HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to
`use THALOMID® safely and effectively. See full prescribing
`information for THALOMID®.
`THALOMID® (thalidomide) capsules for oral use
`Initial U.S. Approval: 1998
`
`
`
`WARNING: EMBRYO-FETAL TOXICITY AND VENOUS
`THROMBOEMBOLISM
`See full prescribing information for complete boxed warning.
`EMBRYO -FETAL TOXICITY
`If thalidomide is taken during pregnancy, it can cause
`
`severe birth defects or embryo-fetal death. Thalidomide
`should never be used by females who are pregnant or who
`could be pregnant while taking the drug. Even a single
`dose [1 capsule (regardless of strength)] taken by a
`pregnant woman during her pregnancy can cause severe
`birth defects.
`Pregnancy must be excluded before start of treatment.
`Prevent pregnancy thereafter by the use of two reliable
`methods of contraception. (5.1)
`THALOMID® (thalidomide) is only available through a
`restricted distribution program, the THALOMID REMSTM
`program (formerly known as the System for Thalomid
`Education and Prescribing Safety (S.T.E.P.S.®) program) (5.2).
`VENOUS THROMBOEMBOLISM
`Significant increased risk of deep vein thrombosis (DVT)
`
`and pulmonary embolism (PE) in patients with multiple
`myeloma receiving THALOMID® (thalidomide) with
`dexamethasone (5.3).
`-----------------------RECENT MAJOR CHANGES------------------
`Warnings and Precautions (5.3)
` 06/2014
`
`
`
`------------------------INDICATIONS AND USAGE------------------
`THALOMID in combination with dexamethasone is
`
`indicated for the treatment of patients with newly diagnosed
`multiple myeloma (MM). (1.1)
`THALOMID is indicated for the acute treatment of the
`cutaneous manifestations of moderate to severe erythema
`nodosum leprosum (ENL).
`THALOMID is not indicated as monotherapy for such ENL
`treatment in the presence of moderate to severe neuritis.
`THALOMID is also indicated as maintenance therapy for
`prevention and suppression of the cutaneous manifestations
`of ENL recurrence. (1.2)
`--------------------DOSAGE AND ADMINISTRATION-------------
`MM: 200 mg orally once daily. The recommended dose of
`
`dexamethasone is 40 mg/day on days 1-4, 9-12, and 17-20
`every 28 days. (2.1)
`ENL: 100 to 300 mg/day for an episode of cutaneous ENL.
`Up to 400 mg/day for severe cutaneous ENL. (2.2)
`-------------------DOSAGE FORMS AND STRENGTHS-----------
`Capsules: 50 mg, 100 mg, 150 mg and 200 mg. (3)
`
`
`
`--------------------------CONTRAINDICATIONS---------------------
`Pregnancy (Boxed Warning, 4.1, 5.1, 5.2, 8.1, 17)
`
`Demonstrated hypersensitivity to the drug or its components
`
`(4.2, 5.14, 6.2)
`
`
`
`
`
`
`
`
`
`
`
`
`
`----------------------WARNINGS AND PRECAUTIONS------------
`Ischemic heart disease (including myocardial infarction) and
`
`stroke have been observed in patients treated with
`THALOMID in combination with dexamethasone. (5.3)
`Drowsiness and Somnolence: Instruct patients to avoid
`situations where drowsiness may be a problem and not to
`take other medications that may cause drowsiness. (5.4)
`Peripheral Neuropathy: Examine patients at monthly
`intervals for the first 3 months of thalidomide therapy and
`periodically thereafter for signs or symptoms of peripheral
`neuropathy. Consider 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. (5.5)
`Dizziness and Orthostatic Hypotension: Advise patients to sit
`upright for a few minutes prior to standing up from a
`recumbent position. (5.6)
`Neutropenia: Patients may require dose interruption and/or
`dose reduction. (5.7)
`Increased HIV Viral Load: Measure viral load after the first
`and third months of treatment and every 3 months thereafter.
`(5.8)
`Bradycardia: Monitor patients for bradycardia and possible
`syncope. Dose reduction or discontinuation may be required.
