CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-880
`
`APPROVED LABELING
`
`

`

`REVLIMID® (lenalidomide)
`
`5 mg & 10 mg capsules
`
`WARNINGS:
`
`l. POTENTIAL FOR HUMAN BIRTH DEFECTS
`
`2. HEMATOLOGIC TOXICITY (NEUTROPENIA AND THROMBO—
`CYTOPENIA)
`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 ARE ABLE TO 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.
`
`CELGENE'S REVASSISTSM PROGRAM DESCRIPTION
`
`Prescribers
`
`REVLIMID® (lenalidomide) will be prescribed only by licensed prescribers who are
`registered in the RevAssi‘stSM program and understand the potential risk of teratogenicity
`if lenalidomide is used during pregnancy.
`
`\OOONONUIAUJN
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` Effective contraception must be used by patients for at least 4 weeks before beginning
`
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`REVLIMID® 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 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.
`
`
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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 successfifl vasectomy.
`
`
`
`
`
`
`
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` 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.
`
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`
` Female Patients
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`Pregnancy test results should be verified by the prescriber and thepharmacist 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
`1-888-4CELGEN. The patient should be referred to an obstetrician/gynecologist
`experienced in reproductive toxicity for further evaluation and counseling.
`
`
`
`

`

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` REVLIMID® (lenalidomide) should be used in females of childbearing potential only
`
`
`
` 0
`to reliably carry out instructions.
`
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`she is capable of complying with the contraceptive measures, pregnancy testing,
`patient registration, and patient survey as described in the RevAssistSM program.
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` she has received both oral and written warnings of the potential risks of taking
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`lenalidomide during pregnancy and of exposing a fetus to the drug.
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` she has received both oral and written warnings of the risk of possible contraception
`
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`when the patient MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is
`unable to become pregnant while on lenalidomide therapy):
`
`she appears to understand the risks associated with the drug and is thought to be able
`
`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) 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.
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` she has had two negative pregnancy tests with a sensitivity of at least 50 mIU/mL,
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`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 are to
`. read the educational materials and agree to try 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:
`
`
`
`
`0
`he appears to understand the risks associated with the drug and is thought to be able
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`to reliably carry out instructions.
`
`
`
`he is capable of complying with the contraceptive measures that are appropriate for
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`men, patient registration, and patient survey as described in the RevAssistSM program.
`
` he has received both oral and written warnings of the potential risks of taking
`
`
`lenalidomide and exposing a fetus to the drug.
`
`

`

`
`
`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
`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 are to
`read the educational materials and agree to try to ensure compliance with the above.
`
` HEMATOLOGIC TOXICITY (NEUTROPENIA AND THROMBOCYTOPENIA)
` This drug is associated with significant neutropenia and thrombocytopenia in
`
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`patients with del Sq MDS. Eighty percent of patients had to have a dose
`delay/reduction during the major study for the indication. 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
`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)
`
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` 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 conj unction‘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.
`'
`
`DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM
`
`
`
`
`
`
`
`
` You can get the information about REVLIMID® and the RevAssistSM program on
`
`the internet at www.REVLIMID.c0m or by calling the manufacturer’s toll free
`
`
`number 1-888-4CELGEN.
`
`
`144
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`DESCRIPTION
`
`

`

`REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent
`with anti-angiogenic properties. The chemical name is 3-(4-amin0—l—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
`
`HN
`
`63:0
`
`NH2
`
`3-(4-amino-1-0xo 1,3 -dihydro-2H-isoindol—2—yl) piperidine—2,6—di0ne
`
`The empirical formula for lenalidomide is C13H13N303, 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 and 10 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 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.
`
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`CLINICAL PHARMACOLOGY
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`166
`
`Mechanism of Action:
`
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`The mechanism of action of lenalidomide remains to be fiilly characterized.
`Lenalidomide possesses 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 (ICSOS) in some but
`not all cell lines. Of cell lines tested, lenalidomide was effective in 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-l cells (human myeloblastic cell
`line, also with a deletion of one chromosome 5) and other cell lines without chromosome
`5 deletions. Lenalidomide inhibited the expression of cyclooxygenase—2 (COX—2) but not
`COX-1 in vitro.
`
`Pharmacokinetics and Drug Metabolism:
`
`

