Thalix

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Thalix uses



WARNING: EMBRYO-FETAL TOXICITY AND VENOUS THROMBOEMBOLISM

EMBRYO-FETAL TOXICITY

If Thalix is taken during pregnancy, it can cause severe birth defects or embryo-fetal death. Thalix 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 Thalix® (thalidomide) as negligible as possible, Thalix® (thalidomide) is approved for marketing only through a special restricted distribution program: Thalix REMS® program, approved by the Food and Drug Administration.

You can get the information about Thalix and the Thalix REMS 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 Thalix® (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 Thalix 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 Thalix 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.

WARNING: EMBRYO-FETAL TOXICITY AND VENOUS THROMBOEMBOLISM

See full prescribing information for complete boxed warning.

EMBRYO-FETAL TOXICITY


Thalix® (thalidomide) is only available through a restricted distribution program, the Thalix REMS® program (5.2).

VENOUS THROMBOEMBOLISM

1.1 Multiple Myeloma

Thalix in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma .

1.2 Erythema Nodosum Leprosum

Thalix is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL).

Thalix is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis.

Thalix is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence .

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2 DOSAGE AND ADMINISTRATION

2.1 General Considerations

Thalix (thalidomide) must only be administered in compliance with all of the terms outlined in the Thalix REMS program. Thalix (thalidomide) may only be prescribed by prescribers certified with the Thalix REMS program and may only be dispensed by pharmacists certified with the Thalix REMS program.

Drug prescribing to females of reproductive potential is contingent upon initial and continued negative results of pregnancy testing .

Consider dose reduction, delay, or discontinuation in patients who develop National Cancer Institute Common Toxicity Criteria (NCI CTC) Grade 3 or 4 adverse reactions and/or based on clinical judgment.

2.2 Multiple Myeloma

Thalix is administered in combination with dexamethasone in 28-day treatment cycles. The dose of Thalix 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.

2.3 Erythema Nodosum Leprosum

For an episode of cutaneous ENL, Thalix 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, Thalix 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 Thalix 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.

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3 DOSAGE FORMS AND STRENGTHS

Thalix 50 mg, 100 mg, 150 mg and 200 mg capsules will be supplied through the Thalix REMS program .

Thalix 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.

Capsules: 50 mg, 100 mg, 150 mg and 200 mg. (3)

4 CONTRAINDICATIONS

4.1 Pregnancy


Thalix can cause fetal harm when administered to a pregnant female . Thalix is contraindicated in females who are pregnant. Thalix is a powerful human teratogen, inducing 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. 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 risk to a fetus. If pregnancy occurs during Thalix treatment, the drug should be discontinued immediately.

4.2 Hypersensitivity

Thalix is contraindicated in patients who have demonstrated hypersensitivity to the drug or its components .

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5 WARNINGS AND PRECAUTIONS

5.1 Embryo-Fetal Toxicity

Thalix 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 Thalix provided adequate precautions are taken to avoid pregnancy. Thalix® (thalidomide) is only available through the Thalix REMS program .

Oral ingestion is the only type of maternal Thalix 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 Thalix; however, females of reproductive potential should avoid contact with Thalix® (thalidomide) Capsules. THALOMID Capsules should be stored in blister packs until ingestion. If there is contact with non-intact Thalix 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 Thalix (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 Thalix.

Females of Reproductive Potential

Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning Thalix 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 Thalix, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of Thalix 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 Thalix therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles or every 2 weeks in females with irregular menstrual cycles .

Males

Thalix 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 Thalix and for up to 4 weeks after discontinuing Thalix, even if they have undergone a successful vasectomy. Male patients taking Thalix must not donate sperm .

Blood Donation

Patients must not donate blood during treatment with Thalix and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to Thalix.

5.2 THALOMID REMS Program

Because of the embryo-fetal risk , Thalix is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the Thalix REMS program.

Required components of the Thalix REMS program include the following:


Further information about the Thalix REMS program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436.

5.3 Venous and Arterial Thromboembolism

The use of Thalix 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 Thalix 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 Thalix 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 Thalix and dexamethasone compared to placebo and dexamethasone (4.7%, 1.7%, and 0.9%, respectively) in one clinical trial .

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 . Agents that also may increase the risk of thromboembolism should be used with caution in patients receiving Thalix .

5.4 Drowsiness and Somnolence

Thalix 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 . 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

Thalix is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common (≥10%) and potentially severe adverse reaction of treatment with Thalix 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 Thalix 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 Thalix treatment. However, the inability clinically to differentiate Thalix 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 Thalix.