`(5.9)
`Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis:
`Do not resume THALOMID following discontinuation for
`these reactions. (5.10)
`Seizures: Monitor patients with a history of seizures or at risk
`for the development of seizures closely for clinical changes
`that could precipitate acute seizure activity. (5.11)
`Tumor Lysis Syndrome: Monitor patients at risk (e.g., those
`with high tumor burden prior to treatment) and take
`appropriate precautions. (5.12)
`Hypersensitivity: Monitor patients for potential
`hypersensitivity to the drug and its components. (5.14)
`
`
`
`
`
`
`
`
`
`------------------------ADVERSE REACTIONS------------------------
`MM: The most common adverse reactions (≥ 20%) are
`
`fatigue, hypocalcemia, edema, constipation, neuropathy-
`sensory, dyspnea, muscle weakness, leukopenia, neutropenia,
`rash/desquamation, confusion, anorexia, nausea,
`anxiety/agitation, asthenia, tremor, fever, weight loss,
`thrombosis/embolism, neuropathy-motor, weight gain,
`dizziness, and dry skin. (6.1)
`ENL: The most common adverse reactions (≥ 10%) are
`somnolence, rash, and headache. (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS or embryo-
`fetal exposure: contact Celgene Corporation at 1-888-423-5436
`or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`-------------------------DRUG INTERACTIONS-----------------------
`Use caution if other drugs which have sedative and hypnotic
`
`properties, slow cardiac conduction and/or cause peripheral
`neuropathy must be used. (7.1, 7.2, 7.3)
`It is not known whether concomitant use of hormonal
`contraceptives further increases the risk of thromboembolism
`with THALOMID. (5.13, 7.4)
`Patients taking concomitant therapies such as erythropoietin
`stimulating agents or estrogen containing therapies may have
`an increased risk of thromboembolism. (7.7)
`
`
`
`
`
`------------------USE IN SPECIFIC POPULATIONS---------------
`Nursing Mothers: Discontinue drug or nursing taking into
`
`consideration importance of drug to the mother. (8.3)
`Safety and effectiveness in pediatric patients below the age of
`12 years have not been established. (8.4)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`Medication Guide.
`
`Revised: 06/2014
`
`1
`
`Page 1 of 29
`
`CELGENE EXHIBIT 2001
`Coalition for Affordable Drugs VI LLC (Petitioner) v. Celgene Corporation (Patent Owner)
`Case IPR2015-01102
`
`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Multiple Myeloma
`1.2 Erythema Nodosum Leprosum
`2 DOSAGE AND ADMINISTRATION
`2.1 Multiple Myeloma
`2.2 Erythema Nodosum Leprosum
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`4.1 Pregnancy
`4.2 Hypersensitivity
`5 WARNINGS AND PRECAUTIONS
`5.1 Embryo-Fetal Toxicity
`5.2 THALOMID REMSTM program
`5.3 Venous and Arterial Thromboembolism
`5.4 Drowsiness and Somnolence
`5.5 Peripheral Neuropathy
`5.6 Dizziness and Orthostatic Hypotension
`5.7 Neutropenia
`5.8
`Increased HIV Viral Load
`5.9 Bradycardia
`5.10 Stevens-Johnson Syndrome and Toxic Epidermal
`Necrolysis
`5.11 Seizures
`5.12 Tumor Lysis Syndrome
`5.13 Contraceptive Risks
`5.14 Hypersensitivity
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Opioids, Antihistamines, Antipsychotics, Anti-anxiety
`Agents, or Other CNS Depressants (Including Alcohol)
`7.2 Drugs which Cause Bradycardia
`
`7.3 Drugs which Cause Peripheral Neuropathy
`7.4 Hormonal Contraceptives
`7.5 Warfarin
`7.6 Drugs that Interfere with Hormonal Contraceptives
`7.7 Concomitant Therapies that may Increase the Risk of
`Thromboembolism
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy Category X
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Females of Reproductive Potential and Males
`8.7 Renal Impairment
`8.8 Hepatic Impairment
`9 DRUG ABUSE AND DEPENDENCE
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Multiple Myeloma (MM)
`14.2 Erythema Nodosum Leprosum (ENL)
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`16.3 Handling and Disposal
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing
`information are not listed.
`
`2
`
`Page 2 of 29
`
`

`
`FULL PRESCRIBING INFORMATION
`
`WARNING: EMBRYO-FETAL TOXICITY AND VENOUS THROMBOEMBOLISM
`
`EMBRYO-FETAL TOXICITY
`If thalidomide is taken during pregnancy, it can cause severe birth defects or embryo-fetal death. Thalidomide should never be used by
`females who are pregnant or who could become pregnant while taking the drug. Even a single dose [1 capsule (regardless of strength)]
`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 embryo-fetal exposure to THALOMID® (thalidomide) as negligible as
`possible, THALOMID® (thalidomide) is approved for marketing only through a special restricted distribution program: THALOMID
`REMSTM program, approved by the Food and Drug Administration. This program was formerly known as the “System for Thalidomide
`Education and Prescribing Safety (S.T.E.P.S.® program)”.
