15 July 1998
`
`THALOMID (thalidomide) Capsules
`Revised Package Insert
`
`TM
`
`WARNING: SEVERE, LIFE-THREATENING HUMAN BIRTH DEFECTS
`
`IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE
`BIRTH DEFECTS OR DEATH TO AN UNBORN BABY. THALIDOMIDE
`SHOULD NEVER BE USED BY WOMEN WHO ARE PREGNANT OR WHO
`COULD BECOME PREGNANT WHILE TAKING THE DRUG. EVEN A SINGLE
`DOSE [1 CAPSULE (50 mg)] TAKEN BY A PREGNANT WOMAN DURING HER
`PREGNANCY CAN CAUSE SEVERE BIRTH DEFECTS.
`
`BECAUSE OF THIS TOXICITY AND IN AN EFFORT TO MAKE THE CHANCE
`OF FETAL EXPOSURE TO THALOMID AS NEGLIGIBLE AS POSSIBLE,
`THALOMID IS APPROVED FOR MARKETING ONLY UNDER A SPECIAL
`RESTRICTED DISTRIBUTION PROGRAM APPROVED BY THE FOOD AND
`DRUG ADMINISTRATION. THIS PROGRAM IS CALLED THE "SYSTEM FOR
`THALIDOMIDE EDUCATION AND PRESCRIBING SAFETY (S.T.E.P.S.)".
`
`UNDER THIS RESTRICTED DISTRIBUTION PROGRAM, ONLY
`PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE PROGRAM
`ARE ALLOWED TO PRESCRIBE AND DISPENSE THE PRODUCT. IN
`ADDITION, PATIENTS MUST BE ADVISED OF, AGREE TO, AND COMPLY
`WITH THE REQUIREMENTS OF THE S.T.E.P.S. PROGRAM IN ORDER TO
`RECEIVE PRODUCT.
`
`PLEASE SEE THE FOLLOWING BOXED WARNINGS CONTAINING SPECIAL
`INFORMATION FOR PRESCRIBERS, FEMALE PATIENTS, AND MALE
`PATIENTS ABOUT THIS RESTRICTED DISTRIBUTION PROGRAM.
`
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`Page 1 of 22
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`Case IPR2015-01103
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`CELGENE EXHIBIT 2067
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`15 July 1998
`
`THALOMID (thalidomide) Capsules
`Revised Package Insert
`
`TM
`
`PRESCRIBERS
`
`THALOMID (thalidomide) may be prescribed only by licensed prescribers who are
`TM
`registered in the S.T.E.P.S. program and understand the risk of teratogenicity if thalidomide
`is used during pregnancy.
`Major human fetal abnormalities related to thalidomide administration during pregnancy
`have been documented: amelia (absence of limbs), phocomelia (short limbs), hypoplasticity
`of the bones, absence of bones, external ear abnormalities (including anotia, micro pinna,
`small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos,
`microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital
`malformations have also been documented. Mortality at or shortly after birth has been
`1
`reported at about 40%.
`2
`
`Effective contraception (see CONTRAINDICATIONS) must be used for at least 1 month
`before beginning thalidomide therapy, during thalidomide therapy, and for 1 month
`following discontinuation of thalidomide therapy. Reliable contraception is indicated even
`where there has been a history of infertility, unless due to hysterectomy or because the
`patient has been post-menopausal for at least 24 months. Two reliable forms of
`contraception must be used simultaneously unless continuous abstinence from reproductive
`heterosexual sexual intercourse is the chosen method. Women of childbearing potential
`should be referred to a qualified provider of contraceptive methods, if needed. Sexually
`mature women who have not undergone a hysterectomy or who have not been
`post-menopausal 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 women of child-bearing
`potential.
`
`Before starting treatment, women of childbearing potential should have a pregnancy test
`(sensitivity of at least 50 mIU/mL). The test should be performed within the 24 hours
`prior to beginning therapy. A prescription for thalidomide for a woman of childbearing
`potential must not be issued by the prescriber until a written report of a negative pregnancy
`test has been obtained by the prescriber.
`
`Once treatment has started, pregnancy testing should occur weekly during the first month
`of use, then monthly thereafter in women 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 menstrual bleeding.