Patients should be examined at monthly intervals for the first 3 months of Thalix 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, Thalix should be discontinued immediately to limit further damage, if clinically appropriate. Usually, treatment with Thalix 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 Thalix .

5.6 Dizziness and Orthostatic Hypotension

Patients should also be advised that Thalix 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 Thalix. Treatment should not be initiated with an absolute neutrophil count 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 Thalix if clinically appropriate.

5.8 Thrombocytopenia

Thrombocytopenia, including Grade 3 or 4 occurrences, has been reported in association with the clinical use of Thalix. Monitor blood counts, including platelet counts. Dose reduction, delay, or discontinuation may be required. Monitor for signs and symptoms of bleeding including petechiae, epistaxis, and gastrointestinal bleeding, especially if concomitant medication may increase the risk of bleeding.

5.9 Increased HIV Viral Load

In a randomized, placebo-controlled trial of Thalix in an HIV-seropositive patient population, plasma HIV RNA levels were found to increase. 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.

5.10 Bradycardia

Bradycardia in association with Thalix 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 Thalix .

5.11 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. Thalix 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 Thalix should not be resumed.

5.12 Seizures

Although not reported from pre-marketing controlled clinical trials, seizures, including grand mal convulsions, have been reported during post-approval use of Thalix 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 Thalix has any epileptogenic influence. During therapy with Thalix, 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.

5.13 Tumor Lysis Syndrome

Monitor patients at risk of tumor lysis syndrome and take appropriate precautions.

5.14 Contraceptive Risks

Some contraceptive methods may pose a higher risk of adverse effects or may be medically contraindicated in some patients treated with Thalix. 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 Thalix, 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.

5.15 Hypersensitivity

Hypersensitivity to Thalix 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, Thalix should be discontinued.

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6 ADVERSE REACTIONS

The following adverse reactions are described in detail in other labeling sections:



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.

6.1 Clinical Trials Experience

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.

Most patients taking Thalix can be expected to experience adverse reactions.

Teratogenicity:

The most serious toxicity associated with Thalix 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, Thalix must not be used at any time during pregnancy.

Because Thalix is present in the semen of patients receiving the drug, males receiving Thalix 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 Thalix .

Peripheral Neuropathy:

Peripheral neuropathy is a very common, potentially severe, adverse reaction of treatment with Thalix 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 Thalix 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 Thalix. Adverse event profiles from clinical trials are summarized in the sections that follow.

Adverse Reactions in Multiple Myeloma Controlled Clinical Trials

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.

*Treatment-emergent adverse reactions reported in ≥10% of patients in THALOMID/dexamethasone arm and with a ≥1% difference in the THALOMID/dexamethasone arm compared to the dexamethasone alone arm.
Body System

Adverse Reaction

Thal + Dex *

(N=102)

Dex Alone*

(N=102)

All Grades

n (%)

Grade 3/4

n (%)

All Grades

n (%)

Grade 3/4

n (%)

Metabolic/Laboratory 97 (95) 33 (32) 96 (94) 30 (29)
Hypocalcemia 73 (72) 11 (11) 60 (59) 5 (5)
Neurology 92 (90) 30 (29) 76 (74) 18 (18)
Neuropathy-sensory 55 (54) 4 (4) 28 (28) 1 (1)
Confusion 29 (28) 9 (9) 12 (12) 3 (3)
Anxiety/agitation 26 (26) 1 (1) 14 (14) 3 (3)
Tremor 26 (26) 1 (1) 6 (6) 0 (0)
Neuropathy-motor 22 (22) 8 (8) 16 (16) 5 (5)
Dizziness/