`You can get the information about THALOMID and the THALOMID REMSTM program on the Internet at
`www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.
`
`VENOUS THROMBOEMBOLISM
`The use of THALOMID® (thalidomide) in multiple myeloma results in an increased risk of venous thromboembolism, such as deep
`venous thrombosis and pulmonary embolism. This risk increases significantly when thalidomide is used in combination with standard
`chemotherapeutic agents including dexamethasone. In one controlled trial, the rate of venous thromboembolism was 22.5% in patients
`receiving thalidomide in combination with dexamethasone compared to 4.9% in patients receiving dexamethasone alone (p = 0.002).
`Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Instruct patients to seek medical
`care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Consider thromboprophylaxis based on an
`assessment of individual patients’ underlying risk factors.
`
`1
`
`INDICATIONS AND USAGE
`
`1.1 Multiple Myeloma
`THALOMID in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma (MM).
`1.2 Erythema Nodosum Leprosum
`THALOMID is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL).
`THALOMID is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis.
`THALOMID is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.
`2
`DOSAGE AND ADMINISTRATION
`THALOMID® (THALIDOMIDE) MUST ONLY BE ADMINISTERED IN COMPLIANCE WITH ALL OF THE TERMS OUTLINED IN THE
`THALOMID REMSTM PROGRAM. THALOMID® (THALIDOMIDE) MAY ONLY BE PRESCRIBED BY PRESCRIBERS CERTIFIED WITH
`THE THALOMID REMSTM PROGRAM AND MAY ONLY BE DISPENSED BY PHARMACISTS CERTIFIED WITH THE THALOMID
`REMSTM PROGRAM.
`Drug prescribing to females of reproductive potential should be contingent upon initial and continued confirmed negative results of pregnancy
`testing.
`2.1 Multiple Myeloma
`THALOMID is administered in combination with dexamethasone in 28-day treatment cycles. The dose of THALOMID is 200 mg administered
`orally once daily with water, preferably at bedtime and at least 1 hour after the evening meal. The dose of dexamethasone is 40 mg daily
`administered orally on days 1-4, 9-12, and 17-20 every 28 days.
`Patients who develop adverse reactions such as constipation, somnolence, or peripheral neuropathy may benefit by either temporarily
`discontinuing the drug or continuing at a lower dose. With the abatement of these adverse reactions, the drug may be started at a lower dose or at
`the previous dose based on clinical judgment.
`2.2 Erythema Nodosum Leprosum
`For an episode of cutaneous ENL, THALOMID dosing should be initiated at 100 to 300 mg/day, administered once daily with water, preferably
`at bedtime and at least 1 hour after the evening meal. Patients weighing less than 50 kilograms should be started at the low end of the dose range.
`In patients with a severe cutaneous ENL reaction, or in those who have previously required higher doses to control the reaction, THALOMID
`dosing may be initiated at higher doses up to 400 mg/day once daily at bedtime or in divided doses with water, at least 1 hour after meals.
`In patients with moderate to severe neuritis associated with a severe ENL reaction, corticosteroids may be started concomitantly with
`THALOMID. Steroid usage can be tapered and discontinued when the neuritis has ameliorated.
`Dosing with THALOMID should usually continue until signs and symptoms of active reaction have subsided, usually a period of at least 2
`weeks. Patients may then be tapered off medication in 50 mg decrements every 2 to 4 weeks.
`Patients who have a documented history of requiring prolonged maintenance treatment to prevent the recurrence of cutaneous ENL or who flare
`during tapering should be maintained on the minimum dose necessary to control the reaction. Tapering off medication should be attempted every
`3 to 6 months, in decrements of 50 mg every 2 to 4 weeks.
`
`3
`
`Page 3 of 29
`
`

`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`THALOMID 50 mg, 100 mg, 150 mg and 200 mg capsules will be supplied through the THALOMID REMSTM program [see How
`Supplied/Storage and Handling (16)].
`
`THALOMID is available in the following capsule strengths:
`
`50 mg capsules [white opaque], imprinted “Celgene/50 mg” with a “Do Not Get Pregnant” logo.