`If pregnancy does occur during thalidomide treatment, thalidomide must be discontinued
`immediately.
`
`Any suspected fetal exposure to THALOMID (thalidomide) must be reported immediately
`to the FDA via the MedWATCH number at 1-800-FDA-1088 and also to Celgene
`Corporation. The patient should be referred to an obstetrician/gynecologist experienced in
`reproductive toxicity for further evaluation and counseling.
`
`2
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`Page 2 of 22
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`

`
`15 July 1998
`
`THALOMID (thalidomide) Capsules
`Revised Package Insert
`
`TM
`
`62
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`FEMALE PATIENTS
`Thalidomide is contraindicated in WOMEN of childbearing potential unless alternative
`therapies are considered inappropriate AND the patient MEETS ALL OF THE
`FOLLOWING CONDITIONS (i.e., she is essentially unable to become pregnant while on
`thalidomide therapy):
`C
`
`she understands and can reliably carry out instructions.
`
`C
`
`C
`
`C
`
`C
`
`C
`
`C
`
`she is capable of complying with the mandatory contraceptive measures, pregnancy
`testing, patient registration, and patient survey as described in the System for
`Thalidomide Education and Prescribing Safety (S.T.E.P.S.) program.
`
`she has received both oral and written warnings of the hazards of taking thalidomide
`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 (see
`CONTRAINDICATIONS), unless continuous abstinence from reproductive
`heterosexual intercourse is the chosen method. (Sexually mature women who have not
`undergone a hysterectomy or who have not been post-menopausal 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 women of child-bearing potential.).
`
`she acknowledges, in writing, her understanding of these warnings and of the need for
`using two reliable methods of contraception for one month prior to starting thalidomide
`therapy, during thalidomide therapy, and for one month after stopping thalidomide
`therapy.
`
`she has had a negative pregnancy test with a sensitivity of at least 50 mIU/mL, within
`the 24 hours prior to beginning therapy. (See PRECAUTIONS,
`CONTRAINDICATIONS.)
`
`if the patient is between 12 and 18 years of age, her parent or legal guardian must have
`read this material and agreed to ensure compliance with the above.
`
`3
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`Page 3 of 22
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`

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`15 July 1998
`
`THALOMID (thalidomide) Capsules
`Revised Package Insert
`
`TM
`
`MALE PATIENTS
`Thalidomide is contraindicated in sexually mature MALES unless the PATIENT MEETS
`ALL OF THE FOLLOWING CONDITIONS:
`C
`
`he understands and can reliably carry out instructions.
`
`C
`
`C
`
`C
`
`C
`
`C
`
`he is capable of complying with the mandatory contraceptive measures that are
`appropriate for men, patient registration, and patient survey as described in the
`S.T.E.P.S. program.
`
`he has received both oral and written warnings of the hazards of taking thalidomide and
`exposing a fetus to the drug.
`
`he has received both oral and written warnings of the risk of possible contraception
`failure and of the need to use barrier contraception when having sexual intercourse
`with women of childbearing potential, even if he has undergone successful vasectomy.
`
`he acknowledges, in writing, his understanding of these warnings and of the need for
`using barrier contraception (latex condom), even if he has undergone successful
`vasectomy, when having sexual intercourse with women of childbearing potential.
`Sexually mature women who have not undergone a hysterectomy or who have not
`been post-menopausal 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 women of
`child-bearing potential.
`
`if the patient is between 12 and 18 years of age, his parent or legal guardian must have
`read this material and agreed to ensure compliance with the above.
`
`DESCRIPTION
`THALOMID (thalidomide), "-(N-phthalimido)glutarimide, is an immunomodulatory agent.
`TM
`The empirical formula for thalidomide is C H N O and the gram molecular weight is 258.2.
`13
`10
`2
`4
`The CAS number of thalidomide is 50-35-1.