lightheadedness

20 (20) 1 (1) 14 (14) 0 (0)
Depressed level of

consciousness

16 (16) 3 (3) 3 (3) 3 (3)
Constitutional Symptoms 91 (89) 19 (19) 84 (82) 16 (16)
Fatigue 81 (79) 17 (17) 72 (71) 13 (13)
Fever 24 (24) 1 (1) 20 (20) 3 (3)
Weight loss 23 (23) 1 (1) 21 (21) 2 (2)
Weight gain 22 (22) 1 (1) 13 (13) 0 (0)
Blood/Bone Marrow 88 (86) 29 (29) 96 (94) 19 (19)
Leukocytes (decreased) 36 (35) 6 (6) 30 (29) 3 (3)
Neutrophils (decreased) 32 (31) 10 (10) 24 (24) 10 (10)
Gastrointestinal 83 (81) 22 (22) 70 (69) 8 (8)
Constipation 56 (55) 8 (8) 29 (28) 1 (1)
Anorexia 29 (28) 4 (4) 25 (24) 2 (2)
Nausea 29 (28) 5 (5) 23 (22) 1 (1)
Mouth dryness 12 (12) 1 (1) 6 (6) 0 (0)
Cardiovascular 70 (69) 37 (36) 60 (59) 21 (21)
Edema 58 (56) 6 (6) 47 (46) 4 (4)
Thrombosis/embolism 23 (22) 21 (21) 5 (5) 5 (5)
Pain 64 (63) 10 (10) 66 (65) 15 (15)
Myalgia 17 (17) 0 (0) 14 (14) 1 (1)
Arthralgia 13 (13) 0 (0) 10 (10) 2 (2)
Pulmonary 52 (51) 19 (19) 51 (50) 20 (20)
Dyspnea 43 (42) 13 (13) 32 (31) 15 (15)
Dermatology/Skin 48 (47) 5 (5) 35 (34) 2 (2)
Rash/desquamation 31 (30) 4 (4) 18 (18) 2 (2)
Dry skin 21 (21) 0 (0) 11 (11) 0 (0)
Hepatic 47 (46) 7 (7) 45 (44) 4 (4)
Bilirubin 14 (14) 2 (2) 10 (10) 2 (2)
Musculoskeletal 42 (41) 9 (9) 41 (40) 14 (14)
Muscle weakness 41 (40) 6 (6) 38 (37) 13 (13)

The safety analysis in Study 2 was conducted on 466 patients who received treatment. Table 2 lists the most common adverse drug reactions (≥ 10%) that were observed. Table 3 lists the most common Grade 3/4 adverse drug reactions (occurring at > 2%) that were observed. The adverse reactions most often reported by patients treated with THALOMID/dexamethasone were constipation, peripheral edema, tremor, asthenia, dizziness and fatigue. Adverse reactions with a frequency at least 2-fold higher in the THALOMID/dexamethasone group than in the placebo/dexamethasone group include constipation, tremor, deep vein thrombosis and peripheral sensory neuropathy.

Twenty-six percent of patients (121/466) discontinued due to adverse events; 37% (86/234) from the THALOMID/dexamethasone arm and 15% (35/232) from the placebo/dexamethasone arm.


*All adverse reactions reported in ≥10% of patients in THALOMID/dexamethasone arm and with a ≥1% difference in proportion of patients between the THALOMID/dexamethasone arm compared to the placebo/dexamethasone arm.


NOS = not otherwise specified.

Body System

Adverse Reaction

Thal/Dex (N=234)*

n (%)

Placebo/Dex (N=232)*

n (%)

Patients with at least 1 Adverse Reaction 233 (99) 230 (99)
General Disorders and Administration Site Conditions 176 (75) 149 (64)
Edema peripheral 80 (34) 57 (25)
Asthenia 56 (24) 47 (20)
Fatigue 50 (21) 36 (16)
Edema NOS 31 (13) 19 (8)
Gastrointestinal Disorders 162 (69) 149 (64)
Constipation 116 (50) 49 (21)
Nausea 30 (13) 27 (12)
Dyspepsia 27 (11) 21 (9)
Nervous System Disorders 161 (69) 138 (60)
Tremor 62 (26) 29 (12)
Dizziness 51 (23) 32 (14)
Paresthesia 27 (12) 15 (6)
Peripheral sensory neuropathy 24 (10) 12 (5)
Infections and Infestations 139 (59) 138 (60)
Pneumonia NOS 35 (15) 28 (12)
Psychiatric Disorders 90 (38) 97 (42)
Anxiety 27 (12) 22 (10)
Depression 24 (10) 19 (8)
Metabolism and Nutrition Disorders 96 (41) 89 (38)
Hyperglycemia NOS 36 (15) 32 (14)
Vascular Disorders 92 (39) 53 (23)
Deep vein thrombosis 30 (13) 4 (2)

*All Grade 3/4 adverse reactions with >2% of patients in THALOMID/dexamethasone arm and with a higher frequency in the THALOMID/dexamethasone arm compared to the placebo/dexamethasone arm.


NOS = not otherwise specified.

