-
`148 days).
`
`Granulocyte colony-stimulating factors were permitted for patients who developed
`neutropenia or fever in association with neutropenia.
`Multiple Myeloma
`Two randomized studies (Studies 1 and 2) were conducted to evaluate the efficacy and
`safety of REVLIMID® (lenalidomide). These multicenter, multinational, double-blind,
`placebo-controlled studies compared REVLIMID® (lenalidomide) plus oral pulse high-
`dose dexamethasone therapy to dexamethasone therapy alone, in patients with multiple
`myeloma who had received at least one prior treatment.
`
`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
`
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`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 Section).
`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
`
`

`

`282
`
`Table 2 Baseline Demographic and Disease-related Characteristics - Studies 1 and 2
`Study 1
`Study 2
`
`
`
`REVLIMID/Dex
`N=170
`
`Placebo/Dex
`N=171
`
`REVLIMID/Dex
`N=176
`
`Placebo/Dex
`N=175
`
`
`
`
`
`
`
`
`
`
`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
`
`
`283
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`
`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
`
`
`
`38%
`62%
`
`60%
`42%
`80%
`11%
`
`34%
`55%
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`32%
`68%
`
`56%
`30%
`66%
`5%
`
`56%
`56%
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`33%
`67%
`
`54%
`38%
`69%
`4%
`
`52%
`57%
`
`
`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
`
`
`
`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
`REVLIMID/Dex
`N=170
`
`
`Placebo/Dex
`N=171
`
`
`Study 2
`REVLIMID/Dex
`N=176
`
`
`Placebo/Dex
`N=175
`
`
`
`
`TTP
`Censored
` n (%)
`Median TTP in
`weeks
`[95% CI]
` Hazard Ratio3
`[95% CI]
`
` Log-rank Test
`p-Value 1
`Response
` Complete
`Response (CR)
`n (%)
` Partial
`Responses
`(RR/PR) n (%)
` Overall
`Response
`n (%)
` p-value
` Odds Ratio
`[95% CI]
`
`115 (68)
`
`61 (36)
`
`133 (76)
`
`78 (45)
`
`37.1
` [28, NE2]
`
`19.9
` [16, 22]
`
`NE2
`
`20
` [19.9, 21.6]
`
`0.356 [0.257,0.494]
`
`<0.0001
`
`
`
`14 (8)
`
`
`
`1 (1)
`
`0.392 [0.274,0.562]
`
`<0.0001
`
`
`
`14 (8)
`
`
`
`1 (1)
`
`76 (44)
`
`27 (16)
`
`76 (43)
`
`33 (19)
`
`90 (53)
`
`28 (16)
`
`90 (51)
`
`34 (19)
`
`<0.0001
`
`5.5 [3.3, 9.1]
`
`<0.0001
`
`4.3 [2.7, 7.0]
`
` 1
`
` The p-value is based on a one-tailed unstratified log rank test.
`2 NE, Not Estimable due to short follow-up.
`3 Hazard Ratio of Revlimid/Dexamethasone to Placebo/Dexamethasone
`
`Figures 1 and 2 depict the Kaplan-Meier estimates of TTP in Studies 1 and 2,
`respectively.
`
`
`
`11
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`

`

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`
`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<0.0001(cid:99)
`
`125
`
`100
`
`75
`
`50
`
`25
`
`Proportion of Patients
`
`0
`
`0
`
`10
`
`20
`
`50
`40
`30
`Time To Progression (wks)
`Data cutoff date: 15Jul2004
`
`60
`
`70
`
`80
`
`309
`310
`311
`312
`
`(cid:99) p-value from log-rank test
`
`
`
`The median duration of Study 1 follow-up was 20.1 weeks.
`
`12
`
`