`

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`
`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 syndrome (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.
`
`192
`
`Pharmacokinetic Parameters:
`
`_ 193
`
`194
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`Distribution:
`
`In vitro (”Q—lenalidomide binding to plasma proteins is approximately 30%.
`
`195
`
`Metabolism and Excretion:
`
`196
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`
`198
`199 -
`
`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.
`
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`Special Populations:
`
`Patients with Renal Insufliciency: 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).
`
`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 phannacokinetic 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.
`
`212
`
`CLINICAL STUDIES
`
`

`

`The efficacy and Safety of REVLIMID® (lenalidomide) were evaluated in patients with
`transfusion dependent anemia in low- or intermediate-l— risk MDS with a 5 q (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.
`
`213
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`
`This major study enrolled 148 patients who had RBC transfusion dependent anemia.
`RBC—transfusion dependence was defined as having received 2 2 units of RBCs within 8
`weeks prior to study treatment. The study enrolled patients with absolute neutrophil
`counts (ANC) 2 500 cells/mm3, platelet counts 2 50,000/mm3, serum creatinine S 2.5
`mg/dL, serum SGOT/AST or SGPT/ALT S 3.0 x upper limit of normal (ULN), and
`serum direct bilirubin S 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.
`able 1: Baseline Demographic and Disease-Related Characteristics
`Overall
`(N=148)
`
`-ge (years)
`Median
`Min, Max
`ender
`.
`
`Female
`' r-ce
`White
`
`" ration of MDS (years)
`Median
`Min, Max
`Hal 5 (q31—33) Cytogenetic Abnormality
`
`H'U><l7.)(DInU] m0OH(D
`
`Other cytogenetic abnormalities
`r-I “I H
`
`71.0
`37.0, 95.0
`n
`(%)
`
`97 (65.5)
`n
`(%)
`143 (96.6)
`
`N U1
`.
`0.1, 20.7
`n
`(%)
`148 (100.0)
`37 ( 25.2)
`n
`(%)
`55 (37.2)
`65 (43.9)
`6
`( 4.1)
`
`
`
`
`
`
`
`
`Low (0)
`Intermediate—1
`Intermediate—2
`
`OHmu u H m H0m(1’I‘-Ou,.
`
`(0.5—1
`m
`1
`
`H.Um ..
`
`O
`
`n...H0gv EnHwH H045-z
`
`(%)
`n
`77 (52.0)
`RA
`16 (10.8)
`RARS
`30 (20.3)
`RAEB
`3
`( 2.0)
`CMML
`Intermediate—1 (combined
`[a]
`IPSS Risk Category: Low (combined score = O),
`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.
`
`228
`
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`232
`
`233
`
`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 transfiision independence was first declared
`
`