Body System

Adverse Reaction

THALOMID/Dex (N=234)*

n (%)

Placebo/Dex (N=232)*

n (%)

Infections and Infestations 50 (21) 36 (16)
Pneumonia NOS 17 (7) 14 (6)
Bronchopneumonia NOS 7 (3) 3 (1)
General Disorders and

Administration Site Conditions

44 (19) 26 (11)
Asthenia 11 (5) 4 (2)
Metabolism and Nutrition

Disorders

33 (14) 34 (15)
Hypokalemia 7 (3) 3 (1)
Nervous System Disorders 47 (20) 20 (9)
Syncope 8 (3) 1 (<1)
Peripheral neuropathy NOS 8 (3) 0 (0)
Cerebrovascular accident 6 (3) 1 (<1)
Cardiac Disorders 35 (15) 27 (11)
Atrial fibrillation 11 (5) 8 (3)
Myocardial ischemia 6 (3) 2 (1)
Vascular Disorders 42 (18) 14 (6)
Deep vein thrombosis 27 (12) 4 (2)
Gastrointestinal Disorders 26 (11) 22 (10)
Constipation 7 (3) 2 (1)
Investigations 21 (9) 21 (9)
Weight increased 8 (3) 4 (2)
Blood and Lymphatic System

Disorders

24 (10) 17 (7)
Neutropenia 8 (3) 6 (3)
Respiratory, Thoracic, and

Mediastinal Disorders

27 (12) 13 (6)
Pulmonary embolism 16 (7) 4 (2)
Psychiatric Disorders 19 (8) 8 (3)
Anxiety 5 (2) 3 (1)
Confusional state 5 (2) 2 (1)
Ear and Labyrinth Disorders 6 (3) 0 (0)
Vertigo 5 (2) 0 (0)

Less Common Adverse Drug Reactions in Multiple Myeloma Controlled Clinical Trials

In Study 2, Thalix in combination with dexamethasone in patients with multiple myeloma, the following adverse drug reactions not described above were reported*:

Gastrointestinal disorders: Vomiting NOS, dry mouth, peritonitis, diverticular perforation

Nervous system disorders: Somnolence, hypoesthesia, polyneuropathy NOS, transient ischemic attack

Respiratory, thoracic, and mediastinal disorders: Bronchitis NOS

Psychiatric disorders: Mood alteration NOS

Vascular disorders: Hypotension NOS, orthostatic hypotension

Cardiac disorders: Bradycardia NOS

Eye disorders: Blurred vision

* All adverse reactions with ≥3% of patients in THALOMID/dexamethasone arm and with a ≥1% difference in proportion of patients between the THALOMID/dexamethasone arm compared to the placebo/dexamethasone arm. All grade 3/4 and serious adverse reactions reported >2 patients in THALOMID/dexamethasone arm and with a percentage higher in the THALOMID/dexamethasone arm compared to the placebo/dexamethasone arm have been considered for possible inclusion. In any cases medical judgment has been applied for consideration of causality assessment.

Adverse Reactions in Erythema Nodosum Leprosum (ENL) Clinical Trials

Table 4 lists treatment-emergent signs and symptoms that occurred in THALOMID-treated patients in clinical trials in ENL. The most common adverse reactions (≥10%) reported in patients with ENL were somnolence, rash, headache. Doses ranged from 50 to 300 mg/day. All adverse reactions were mild to moderate in severity, and none resulted in discontinuation.

Body System/Adverse Event All AEs Reported

in Patients with ENL

AEs Reported in ≥3 HIV-seropositive Patients
Thalix Placebo
50 to 300 mg/day

(N=24)

100 mg/day

(N=36)

200 mg/day

(N=32)