`
`Chemical Structure of thalidomide
`
`4
`
`Page 4 of 22
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`

`
`15 July 1998
`
`THALOMID (thalidomide) Capsules
`Revised Package Insert
`
`TM
`
`NOOHNOO
`
`Note: C = asymmetric carbon atom
`Thalidomide is an off-white to white, nearly odorless, crystalline powder that is soluble at 25EC in
`dimethyl sulfoxide and sparingly soluble in water and ethanol. The glutarimide moiety contains a
`single asymmetric center and, therefore, may exist in either of two optically active forms
`designated S-(-) or R-(+). THALOMID (thalidomide) is an equal mixture of the S-(-) and R-(+)
`forms and, therefore, has a net optical rotation of zero.
`
`THALOMID (thalidomide) is available in 50 mg capsules for oral administration. Active
`ingredient: thalidomide. Inactive ingredients: anhydrous lactose, microcrystalline cellulose,
`polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`
`Thalidomide is an immunomodulatory agent with a spectrum of activity that is not fully
`characterized. In patients with erythema nodosum leprosum (ENL) the mechanism of action is
`not fully understood.
`
`Available data from in vitro studies and preliminary clinical trials suggest that the immunologic
`effects of this compound can vary substantially under different conditions, but, may be related to
`suppression of excessive tumor necrosis factor-alpha (TNF-") production and down-modulation
`of selected cell surface adhesion molecules involved in leukocyte migration
`. For example,
`3,4,5,6
`administration of thalidomide has been reported to decrease circulating levels of TNF-" in
`patients with ENL , however, it has also been shown to increase plasma TNF-" levels in HIV-
`3
`seropositive patients .
`7
`
`Pharmacokinetics and Drug Metabolism
`
`Absorption
`
`The absolute bioavailability of thalidomide from THALOMID capsules has not yet been
`characterized in human subjects due to its poor aqueous solubility. In studies of both healthy
`volunteers and subjects with Hansen’s disease, the mean time to peak plasma concentrations
`(T ) of THALOMID ranged from 2.9 to 5.7 hours indicating that THALOMID is slowly
`max
`absorbed from the gastrointestinal tract. While the extent of absorption (as measured by area
`
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`Page 5 of 22
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`

`
`15 July 1998
`
`THALOMID (thalidomide) Capsules
`Revised Package Insert
`
`TM
`
`under the curve [AUC]) is proportional to dose in healthy subjects, the observed peak
`concentration (C ) increased in a less than proportional manner (see Table 1 below). This lack
`max
`of C dose proportionality, coupled with the observed increase in T values, suggests that the
`max
`max
`poor solubility of thalidomide in aqueous media may be hindering the rate of absorption.
`
`Table 1
`Pharmacokinetic Parameter Values for THALOMID (thalidomide)
`Mean (%CV)
`
`AUC
`Population/
`0-44
`(µgqqhr/mL)
`Single Dose
`Healthy Subjects (n=14)
`4.9 (16%)
`50 mg
`18.9 (17%)
`200 mg
`36.4 (26%)
`400 mg
`Patients with Hansen’s Disease (n=6)
`400 mg
`46.4 (44.1%)
`
`C
`max
`(µg/mL)
`
`0.62 (52%)
`1.76 (30%)
`2.82 (28%)
`
`3.44 (52.6%)
`
`T
`max
`(hrs)
`
`2.9 (66%)
`3.5 (57%)
`4.3 (37%)
`
`5.7 (27%)
`
`Half-life
`(hrs)
`
`5.52 (37%)
`5.53 (25%)
`7.29 (36%)
`
`6.86 (17%)
`
`Co-administration of THALOMID with a high fat meal causes minor (<10%) changes in the
`observed AUC and C values: however, it causes an increase in T to approximately 6 hours.
`max
`max
`
`Distribution
`
`It is not known whether thalidomide is present in the ejaculate of males.
`The extent of plasma protein binding of thalidomide is unknown.
`
`Metabolism
`
`At the present time, the exact metabolic route and fate of thalidomide is not known in humans.
`Thalidomide itself does not appear to be hepatically metabolized to any large extent, but appears to
`undergo non-enzymatic hydrolysis in plasma to multiple metabolites. In a repeat dose study in which
`THALOMID (thalidomide) 200 mg was administered to 10 healthy females for 18 days, thalidomide
`displayed similar pharmacokinetic profiles on the first and last day of dosing. This suggests that
`thalidomide does not induce or inhibit its own metabolism.