`100 mg capsules [tan], imprinted “Celgene/100 mg” with a “Do Not Get Pregnant” logo.
`150 mg capsules [tan and blue], imprinted “Celgene/150 mg” with a “Do Not Get Pregnant” logo
`200 mg capsule [blue], imprinted “Celgene/200 mg” with a “Do not Get Pregnant” logo.
`
`4
`
`CONTRAINDICATIONS
`
`4.1 Pregnancy
`[see Boxed Warning]
`THALOMID can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations
`(8.1). Thalidomide is contraindicated in females who are pregnant. Thalidomide is a powerful human teratogen, inducing a high frequency of
`severe and life-threatening birth defects, even after a single dose [see Boxed Warning]. Mortality at or shortly after birth has been reported in
`about 40% of infants. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
`apprised of the potential hazard to the fetus. If pregnancy occurs during thalidomide treatment, the drug should be discontinued immediately.
`4.2 Hypersensitivity
`
`THALOMID is contraindicated in patients who have demonstrated hypersensitivity to the drug or its components [see Warnings and Precautions
`(5.14)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Embryo-Fetal Toxicity
`Thalidomide is a powerful human teratogen that induces a high frequency of severe and life-threatening birth defects, even after a single dose.
`Mortality at or shortly after birth has been reported in about 40% of infants. When there is no satisfactory alternative treatment, females of
`reproductive potential may be treated with thalidomide provided adequate precautions are taken to avoid pregnancy. THALOMID®
`(thalidomide) is only available through the THALOMID REMSTM program (formerly known as the “S.T.E.P.S.® program”), [see Warnings and
`Precautions (5.2)].
`Oral ingestion is the only type of maternal thalidomide exposure known to result in drug-associated birth defects. There are no specific data
`available regarding the reproductive risks of cutaneous absorption or inhalation of thalidomide; however, females of reproductive potential should
`avoid contact with THALOMID® (thalidomide) Capsules. THALOMID Capsules should be stored in blister packs until ingestion. If there is
`contact with non-intact thalidomide capsules or the powder contents, the exposed area should be washed with soap and water.
`If healthcare providers or other care givers are exposed to body fluids from patients receiving THALOMID (thalidomide) the exposed area should
`be washed with soap and water. Appropriate precautions should be utilized, such as wearing gloves to prevent the potential cutaneous exposure
`to THALOMID.
`Females of Reproductive Potential
`Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning THALOMID therapy, during therapy, during dose
`interruptions and for at least 4 weeks after completing therapy.
`
`Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control,
`beginning 4 weeks prior to initiating treatment with THALOMID, during therapy, during dose interruptions and continuing for 4 weeks following
`discontinuation of THALOMID therapy.
`
`Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second
`test within 24 hours prior to prescribing THALOMID therapy and then weekly during the first month, then monthly thereafter in women with
`regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].
`
`Males
`Thalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any
`sexual contact with females of reproductive potential while taking THALOMID and for up to 28 days after discontinuing THALOMID, even if
`they have undergone a successful vasectomy. Male patients taking THALOMID must not donate sperm [see Use in Specific Populations (8.6)].
`
`Blood Donation
`Patients must not donate blood during treatment with THALOMID and for 1 month following discontinuation of the drug because the blood
`might be given to a pregnant female patient whose fetus must not be exposed to THALOMID.
`
`5.2 THALOMID REMSTM Program (S.T.E.P.S.®)
`Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], THALOMID is available only through a restricted program under a Risk
`Evaluation and Mitigation Strategy (REMS), the THALOMID REMSTM program (formerly known as the “S.T.E.P.S.®” program).
`Required components of the THALOMID REMSTM program include the following:
`Prescribers must be certified with the THALOMID REMSTM program by enrolling and complying with the REMS requirements.
`
`Patients must sign a Patient-Physician Agreement Form and comply with the REMS requirements. In particular, female patients of
`
`reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in
`Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)].
`4
`
`Page 4 of 29
`
`

`
`
`
`Pharmacies must be certified with the THALOMID REMSTM program, must only dispense to patients who are authorized to receive
`THALOMID and comply with REMS requirements.
`
`Further information about the THALOMID REMSTM program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-
`5436.