(N=35)
Blood and Lymphatic 0 8 (22.2%) 13 (40.6%) 10 (28.6%)
Anemia 0 2 (5.6%) 4 (12.5%) 3 (8.6%)
Leukopenia 0 6 (16.7%) 8 (25.0%) 3 (8.6%)
Lymphadenopathy 0 2 (5.6%) 4 (12.5%) 3 (8.6%)
Body as a Whole 16 (66.7%) 18 (50.0%) 19 (59.4%) 13 (37.1%)
Abdominal pain 1 (4.2%) 1 (2.8%) 1 (3.1%) 4 (11.4%)
Accidental injury 1 (4.2%) 2 (5.6%) 0 1 (2.9%)
Asthenia 2 (8.3%) 2 (5.6%) 7 (21.9%) 1 (2.9%)
Back pain 1 (4.2%) 2 (5.6%) 0 0
Chills 1 (4.2%) 0 3 (9.4%) 4 (11.4%)
Facial edema 1 (4.2%) 0 0 0
Fever 0 7 (19.4%) 7 (21.9%) 6 (17.1%)
Headache 3 (12.5%) 6 (16.7%) 6 (18.7%) 4 (11.4%)
Infection 0 3 (8.3%) 2 (6.3%) 1 (2.9%)
Malaise 2 (8.3%) 0 0 0
Neck pain 1 (4.2%) 0 0 0
Neck rigidity 1 (4.2%) 0 0 0
Pain 2 (8.3%) 0 1 (3.1%) 2 (5.7%)
Digestive System 5 (20.8%) 16 (44.4%) 16 (50.0%) 15 (42.9%)
Anorexia 0 1 (2.8%) 3 (9.4%) 2 (5.7%)
Constipation 1 (4.2%) 1 (2.8%) 3 (9.4%) 0
Diarrhea 1 (4.2%) 4 (11.1%) 6 (18.7%) 6 (17.1%)
Dry mouth 0 3 (8.3%) 3 (9.4%) 2 (5.7%)
Flatulence 0 3 (8.3%) 0 2 (5.7%)
Liver function tests

multiple abnormalities

0 0 3 (9.4%) 0
Nausea 1 (4.2%) 0 4 (12.5%) 1 (2.9%)
Oral moniliasis 1 (4.2%) 4 (11.1%) 2 (6.3%) 0
Tooth pain 1 (4.2%) 0 0 0
Metabolic and Endocrine Disorders 1 (4.2%) 8 (22.2%) 12 (37.5%) 8 (22.9%)
Edema peripheral 1 (4.2%) 3 (8.3%) 1 (3.1%) 0
Hyperlipemia 0 2 (5.6%) 3 (9.4%) 1 (2.9%)
SGOT increased 0 1 (2.8%) 4 (12.5%) 2 (5.7%)
Nervous System 13 (54.2%) 19 (52.8%) 18 (56.3%) 12 (34.3%)
Agitation 0 0 3 (9.4%) 0
Dizziness 1 (4.2%) 7 (19.4%) 6 (18.7%) 0
Insomnia 0 0 3 (9.4%) 2 (5.7%)
Nervousness 0 1 (2.8%) 3 (9.4%) 0
Neuropathy 0 3 (8.3%) 0 0
Paresthesia 0 2 (5.6%) 5 (15.6%) 4 (11.4%)
Somnolence 9 (37.5%) 13 (36.1%) 12 (37.5%) 4 (11.4%)
Tremor 1 (4.2%) 0 0 0
Vertigo 2 (8.3%) 0 0 0
Respiratory System 3 (12.5%) 9 (25.0%) 6 (18.7%) 9 (25.7%)
Pharyngitis 1 (4.2%) 3 (8.3%) 2 (6.3%) 2 (5.7%)
Rhinitis 1 (4.2%) 0 0 4 (11.4%)
Sinusitis 1 (4.2%) 3 (8.3%) 1 (3.1%) 2 (5.7%)
Skin and Appendages 10 (41.7%) 17 (47.2%) 18 (56.3%) 19 (54.3%)
Acne 0 4 (11.1%) 1 (3.1%) 0
Dermatitis fungal 1 (4.2%) 2 (5.6%) 3 (9.4%) 0
Nail disorder 1 (4.2%) 0 1 (3.1%) 0
Pruritus 2 (8.3%) 1 (2.8%) 2 (6.3%) 2 (5.7%)
Rash 5 (20.8%) 9 (25.0%) 8 (25.0%) 11 (31.4%)
Rash maculopapular 1 (4.2%) 6 (16.7%) 6 (18.7%) 2 (5.7%)
Sweating 0 0 4 (12.5%) 4 (11.4%)
Urogenital System 2 (8.3%) 6 (16.7%) 2 (6.3%) 4 (11.4%)
Albuminuria 0 3 (8.3%) 1 (3.1%) 2 (5.7%)
Hematuria 0 4 (11.1%) 0 1 (2.9%)
Impotence 2 (8.3%) 1 (2.8%) 0 0

Other Adverse Events Observed in ENL Patients

Thalix in doses up to 400 mg/day has been administered investigationally in the United States over a 19-year period in 1465 patients with ENL. The published literature describes the treatment of an additional 1678 patients. To provide a meaningful estimate of the proportion of the individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using a modified COSTART dictionary/terminology. These categories are used in the listing below. All reported events are included except those already listed in the previous table. Due to the fact that these data were collected from uncontrolled studies, the incidence rate cannot be determined. No causal relationship between Thalix and these events can be conclusively determined at this time. These are reports of all adverse events noted by investigators in patients to whom they had administered Thalix.