`
`Elimination
`
`As indicated in Table 1 (above) the mean half-life of elimination ranges from approximately 5 to 7
`hours following a single dose and is not altered upon multiple dosing. As noted in the metabolism
`subsection, the precise metabolic fate and route of elimination of thalidomide in humans is not known
`at this time. Thalidomide itself has a renal clearance of 1.15 mL/minute with less than 0.7% of the
`dose excreted in the urine as unchanged drug. Following a single dose, urinary levels of thalidomide
`were undetectable 48 hrs after dosing. Although thalidomide is thought to be hydrolyzed to a number
`of metabolites , only a very small amount (0.02% of the administered dose) of 4-OH-thalidomide was
`8
`identified in the urine of subjects 12 to 24 hours after dosing.
`
`Pharmacokinetic Data in Special Populations
`
`HIV-seropositive Subjects: There is no apparent significant difference in measured pharmacokinetic
`
`6
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`Page 6 of 22
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`

`
`15 July 1998
`
`THALOMID (thalidomide) Capsules
`Revised Package Insert
`
`TM
`
`parameter values between healthy human subjects and HIV-seropositive subjects following single
`dose administration of THALOMID (thalidomide) capsules.
`
`Patients with Hansen’s Disease: Analysis of data from a small study in Hansen’s patients suggests
`that these patients, relative to healthy subjects, may have an increased bioavailability of THALOMID.
`The increase is reflected both in an increased area under the curve and in increased peak plasma
`levels. The clinical significance of this increase is unknown.
`
`Patients with Renal Insufficiency: The pharmacokinetics of thalidomide in patients with renal
`dysfunction have not been determined.
`
`Patients with Hepatic Disease: The pharmacokinetics of thalidomide in patients with hepatic
`impairment have not been determined.
`
`Age: Analysis of the data from pharmacokinetic studies in healthy volunteers and patients with
`Hansen’s disease ranging in age from 20 to 69 years does not reveal any age-related changes.
`
`Pediatric: No pharmacokinetic data are available in subjects below the age of 18 years.
`
`Gender: While a comparative trial of the effects of gender on thalidomide pharmacokinetics has not
`been conducted, examination of the data for thalidomide does not reveal any significant gender
`differences in pharmacokinetic parameter values.
`
`Race: Pharmacokinetic differences due to race have not been studied.
`
`Clinical Studies
`
`The primary data demonstrating the efficacy of thalidomide in the treatment of the cutaneous
`manifestations of moderate to severe ENL are derived from the published medical literature and from
`a retrospective study of 102 patients treated by the U.S. Public Health Service.
`
`Two double blind, randomized, controlled trials reported the dermatologic response to a 7 day course
`of 100 mg thalidomide (four times daily) or control. Dosage was lower for patients under 50 kg in
`weight.
`
`Table 2
`Double Blind, Controlled Clinical Trials of Thalidomide in Patients with ENL:
`Cutaneous Response
`
`Reference
`
`No. of Patients
`
`Percent Responding**
`
`Iyer et al.
`9
`Bull World Health
`Organization 1971;
`45:719
`
`Sheskin et al.
`10
`Int J Lep 1969; 37:135
`
`92
`
`52
`
`Thalidomide
`75%
`
`Thalidomide
`66%
`
`Aspirin
`25%
`
`Placebo
`10%
`
`No. Treatment
`Courses*
`
`204
`
`173
`
`7
`
`* In patients with cutaneous lesions
`** Iyer: Complete response or lesions absent
`
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`

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`15 July 1998
`
`THALOMID (thalidomide) Capsules
`Revised Package Insert
`
`TM
`
`** Sheskin: Complete Improvement + "striking" improvement (i.e., >50% improvement)
`
`Waters reported the results of two studies, both double blind, randomized, placebo controlled,
`11
`crossover trials in a total of 10 hospitalized, steroid-dependent patients with chronic ENL treated
`with 100 mg thalidomide or placebo (three times daily). All patients also received dapsone. The
`primary endpoint was reduction in weekly steroid dosage.