`5.3 Venous and Arterial Thromboembolism
`The use of THALOMID in patients with MM results in an increased risk of venous thromboembolism, such as deep venous thrombosis and
`pulmonary embolism. This risk increases significantly when thalidomide is used in combination with standard chemotherapeutic agents including
`dexamethasone. In one controlled trial, the rate of venous thromboembolism was 22.5% in patients receiving thalidomide in combination with
`dexamethasone compared to 4.9% in patients receiving dexamethasone alone (p = 0.002).
`Ischemic heart disease (11.1%), including myocardial infarction (1.3%), and stroke (cerebrovascular accident, 2.6%) have also occurred in
`patients with previously untreated MM treated with THALOMID and dexamethasone compared to placebo and dexamethasone (4.7%, 1.7%, and
`0.9%, respectively) in one clinical trial [see Adverse Reactions (6.1)].
`Consider thromboprophylaxis based on an assessment of individual patients’ underlying risk factors. Patients and physicians should be observant
`for the signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of
`breath, chest pain, or arm or leg swelling [see Boxed Warning]. Agents that also may increase the risk of thromboembolism should be used with
`caution in patients receiving THALOMID [see Drug Interactions (7.7)].
`5.4 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 [see Drug Interactions (7.1)]. Advise patients 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. Dose reductions may be required.
`5.5 Peripheral Neuropathy
`Thalidomide is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common (≥10%) and potentially severe adverse
`reaction of treatment with thalidomide that may be irreversible. Peripheral neuropathy generally occurs following chronic use over a period of
`months; however, peripheral neuropathy following relatively short-term use has been reported. 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 [see Drug Interactions (7.3)].
`5.6 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.
`5.7 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.
`5.8
`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). A similar trend was observed in a second,
`unpublished study conducted in patients who were HIV-seropositive. 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.
`5.9 Bradycardia
`Bradycardia in association with thalidomide use has been reported. Cases of bradycardia have been reported, some required medical
`interventions. The clinical significance and underlying etiology of the bradycardia noted in some thalidomide-treated patients are presently
`unknown. Monitor patients for bradycardia and syncope. Dose reduction or discontinuation may be required.
`Medications known to decrease heart rate should be used with caution in patients receiving thalidomide [see Drug Interactions (7.2)].
`5.10 Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
`
`5
`
`Page 5 of 29
`
`

`
`Serious dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be fatal, have been reported.
`THALOMID should be discontinued if a skin rash occurs and only resumed following appropriate clinical evaluation. If the rash is exfoliative,
`purpuric, or bullous or if Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, use of THALOMID should not be resumed.
`5.11 Seizures
`Although not reported from pre-marketing controlled clinical trials, seizures, including grand mal convulsions, have been reported during post-
`approval use of THALOMID in clinical practice. Because these events are reported voluntarily from a population of unknown 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.
`5.12 Tumor Lysis Syndrome
`Monitor patients at risk of tumor lysis syndrome (e.g., patients with high tumor burden prior to treatment) and take appropriate precautions.
`5.13 Contraceptive Risks
`Some contraceptive methods may pose a higher risk of adverse effects or may be medically contraindicated in some patients treated with
`THALOMID. Because some patients may develop sudden, severe neutropenia and/or thrombocytopenia, use of an intrauterine device (IUD) or
`implantable contraception in these patients may carry an increased risk for infection or bleeding either at insertion, removal or during use.
`Treatment with THALOMID, the presence of an underlying malignancy, and/or use of an estrogen-containing contraceptive can each increase the
`risk of thromboembolism. It is not known if these risks of thromboembolism are additive. However, they should be taken into consideration
`when choosing contraceptive methods.
`5.14 Hypersensitivity
`Hypersensitivity to THALOMID 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 should be discontinued.
`6
`ADVERSE REACTIONS
`The following adverse reactions are described in detail in other labeling sections:
`Teratogenicity [see Boxed Warning, Warnings and Precautions (5.1, 5.2), and Patient Counseling Information (17)]
`
`Thromboembolism [see Boxed Warning, Warnings and Precautions (5.3), and Patient Counseling Information (17)]
`
`Drowsiness and Somnolence [see Warnings and Precautions (5.4)]
`
`Peripheral Neuropathy [see Warnings and Precautions (5.5)]
`
`Dizziness and Orthostatic Hypotension [see Warnings and Precautions (5.6)]
`
`Neutropenia [see Warnings and Precautions (5.7)]
`
`Increased HIV Viral Load [see Warnings and Precautions (5.8)]
`
`Bradycardia [see Warnings and Precautions (5.9)]
`
`Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis [see Warnings and Precautions (5.10)]
`
`Seizures [see Warnings and Precautions (5.11)]
`
`Tumor Lysis Syndrome [see Warnings and Precautions (5.12)]
`
`Hypersensitivity [see Warnings and Precautions (5.14)]
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be
`directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
`6.1 Clinical Trials Experience
`Most patients taking thalidomide can be expected to experience adverse reactions.
