THALOMID® Capsules
`(thalidomide)
`
`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® (thalidomide) AS NEGLIGIBLE AS POSSIBLE,
`THALOMID® (thalidomide) 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.(cid:228)(cid:228) )."
`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.(cid:228)(cid:228) 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.
`
`1
`
`CELGENE EXHIBIT 2008
`Coalition for Affordable Drugs VI LLC (Petitioner) v. Celgene Corporation (Patent Owner)
`Case IPR2015-01103
`
`Page 1 of 24
`
`

`
`PRESCRIBERS
`THALOMID® (thalidomide) may be prescribed only by licensed prescribers who are registered in
`the S.T.E.P.S.(cid:228)
` 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.1
`Mortality at or shortly after birth has been reported at about 40%.2
`Effective contraception (see CONTRAINDICATIONS) must be used for at least 4 weeks before
`beginning thalidomide therapy, during thalidomide therapy, and for 4 weeks 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 postmenopausal for at least 24
`months. Two reliable forms of contraception must be used simultaneously unless continuous
`abstinence from heterosexual sexual contact 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 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 women of childbearing 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.
`Male Patients: Because thalidomide is present in the semen of patients receiving the drug, males
`receiving thalidomide must always use a latex condom during any sexual contact with women of
`childbearing potential.
`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.
`
`FEMALE PATIENTS
`Thalidomide is contraindicated in WOMEN of childbearing potential unless alternative therapies are
`
`2
`
`Page 2 of 24
`
`

`
`considered inappropriate AND the patient MEETS ALL OF THE FOLLOWING CONDITIONS
`(i.e., she is essentially unable to become pregnant while on thalidomide therapy):
`•
`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 System for Thalidomide Education and
`Prescribing Safety (S.T.E.P.S.(cid:228) ) 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 heterosexual sexual contact is
`the chosen method. (Sexually mature women 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 women 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 starting thalidomide therapy, during
`thalidomide therapy, and for 4 weeks 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
`
`Page 3 of 24
`
`

`
`
`
` MALE PATIENTS
` Thalidomide is contraindicated in sexually mature MALES unless 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 S.T.E.P.S.(cid:228)
` 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 presence of thalidomide in semen. He has been instructed that he must always use barrier
`contraception (latex condom) during any sexual contact 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 to use barrier
`contraception (latex condom) during any sexual contact with women of childbearing potential,
`even if he has undergone successful vasectomy. 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 any time in the preceding 24 consecutive months) are considered to be
`women of childbearing 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.
`
`•
`
`
`
`4
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`Page 4 of 24
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`

`
`
` DESCRIPTION
` THALOMID® (thalidomide), a -(N-phthalimido)glutarimide, is an immunomodulatory agent. The
`empirical formula for thalidomide is C13H10N2O4 and the gram molecular weight is 258.2. The
`CAS number of thalidomide is 50-35-1.
` Chemical Structure of thalidomide
`
`
`
`
`
`
`
`H
`N
`
`
`
`O
`
`O
`
`O
`
`N
`
`O
`
`
`
`
`
` Note: • = asymmetric carbon atom
`
` Thalidomide is an off-white to white, nearly odorless, crystalline powder that is soluble at 25(cid:176) C 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-a
`) production and down-modulation
`of selected cell surface adhesion molecules involved in leukocyte migration.3-6 For example,
`administration of thalidomide has been reported to decrease circulating levels of TNF-a
` in
`patients with ENL, 3 however, it has also been shown to increase plasma TNF-a
` levels in HIV-
`seropositive patients.7
`
`
`5
`
`Page 5 of 24
`
`

`
`
` Pharmacokinetics and Drug Metabolism
`
` Absorption
` The absolute bioavailability of thalidomide from THALOMID® (thalidomide) 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
`(Tmax) of THALOMID® (thalidomide) ranged from 2.9 to 5.7 hours indicating that
`THALOMID® (thalidomide) is slowly absorbed from the gastrointestinal tract. While the extent
`of absorption (as measured by area under the curve [AUC]) is proportional to dose in healthy
`subjects, the observed peak concentration (Cmax) increased in a less than proportional manner
`(see Table 1 below). This lack of Cmax dose proportionality, coupled with the observed increase
`in Tmax values, suggests that the poor solubility of thalidomide in aqueous media may be hindering
`the rate of absorption.
`
` Table 1
` Pharmacokinetic Parameter Values for THALOMID® (thalidomide)
` Mean (%CV)
` Cmax
` µg/mL
`
` Tmax
` (hrs)
`
` Half-life
` (hrs)
`
` AUC0¥¥
` µg•hr/mL
`
` Population/
` 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%)
`
` 0.62 (52%)
` 1.76 (30%)
` 2.82 (28%)
`
` 2.9 (66%)
` 3.5 (57%)
` 4.3 (37%)
`
` 5.52 (37%)
` 5.53 (25%)
` 7.29 (36%)
`
` 3.44 (52.6%)
`
` 5.7 (27%)
`
` 6.86 (17%)
`
`
` Coadministration of THALOMID® (thalidomide) with a high fat meal causes minor (<10%)
`changes in the observed AUC and Cmax values; however, it causes an increase in Tmax to
`approximately 6 hours.
`
` Distribution
` In human blood plasma, the geometric mean plasma protein binding was 55% and 66%,
`respectively, for (+)-(R)- and (-)-(S)-thalidomide.8 In a pharmacokinetic study of thalidomide in
`HIV-seropositive adult male subjects receiving thalidomide 100 mg/day, thalidomide was
`detectable in the semen.
`
` 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,
`
`6
`
`Page 6 of 24
`
`