Blood and Lymphatic: ESR decrease, eosinophilia, granulocytopenia, hypochromic anemia, leukemia, leukocytosis, leukopenia, MCV elevated, RBC abnormal, spleen palpable, thrombocytopenia.

Body as a Whole: Abdomen enlarged, fever, photosensitivity, upper extremity pain.

Cardiovascular System: Bradycardia, hypertension, hypotension, peripheral vascular disorder, tachycardia, vasodilation.

Digestive System: Anorexia, appetite increase/weight gain, dry mouth, dyspepsia, enlarged liver, eructation, flatulence, increased liver function tests, intestinal obstruction, vomiting.

Metabolic and Endocrine: ADH inappropriate, amyloidosis, bilirubinemia, BUN increased, creatinine increased, cyanosis, diabetes, edema, electrolyte abnormalities, hyperglycemia, hyperkalemia, hyperuricemia, hypocalcemia, hypoproteinemia, LDH increased, phosphorus decreased, SGPT increased.

Muscular Skeletal: Arthritis, bone tenderness, hypertonia, joint disorder, leg cramps, myalgia, myasthenia, periosteal disorder.

Nervous System: Abnormal thinking, agitation, amnesia, anxiety, causalgia, circumoral paresthesia, confusion, depression, euphoria, hyperesthesia, insomnia, nervousness, neuralgia, neuritis, neuropathy, paresthesia, peripheral neuritis, psychosis.

Respiratory System: Cough, emphysema, epistaxis, pulmonary embolus, rales, upper respiratory infection, voice alteration.

Skin and Appendages: Acne, alopecia, dry skin, eczematous rash, exfoliative dermatitis, ichthyosis, perifollicular thickening, skin necrosis, seborrhea, sweating, urticaria, vesiculobullous rash.

Special Senses: Amblyopia, deafness, dry eye, eye pain, tinnitus.

Urogenital: Decreased creatinine clearance, hematuria, orchitis, proteinuria, pyuria, urinary frequency.

Other Adverse Events Observed in HIV-seropositive Patients

In addition to controlled clinical trials, Thalix has been used in uncontrolled studies in 145 patients. Less frequent adverse events that have been reported in these HIV-seropositive patients treated with Thalix were grouped into a smaller number of standardized categories using modified COSTART dictionary/terminology and these categories are used in the listing below. Adverse events that have already been included in the tables and narrative above, or that are too general to be informative are not listed.

Blood and Lymphatic: Aplastic anemia, macrocytic anemia, megaloblastic anemia, microcytic anemia.

Body as a Whole: Ascites, AIDS, allergic reaction, cellulitis, chest pain, chills and fever, cyst, decreased CD4 count, facial edema, flu syndrome, hernia, thyroid hormone level altered, moniliasis, photosensitivity reaction, sarcoma, sepsis, viral infection.

Cardiovascular System: Angina pectoris, arrhythmia, atrial fibrillation, bradycardia, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, heart arrest, heart failure, hypertension, hypotension, murmur, myocardial infarct, palpitation, pericarditis, peripheral vascular disorder, postural hypotension, syncope, tachycardia, thrombophlebitis, thrombosis.

Digestive System: Cholangitis, cholestatic jaundice, colitis, dyspepsia, dysphagia, esophagitis, gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, gum disorder, hepatitis, pancreatitis, parotid gland enlargement, periodontitis, stomatitis, tongue discoloration, tooth disorder.

Metabolic and Endocrine: Avitaminosis, bilirubinemia, dehydration, hypercholesterolemia, hypoglycemia, increased alkaline phosphatase, increased lipase, increased serum creatinine, peripheral edema.

Muscular Skeletal: Myalgia, myasthenia.

Nervous System: Abnormal gait, ataxia, decreased libido, decreased reflexes, dementia, dysesthesia, dyskinesia, emotional lability, hostility, hypalgesia, hyperkinesia, incoordination, meningitis, neurologic disorder, tremor, vertigo.