`Teratogenicity:
`The most serious toxicity associated with thalidomide is its documented human teratogenicity. The risk of severe birth defects, primarily
`phocomelia or death to the fetus, is extremely high during the critical period of pregnancy. The critical period is estimated, depending on the
`source of information, to range from 35 to 50 days after the last menstrual period. The risk of other potentially severe birth defects outside this
`critical period is unknown, but may be significant. Based on present knowledge, thalidomide must not be used at any time during pregnancy.
`Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex or synthetic
`condom during any sexual contact with females of reproductive potential, even if he has undergone a successful vasectomy.
`
`Venous and Arterial Thromboembolism:
`An increased risk of venous thromboembolism (such as deep vein thrombosis and pulmonary embolism), ischemic heart disease (including
`myocardial infarction), and stroke have been reported in patients with multiple myeloma treated with thalidomide [see Venous and Arterial
`Thromboembolism (5.3)].
`
`Peripheral Neuropathy:
`Peripheral neuropathy is a very common, potentially severe, adverse reaction of treatment with thalidomide that may result in irreversible
`damage. Peripheral neuropathy generally occurs following chronic use over a period of months. However, reports following relatively short-term
`use also exist. Incidence of neuropathy events leading to discontinuation, dose reduction or interruption increases with cumulative dose and
`duration of therapy. Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all.
`Somnolence, dizziness, and rash are the most commonly observed adverse reactions associated with the use of thalidomide. Adverse event
`profiles from clinical trials are summarized in the sections that follow.
`Adverse Reactions in Multiple Myeloma Controlled Clinical Trials
`
`6
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`Page 6 of 29
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`The safety analyses were conducted in two controlled clinical studies (Study 1 and Study 2). The safety analysis in Study 1 was conducted on
`204 patients who received treatment. Table 1 lists the most common adverse drug reactions (≥ 10%). The most frequently reported adverse
`reactions were fatigue, hypocalcemia, edema, constipation, sensory neuropathy, dyspnea, muscle weakness, leukopenia, neutropenia,
`rash/desquamation, confusion, anorexia, nausea, anxiety/agitation , tremor, fever, weight loss, thrombosis/embolism, neuropathy-motor, weight
`gain, dizziness, and dry skin .
`Twenty-three percent of patients (47/204) discontinued due to adverse reactions; 30% (31/102) from the THALOMID/dexamethasone arm and
`16% (16/102) from the dexamethasone alone arm.
`
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`Table 1: Adverse Drug Reactions Reported in 10% of Patients in the THALOMID/Dexamethasone Arm
`
`(Study 1 - Safety Population; N=204)
`
`Organ System
`Class/Preferred Term
`
`Thal + Dex *
`(N=102)
`All Grades
`n (%)
`97 (95)
`73 (72)
`92 (90)
`55 (54)
`29 (28)
`26 (26)
`26 (26)
`22 (22)
`
`Grade 3/4
`n (%)
`33 (32)
`11 (11)
`30 (29)
`4 (4)
`9 (9)
`1 (1)
`1 (1)
`8 (8)
`
`Dex Alone*
`(N=102)
`All Grades
`n (%)
`96 (94)
`60 (59)
`76 (74)
`28 (28)
`12 (12)
`14 (14)
`6 (6)
`16 (16)
`
`Grade 3/4
`n (%)
`30 (29)
`5 (5)
`18 (18)
`1 (1)
`3 (3)
`3 (3)
`0 (0)
`5 (5)
`
`0 (0)
`
`Metabolic/Laboratory
`Hypocalcemia
`Neurology
`Neuropathy-sensory
`Confusion
`Anxiety/agitation
`Tremor
`Neuropathy-motor
`Dizziness/
` lightheadedness
`Depressed level of
`3 (3)
`3 (3)
`3 (3)
`16 (16)
` consciousness
`16 (16)
`84 (82)
`19 (19)
`91 (89)
`Constitutional Symptoms
`13 (13)
`72 (71)
`17 (17)
`81 (79)
`Fatigue
`