`
`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,9 only a very small amount (0.02% of the administered
`dose) of 4-OH-thalidomide was 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 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® (thalidomide). 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.
`
`7
`
`
`
`Page 7 of 24
`
`

`
` Percent Responding**
`
`
`
` Reference
`
` Table 2
` Double-Blind, Controlled Clinical Trials of Thalidomide in Patients with ENL:
` Cutaneous Response
` No. of Patients
` No. Treatment
`Courses*
`
` 204
` 92
`
`
`
`
` 173
` 52
` *In patients with cutaneous lesions
` **Iyer: Complete response or lesions absent
` **Sheskin: Complete improvement + “striking” improvement (i.e., >50% improvement)
` Waters12 reported the results of two studies, both double-blind, randomized, placebo-controlled,
`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
` Duration of
` No. of Patients
` Treatment
` 4 weeks
` 6 weeks (crossover)
`
` Reference
`
` Waters12
` Lep Rev 1971;42:26
`
`
`
` 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 with 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.
`
`
`8
`
` Iyer et al.10
` Bull World Health Organization
`1971;45:719
` Sheskin et al.11
` Int J Lep 1969;37:135
`
`
`
`
`
` Thalidomide
` 75%
`
` Thalidomide
` 66%
`
` Aspirin
` 25%
`
` Placebo
` 10%
`
`Page 8 of 24
`
`

`
` 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
`must commit either to abstain continuously from heterosexual sexual contact 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.
` Because thalidomide is present in the semen of patients receiving the drug, males receiving
`thalidomide must always use a latex condom during any sexual contact with women of
`childbearing potential.
` THALOMID® (thalidomide) is contraindicated in patients who have demonstrated
`hypersensitivity to the drug and its components.
`
` WARNINGS (See BOXED WARNINGS.)
`
` Birth defects:
`
`9
`
`Page 9 of 24
`
`

`
` Thalidomide can cause severe birth defects in humans. (See BOXED WARNINGS and
`CONTRAINDICATIONS.) Patients should be instructed to take thalidomide only as
`prescribed and not to share their thalidomide with anyone else. Because thalidomide is present in
`the semen of patients receiving the drug, males receiving thalidomide must always use a latex
`condom during any sexual contact 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
`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.
`
`
`10
`
`Page 10 of 24
`
`

`
` 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/mm3. White blood cell count and differential should be monitored on an ongoing
`basis, especially in patients who may be more prone to neutropenia, such as patients who are
`HIV-seropositive. If ANC decreases to below 750/mm3 while on treatment, the patient’s
`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 log10 copies
`HIV RNA/mL, p = 0.04 compared to placebo). 7 A similar trend was observed in a second,
`unpublished study conducted in patients who were HIV- seropositive13 The clinical significance of
`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.
`
` 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 presently
`unknown.
`
` Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis:
` Serious dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal
`necrolysis, which may be fatal, have been reported. THALOMID® (thalidomide) should be
`discontinued if a skin rash occurs and only resumed following approriate clinical evaluation. If the
`rash is exfoliative, purpuric, or bullous or if Stevens-Johnson syndrome or toxic epidermal
`necrolysis is suspected, use of THALOMID® (thalidomide) should not be resumed.
`
` Seizures:
` Although not reported from pre-marketing controlled clinical trials, seizures, including grand mal
`convulsions, have been reported during post-approval use of THALOMID(cid:210) (thalidomide)
`in clinical practice. Because these events are reported voluntarily from a population of unknown
`
`11
`
`Page 11 of 24
`
`

`
`size, estimates of frequency cannot be made. Most patients had disorders that may have
`predisposed them to seizure activity, and it is not currently known whether thalidomide has any
`epileptogenic influence. During therapy with thalidomide, patients with a history of seizures or
`with other risk factors for the development of seizures should be monitored closely for clinical
`changes that could precipitate acute seizure activity.
`
` Information for Patients (See BOXED WARNINGS.)
` Patients 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.(cid:228)
` 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.(cid:228)
` 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 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.)
`
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` 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 heterosexual sexual contact.
`
` 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
`control or who are not continually abstaining from heterosexual sexual contact. 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
`counseling. 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.
`
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` Because thalidomide is present in the semen of patients receiving the drug, males receiving
`thalidomide must always use a latex condom during any sexual contact with women of
`childbearing potential.
` 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 have not been
`established.
`
` Geriatric Use
` No systematic studies in geriatric patients have been conducted. Thalidomide has been used in
`clinical trials in patients up to 90 years of age. Adverse events in patients over the age of 65 years
`did not appear to differ in kind from those reported for younger individuals.
`
` ADVERSE REACTIONS
` The most serious toxicity