`

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`314
`
`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<0.0001(cid:99)
`
`10
`
`30
`20
`Time To Progression (wks)
`Data cutoff date: 15Sep2004
`
`40
`
`50
`
`125
`
`100
`
`75
`
`50
`
`25
`
`Proportion of Patients
`
`0
`
`0
`
`(cid:99) p-value from log-rank test
`
`
`
`The median duration of Study 2 follow-up was 22.3 weeks.
`
`INDICATIONS AND USAGE:
`
`REVLIMID® (lenalidomide) is indicated for the treatment of patients with transfusion-
`dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes
`associated with a deletion 5q cytogenetic abnormality with or without additional
`cytogenetic abnormalities.
`
`REVLIMID® (lenalidomide) in combination with dexamethasone is indicated for the
`treatment of multiple myeloma patients who have received at least one prior therapy.
`
`CONTRAINDICATIONS:
`
`Pregnancy Category X: (See ‘BOXED WARNING’)
`
`Due to its structural similarities to thalidomide, a known human teratogen, lenalidomide
`is contraindicated in pregnant women and women capable of becoming pregnant. (See
`BOXED WARNINGS.) When there is no alternative, females of childbearing potential
`may be treated with lenalidomide provided adequate precautions are taken to avoid
`pregnancy. Females must commit either to abstain continuously from heterosexual
`sexual intercourse or to use two methods of reliable birth control, including at least one
`highly effective method (e.g., IUD, hormonal contraception, tubal ligation, or partner’s
`
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`
`

`

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`vasectomy) and one additional effective method (e.g., latex condom, diaphragm, or
`
`cervical cap), beginning 4 weeks prior to initiating treatment with REVLIMID®
`(lenalidomide), during therapy with REVLIMID® (lenalidomide), during therapy delay,
`and continuing for 4 weeks following discontinuation of REVLIMID® (lenalidomide)
`therapy. If hormonal or IUD contraception is medically contraindicated, two other
`effective or highly effective methods may be used.
`
`Females of childbearing potential being treated with REVLIMID® (lenalidomide) should
`have pregnancy testing (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 beginning
`REVLIMID® (lenalidomide) therapy and then weekly during the first month of
`REVLIMID® (lenalidomide), then monthly thereafter in women with regular menstrual
`cycles or every 2 weeks in women with irregular menstrual cycles. Pregnancy testing
`and counseling should be performed if a patient misses her period or if there is any
`abnormality in menstrual bleeding. If pregnancy occurs, REVLIMID® (lenalidomide)
`must be immediately discontinued. Under these conditions, the patient should be referred
`to an obstetrician / gynecologist experienced in reproductive toxicity for further
`evaluation and counseling.
`
`REVLIMID® (lenalidomide) is contraindicated in any patients who have demonstrated
`hypersensitivity to the drug or its components.
`
`WARNINGS:
`
`Pregnancy Category X: (See ‘BOXED WARNING’ and CONTRAINDICATIONS)
`
`REVLIMID® (lenalidomide) is an analogue of thalidomide. Thalidomide is a known
`human teratogen that causes life-threatening human birth defects. REVLIMID®
`(lenalidomide) may cause fetal harm when administered to a pregnant female. Females of
`childbearing potential should be advised to avoid pregnancy while on REVLIMID®
`(lenalidomide). Two effective contraceptive methods should be used during therapy,
`during therapy interruptions and for at least 4 weeks after completing therapy.
`
`There are no adequate and well-controlled studies in pregnant females.
`
`Because of this potential toxicity and to avoid fetal exposure to REVLIMID®
`(lenalidomide), REVLIMID® (lenalidomide) is only available under a special restricted
`distribution program. This program is called "RevAssistSM".
`
`Lenalidomide has been shown to have an embryocidal effect in rabbits at a dose of 50
`mg/kg (approximately 120 times the human dose of 10 mg based on body surface area).
`
`An embryo-fetal development study in rats revealed no teratogenic effects at the highest
`dose of 500 mg/kg (approximately 600 times the human dose of 10 mg based on body
`surface area). At 100, 300 or 500 mg/kg/day there was minimal maternal toxicity that
`included slight, transient, reduction in mean body weight gain and food intake. However
`
`14
`
`

`

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`406
`407
`408
`
`this animal model may not adequately address the full spectrum of the potential embryo-
`fetal developmental effects of lenalidomide.
`
`A pre- and post-natal development study in rats revealed few adverse effects on the
`offspring of female rats treated with lenalidomide at doses up to 500 mg/kg
`(approximately 600 times the human dose of 10 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.
`
`Reproductive effects of lenalidomide have not been thoroughly assessed. The structural
`similarity of lenalidomide to thal