`
`Table 3
`Double Blind, Controlled Trial of Thalidomide in Patients with ENL:
`Reduction in Steroid Dosage
`
`Reference
`
`Waters
`11
`Lep Rev 1971; 42:26
`
`Duration of
`Treatment
`4 weeks
`6 weeks (crossover)
`
`No. of Patients
`
`9
`8
`
`Number Responding
`Thalidomide
`Placebo
`4/5
`0/4
`8/8
`1/8
`
`Data on the efficacy of thalidomide in prevention of ENL relapse were derived from a
`retrospective evaluation of 102 patients treated under the auspices of the U.S. Public Health
`Service. A subset of patients with ENL controlled on thalidomide demonstrated repeated relapse
`upon drug withdrawal and remission with reinstitution of therapy.
`
`Twenty U.S. patients between the ages of 11 and 17 years were treated wtih thalidomide,
`generally at 100 mg daily. Response rates and safety profiles were similar to that observed in the
`adult population.
`
`Thirty-two other published studies containing over 1600 patients consistently report generally
`successful treatment of the cutaneous manifestations of moderate to severe ENL with
`thalidomide.
`
`INDICATIONS AND USAGE
`
`THALOMID (thalidomide) is indicated for the acute treatment of the cutaneous manifestations of
`moderate to severe erythema nodosum leprosum (ENL). THALOMID (thalidomide) is not
`indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis.
`
`THALOMID (thalidomide) is also indicated as maintenance therapy for prevention and
`suppression of the cutaneous manifestations of ENL recurrence.
`
`CONTRAINDICATIONS (See BOXED WARNINGS.)
`
`Pregnancy: Category X
`
`Due to its known human teratogenicity, even following a single dose, thalidomide is
`contraindicated in pregnant women and women capable of becoming pregnant. (See BOXED
`WARNINGS.) When there is no alternative treatment, women of childbearing potential may be
`treated with thalidomide provided adequate precautions are taken to avoid pregnancy. Women
`
`8
`
`Page 8 of 22
`
`

`
`15 July 1998
`
`THALOMID (thalidomide) Capsules
`Revised Package Insert
`
`TM
`
`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 thalidomide, during therapy with thalidomide, and continuing for 4 weeks
`following discontinuation of thalidomide therapy. If hormonal or IUD contraception is medically
`contraindicated (see also PRECAUTIONS: DRUG INTERACTIONS), two other effective or
`highly effective methods may be used.
`
`Women of childbearing potential being treated with thalidomide should have pregnancy testing
`(sensitivity of at least 50 mIU/mL). The test should be performed within the 24 hours before
`beginning thalidomide therapy and then weekly during the first month of thalidomide therapy, 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 during
`thalidomide treatment, thalidomide 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.
`
`THALOMID (thalidomide) is contraindicated in patients who have demonstrated hypersensitivity
`to the drug and its components.
`
`WARNINGS (See BOXED WARNINGS.)
`
`Birth defects:
`
`Thalidomide can cause severe birth defects in humans. (See BOXED WARNING and
`CONTRAINDICATIONS.) Patients should be instructed to take thalidomide only as prescribed
`and not to share their thalidomide with anyone else. Because it is not known whether or not
`thalidomide is present in the ejaculate of males receiving the drug, males receiving thalidomide
`must always use a latex condom when engaging in sexual activity with women of childbearing
`potential.
`
`Drowsiness and somnolence:
`
`Thalidomide frequently causes drowsiness and somnolence. Patients should be instructed to avoid
`situations where drowsiness may be a problem and not to take other medications that may cause
`drowsiness without adequate medical advice. Patients should be advised as to the possible
`impairment of mental and/or physical abilities required for the performance of hazardous tasks,
`such as driving a car or operating other complex or dangerous machinery.
`
`Peripheral neuropathy:
`
`Thalidomide is known to cause nerve damage that may be permanent. Peripheral neuropathy is a
`common, potentially severe, side effect of treatment with thalidomide that may be irreversible.