Respiratory System: Apnea, bronchitis, lung disorder, lung edema, pneumonia (including Pneumocystis carinii pneumonia), rhinitis.

Skin and Appendages: Angioedema, benign skin neoplasm, eczema, herpes simplex, incomplete Stevens-Johnson syndrome, nail disorder, pruritus, psoriasis, skin discoloration, skin disorder.

Special Senses: Conjunctivitis, eye disorder, lacrimation disorder, retinitis, taste perversion.

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during post approval use of Thalix and are not already included in Clinical Trials Experience . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic: Decreased white blood cell counts including febrile neutropenia, changes in prothrombin time, pancytopenia, chronic myelogenous leukemia, nodular sclerosing Hodgkin’s disease, erythroleukemia, lymphedema, lymphopenia.

Body as a Whole: Hangover effect

Cardiovascular System: Sick sinus syndrome, EKG abnormalities, pulmonary hypertension.

Digestive System: Intestinal perforation, gastrointestinal perforations, bile duct obstruction, stomach ulcer, aphthous, stomatitis.

Ear and Labyrinthine Disorders: Hearing impairment.

Immune System Disorders: Hypersensitivity.

Infections and infestations: Severe infections (e.g., fatal sepsis including septic shock) and viral infections (including varicella zoster virus, cytomegalovirus, and hepatitis B virus reactivation).

Metabolic and Endocrine: Electrolyte imbalance including hypercalcemia, hyponatremia and hypomagnesemia, hypothyroidism, increased alkaline phosphatase, tumor lysis syndrome, myxedema.

Nervous System: Changes in mental status or mood including suicide attempts, disturbances in consciousness including lethargy, loss of consciousness or stupor, seizures including grand mal convulsions and status epilepticus, Parkinson’s disease, stroke, carpal tunnel, Raynaud’s syndrome, migraine, foot drop.

Renal and Urinary Disorders: Renal failure, acute renal failure, oliguria, enuresis.

Reproductive System and Breast Disorders: amenorrhea, sexual dysfunction, galactorrhea, gynecomastia, metrorrhagia.

Respiratory System: Pleural effusion, interstitial lung disease.

Skin and Appendages: Erythema multiforme, erythema nodosum, toxic epidermal necrolysis, purpura, petechiae.

Special Senses: Diplopia, nystagmus

7 DRUG INTERACTIONS

7.1 Opioids, Antihistamines, Antipsychotics, Anti-anxiety Agents, or Other CNS Depressants (Including Alcohol)

The use of opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants concomitantly with Thalix may cause an additive sedative effect and should be avoided.

7.2 Drugs which Cause Bradycardia

The use of drugs which slow cardiac conduction concomitantly with Thalix may cause an additive bradycardic effect and should be used with caution. Cardiovascular medications which may cause bradycardia include calcium channel blockers, beta blockers, alpha/beta-adrenergic blockers, and digoxin. Non-cardiac drugs that may cause bradycardia include H2 blockers, lithium, tricyclic antidepressants and neuromuscular blockers (succinylcholine).

In 16 healthy men, the pharmacokinetic profile of a single 0.5 mg digoxin dose was similar with and without the coadministration of Thalix 200 mg/day at steady state levels. The single dose of digoxin had no effect on the pharmacokinetic profile of Thalix. The safety of long-term concomitant use of Thalix and digoxin has not been evaluated.

7.3 Drugs which Cause Peripheral Neuropathy

The use of drugs which cause peripheral neuropathy (e.g., bortezomib, amiodarone, cisplatin, docetaxel, paclitaxel, vincristine, disulfiram, phenytoin, metronidazole, alcohol) can cause an additive effect and should be used with caution.

7.4 Hormonal Contraceptives

Hormonal contraceptives increase the risk of thromboembolism. It is not known whether concomitant use of hormonal contraceptives further increases the risk of thromboembolism with Thalix.

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 mcg of ethinyl estradiol were studied. The results were similar with and without coadministration of Thalix 200 mg/day to steady-state levels.

7.5 Warfarin

In 13 healthy men, the pharmacokinetic profile and international normalized ratio of prothrombin time for warfarin, following a single oral dose of 25 mg, were similar with and without the coadministration of Thalix 200 mg/day at steady-state levels. The single dose of warfarin had no effect on the pharmacokinetic profile of Thalix.

7.6 Drugs that Interfere with Hormonal Contraceptives

Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John’s Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception up to one month after discontinuation of these concomitant therapies. Therefore, females requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception while taking Thalix.