`

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`(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.
`
`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.
`
`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
`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. 11‘ hormonal or IUD contraception is medically contraindicated, two other
`effective or highly effective methods may be used.
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`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.
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`REVLIMID® (lenalidomide) is contraindicated in any patients who have demonstrated
`hypersensitivity to the drug or its components.
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`WARNINGS:
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`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 afier completing therapy.
`
`There are no adequate and well—controlled studies in pregnant females.
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`Because of this potential toxicity and to avoid fetal exposure to REVLIMID®
`(lenalidomide), Celgene has made REVLIMID® (lenalidomide) only available under a
`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).
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`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
`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.
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`Reproductive effects of lenalidomide have not been thoroughly assessed. The structural
`similarity of lenalidomide to thalidomide, a known human teratogen, suggests a potential
`risk to the developing fetus.
`'
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`HEMATOLOGIC TOXICITY (NEUTROPENIA AND THROMBOCYTOPENIA):
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`This drug is associated with significant neutropenia and thrombocytopenia in
`patients with del Sq MDS. Eighty percent of patients had to have a dose delay or
`reduction during the major study for the indication. 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. 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). Patients on therapy 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 ENIBOLISM:
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`This drug has demonstrated a significantly increased risk of DVT and 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.
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`PRECAUTIONS:
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`General:
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`No formal studies have been conducted in patients with renal impairment. This drug is
`known to be excreted by the kidney, and the risk of adverse reactions to this drug may be
`greater in patients with impaired renal function.
`
`Information for Patients:
`
`Patients should be counseled on lenalidomide’s potential risk of teratogenicity due to its
`structural similarity to thalidomide. Under the RevAssist SM program, patients may only
`acquire a prescription for REVLIMID® (lenalidomide) therapy through a controlled
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`distribution program through contracted pharmacies. Female patients of childbearing
`potential will be educated and counseled on the requirements of the RevAssistSM program
`and the precautions to be taken to preclude fetal exposure to REVLIMID®
`(lenalidomide). Patients should become familiar with the REVLIMID® RevAssistSM
`educational materials, Patient Medication Guide, and direct any questions to their
`physician or pharmacist prior to starting REVLIMID® (lenalidomide) therapy.
`
`Laboratory tests:
`
`The clinical study enrolled patients with absolute neutrophil counts (ANC) 2 500
`cells/mm3, platelet counts 2 50,000/mm3, serum creatinine S 2.5 mg/dL, serum
`SGOT/AST or SGPT/ALT S 3.0 x upper limit of normal (ULN), and serum direct
`bilirubin S 2.0 mg/dL. A complete blood cell count, including white blood cell count with
`differential, platelet count, hemoglobin, and hematocrit should be performed weekly for
`the first 8 weeks of REVLIMID® (lenalidomide) treatment and monthly thereafter to
`monitor for cytopenias.
`
`Drug Interactions:
`
`Results from human in vitro metabolism studies and nonclinical studies show that
`REVLIMID® (lenalidomide) is neither metabolized by nor inhibits or induces the
`cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be
`subject to P450-based metabolic drug interactions in man.
`
`Co-administration of multiple doses of 10 mg of lenalidomide had no effect on the single
`dose pharmacokinetics of R— and S— warfarin. Co-administration of single 25-mg dose
`warfarin had no effect on the pharmacokinetics of total lenalidomide. Expected changes
`in laboratory assessments of PT and INR were observed after warfarin administration, but
`these changes were not affected by concomitant lenalidomide administration.
`
`Carcinogenesis, mutagenesis, impairment of fertility:
`
`Carcinogenicity: Carcinogenicity studies with lenalidomide have not been conducted.
`
`Mutagenesis: Lenalidomide did not induce mutation in the Ames test, chromosome
`aberrations in cultured human peripheral blood lymphocytes, or mutation at the
`thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not
`increase morphological transformation in Syrian Hamster Embryo assay or induce
`micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.
`
`Fertility: A fertility and early embryonic development study in rats, with administration
`of lenalidomide up to 500 mg/kg (approximately 600 times the human dose of 10 mg,
`based on body surface area) produced no parental toxicity and no adverse effects on
`fertility.
`
`Pregnancy:
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`Pregnancy Category X: (See ‘BOXED WARNINGS’ and CONTRAINDICATIONS)
`
`Because of the structural similarity to thalidomide, a known human teratogen, and the
`lack of sufficient information regarding lenalidomide’s teratogenic potential,
`REVLIMID® (lenalidomide) is contraindicated in females who are or may become
`pregnant and who are not using the two required types of birth control or who are not
`continually abstaining from reproductive heterosexual sexual intercourse. REVLIMID®
`(lenalidomide) should not be used by females who are pregnant or who could become
`pregnant while taking the drug. If pregnancy does occur dufing treatment, the drug
`should be immediately discontinued. Under these conditions, the patient should be
`referred to an obstetrician / gynecologist experienced in reproductive toxicity for further
`evaluation and counseling. Any suspected fetal exposure to. REVLIMID® (lenalidomide)
`should be reported to the FDA via the MedWatch program at 1-800—FDA-1088 and also
`to Celgene Corporation at 1-888—4CELGEN (1—888-423-5436).
`
`Use ‘in Nursing Mothers:
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`It is not known whether this drug is excreted in human milk. Because many drugs are
`excreted in human milk and because of the potential for adverse reactions in nursing
`infants from lenalidomide, a decision should be made whether to discontinue nursing or
`to discontinue the drug, taking into account the importance of the drug to the mother.
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`Pediatric Use:
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`Safety and effectiveness in pediatric patients below the age of 18 have not been
`established.
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`REVLIMID® (lenalidomide) has been used in clinical trials in patients up to 95 years of
`age. Of the 148 patients with del Sq 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
`events (100%) was the same in patients over 65 years of age as in younger patients, the
`frequency of serious adverse events 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 events 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.
`
`This drug is known to be substantially excreted by the kidney, and the risk of toxic
`reactions to this drug may be greater in patients with impaired renal filnction. Because
`elderly patients are. more likely to have decreased renal fimction, care should be taken in
`dose selection, and it would be prudent to monitor renal function.
`
`Renal Impairment:
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