`Peripheral neuropathy generally occurs following chronic use over a period of months, however,
`reports following relatively short term use also exist. The correlation with cumulative dose is
`9
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`

`
`15 July 1998
`
`THALOMID (thalidomide) Capsules
`Revised Package Insert
`
`TM
`
`unclear. Symptoms may occur some time after thalidomide treatment has been stopped and may
`resolve slowly or not at all. Few reports of neuropathy have arisen in the treatment of ENL
`despite long-term thalidomide treatment. However, the inability clinically to differentiate
`thalidomide neuropathy from the neuropathy often seen in Hansen's disease makes it difficult to
`determine accurately the incidence of thalidomide-related neuropathy in ENL patients treated with
`thalidomide.
`
` Patients should be examined at monthly intervals for the first 3 months of thalidomide therapy to
`enable the clinician to detect early signs of neuropathy, which include numbness, tingling or pain
`in the hands and feet. Patients should be evaluated periodically thereafter during treatment.
`Patients should be regularly counseled, questioned, and evaluated for signs or symptoms of
`peripheral neuropathy. Consideration should be given to electrophysiological testing, consisting
`of measurement of sensory nerve action potential (SNAP) amplitudes at baseline and thereafter
`every 6 months in an effort to detect asymptomatic neuropathy. If symptoms of drug-induced
`neuropathy develop, thalidomide should be discontinued immediately to limit further damage, if
`clinically appropriate. Usually, treatment with thalidomide should only be reinitiated if the
`neuropathy returns to baseline status. Medications known to be associated with neuropathy
`should be used with caution in patients receiving thalidomide.
`
`Dizziness and orthostatic hypotension:
`
`Patients should also be advised that thalidomide may cause dizziness and orthostatic hypotension
`and that, therefore, they should sit upright for a few minutes prior to standing up from a
`recumbent position.
`
`Neutropenia:
`
`Decreased white blood cell counts, including neutropenia, have been reported in association with
`the clinical use of thalidomide. Treatment should not be initiated with an absolute neutrophil
`count (ANC) of <750/mm . White blood cell count and differential should be monitored on an
`3
`on-going basis, especially in patients who may be more prone to neutropenia, such as patients
`who are HIV-seropositive. If ANC decreases to below 750/mm while on treatment, the patient’s
`3
`medication regimen should be re-evaluated and, if the neutropenia persists, consideration should
`be given to withholding thalidomide if clinically appropriate.
`
`Increased HIV-Viral Load:
`
`In a randomized, placebo controlled trial of thalidomide in an HIV-seropositive patient
`population, plasma HIV RNA levels were found to increase (median change = 0.42 log copies
`10
`HIV RNA/mL, p = 0.04 compared to placebo) . A similar trend was observed in a second,
`7
`unpublished study conducted in patients who were HIV-seropostive . The clinical significance of
`12
`this increase is unknown. Both studies were conducted prior to availability of highly active
`antiretroviral therapy. Until the clinical significance of this finding is further understood, in HIV-
`seropositive patients, viral load should be measured after the first and third months of treatment
`and every 3 months thereafter.
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`

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`15 July 1998
`
`THALOMID (thalidomide) Capsules
`Revised Package Insert
`
`TM
`
`PRECAUTIONS
`
`Hypersensitivity:
`
`Hypersensitivity to THALOMID (thalidomide) has been reported. Signs and symptoms have
`included the occurrence of erythematous macular rash, possibly associated with fever,
`tachycardia, and hypotension, and if severe, may necessitate interruption of therapy. If the
`reaction recurs when dosing is resumed, THALOMID (thalidomide) should be discontinued.
`
`Bradycardia:
`
`Bradycardia in association with thalidomide use has been reported. At present there have been
`no reports of bradycardia requiring medical or other intervention. The clinical significance and
`underlying etiology of the bradycardia noted in some thalidomide-treated patients are present
`unknown.
`
`Information for Patients (See BOXED WARNINGS.)
`
`Patient should be instructed about the potential teratogenicity of thalidomide and the precautions
`that must be taken to preclude fetal exposure as per the S.T.E.P.S. program and boxed warnings
`in this package insert. Patients should be instructed to take thalidomide only as prescribed in
`compliance with all of the provisions of the S.T.E.P.S. Restricted Distribution Program.
`
`Patients should be instructed not to share medication with anyone else.
`
`Patients should be instructed that thalidomide frequently causes drowsiness and somnolence.
`Patients should be instructed to avoid situations where drowsiness may be a problem and not to
`take other medications that may cause drowsiness without adequate medical advice. Patients
`should be advised as to the possible impairment of mental and/or physical abilities required for the
`performance of hazardous tasks, such as driving a car or operating other complex machinery.
`Patients should be instructed that thalidomide may potentiate the somnolence caused by alcohol.
`
`Patients should be instructed that thalidomide can cause peripheral neuropathies that may be
`initially signaled by numbness, tingling, or pain or a burning sensation in the feet or hands.
`Patients should be instructed to report such occurrences to their prescriber immediately.
`
`Patients should also be instructed that thalidomide may cause dizziness and orthostatic
`hypotension and that, therefore, they should sit upright for a few minutes prior to standing up
`from a recumbent position.
`
`Patients should be instructed that they are not permitted to donate blood while taking thalidomide.
`In addition, male patients should be instructed that they are not permitted to donate sperm while
`taking thalidomide.
`
`Laboratory Tests
`
`Pregnancy Testing: (See BOXED WARNINGS.) Women of childbearing potential should have
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`

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`15 July 1998
`
`THALOMID (thalidomide) Capsules
`Revised Package Insert
`
`TM
`
`pregnancy testing performed (sensitivity of at least 50 mIU/mL). The test should be performed
`within the 24 hours prior to beginning thalidomide therapy and then weekly during the first month
`of use, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in
`women with irregular menstrual cycles. Pregnancy testing should also be performed if a patient
`misses her period or if there is any abnormality in menstrual bleeding.
`
`Neutropenia: (See WARNINGS.)
`
`HIV Viral Load: (See WARNINGS.)
`
`Drug Interactions
`
`Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol,
`chlorpromazine, and reserpine.
`
`Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should
`be used with caution in patients receiving thalidomide.
`
`Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and
`ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone
`acetate and 75 µg of ethinyl estradiol were studied. The results were similar with and without
`coadministration of thalidomide 200 mg/day to steady-state levels.
`
`Important Non-Thalidomide Drug Interactions
`
`Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease
`inhibitors, griseofulvin, rifampin, rifabutin, phenytoin, or carbamazepine with hormonal
`contraceptive agents, may reduce the effectiveness of the contraception. Therefore, women
`requiring treatment with one or more of these drugs must use two OTHER effective or highly
`effective methods of contraception or abstain from reproductive heterosexual sexual intercourse.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Long-term carcinogenicity tests have not been conducted using thalidomide. Thalidomide gave
`no evidence of mutagenic effects when assayed in in vitro bacterial (Salmonella typhimurium and
`Escherichia coli; Ames mutagenicity test), in vitro mammalian (AS52 Chinese hamster ovary
`cells; AS52/XPRT mammalian cell forward gene mutation assay) and in vivo mammalian (CD-1
`mice; in vivo micronucleus test) test systems.
`
`Animal studies to characterize the effects of thalidomide on fertility have not been conducted.
`
`Pregnancy
`
`Pregnancy Category X: See BOXED WARNING and CONTRAINDICATIONS.
`
`Because of the known human teratogenicity of thalidomide, thalidomide is contraindicated in
`women who are or may become pregnant and who are not using the two required types of birth
`
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`15 July 1998
`
`THALOMID (thalidomide) Capsules
`Revised Package Insert
`
`TM
`
`control or who are not continually abstaining from reproductive heterosexual sexual intercourse.
`If thalidomide is taken during pregnancy, it can cause severe birth defects or death to an unborn
`baby. Thalidomide should never be used by women who are pregnant or who could become
`pregnant while taking the drug. Even a single dose [1 capsule (50 mg)] taken by a pregnant
`woman can cause birth defects. If pregnancy does occur during 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
`counselling. Any suspected fetal exposure to THALOMID (thalidomide) must be reported to the
`FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation.
`
`Animal studies to characterize the effects of thalidomide on late stage pregnancy have not been
`conducted.
`
`Use in Nursing Mothers
`
`It is not known whether thalidomide is excreted in human milk. Because many drugs are excreted
`in human milk and because of the potential for serious adverse reactions in nursing infants from
`thalidomide, 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.
`
`Pediatric Use
`
`Safety and effectiveness in pediatric patients below the age of 12 years hav