7.7 Concomitant Therapies that may Increase the Risk of Thromboembolism

Erythropoietic agents, or other agents that may increase the risk of thromboembolism, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving Thalix with dexamethasone .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to Thalix during pregnancy as well as female partners of male patients who are exposed to Thalix. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to Thalix to the FDA via the MedWatch program at 1-800-FDA-1088 and to Celgene Corporation at 1-888-423-5436.

Risk Summary

Based on the mechanism of action , human and animal data , Thalix can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy .

Thalix is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, 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 and mortality at or shortly after birth has been reported in about 40% of infants. Even a single dose taken by a pregnant woman can cause birth defects. 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 risk to a fetus.

If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to Thalix to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.

Thalix crossed the placenta after administration to pregnant hamsters .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Data

Animal data

A pre- and postnatal reproductive toxicity study was conducted in pregnant female rabbits. Compound-related increased abortion incidences and elevated fetotoxicity were observed at the lowest oral dose level of 30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA) and all higher dose levels. Neonatal mortality was elevated at oral dose levels to the lactating female rabbits ≥150 mg/kg/day (approximately 7.5-fold the maximum human dose based upon BSA). No delay in postnatal development, including learning and memory functions, were noted at the oral dose level to the lactating female rabbits of 150 mg/kg/day (average Thalix concentrations in milk ranged from 22 to 36 mcg per mL).

In a study conducted in pregnant rabbits, Thalix levels in fetal plasma were approximately 11% to 73% of the maternal Cmax. In a study conducted with 14C-thalidomide (150 mg/kg orally) in pregnant hamsters, radioactivity was detected in the embryo, and the relative concentrations of radioactivity in the embryo and maternal plasma were about the same at 4, 12 and 24 hours after dosing. Based on the radioactivity data, Thalix crossed the placental barrier, and the fetal levels of drug-related material were approximately similar to those of maternal levels.

8.2 Lactation

Risk Summary

There is no information regarding the presence of Thalix in human milk, the effects of Thalix on the breastfed infant, or the effects of Thalix on milk production. Thalix is excreted in the milk of lactating rabbits . Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from Thalix, advise women not to breastfeed during treatment with Thalix.

Data

Animal Data

In lactating female rabbits at an oral dose of 150 mg/kg/day, the average Thalix concentrations in milk ranged from 22 to 36 mcg per mL. In the study of lactating female rabbits, high concentrations of Thalix were noted in milk during four weeks of pre-weaning period. Milk concentrations were 1.16 - 2.11, 1.05 – 2.43, and 0.64 – 3.63 times that of plasma at 30, 150 and 500 mg/kg Thalix doses, respectively; Thalix, as a lipophilic compound, distributed into milk, with concentrations attained similar to or slightly higher than those of systemic concentrations.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Thalix can cause fetal harm when administered during pregnancy . Verify the pregnancy status of females of reproductive potential prior to initiating Thalix therapy and during therapy. Advise females of reproductive potential that they must avoid pregnancy 4 weeks before therapy, while taking Thalix, during dose interruptions and for at least 4 weeks after completing therapy.

Females of reproductive potential must have 2 negative pregnancy tests before initiating Thalix. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing Thalix. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. Thalix treatment must be discontinued during this evaluation.

Contraception

Females

Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously: one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner’s vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with Thalix, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of Thalix therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed.

Males

Thalix is present in the semen of males who take Thalix. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Thalix, during dose interruptions and for up to 28 days after discontinuing Thalix, even if they have undergone a successful vasectomy. Male patients taking Thalix must not donate sperm.

Infertility

Based on findings in animals, male fertility may be compromised by treatment with Thalix .

8.4 Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

8.5 Geriatric Use

One hundred and seventy-six of 336 patients treated with Thalix in combination with dexamethasone were ≥ 65 of age while 50 (15%) were ≥75. Patients ≥65 years of age on Study 2 had higher incidences of atrial fibrillation, constipation, fatigue, nausea, hypokalemia, deep venous thrombosis, hyperglycemia, pulmonary embolism, and asthenia compared to patients <65.

8.6 Renal Impairment

No clinical studies were conducted with Thalix in patients with mild, moderate or severe renal function. Renal impairment is not expected to influence drug exposure since <3.5% of the dose is excreted in the urine as unchanged drug.

In a study of 6 patients with end-stage renal disease, Thalix (200 mg/day) was administered on a non-dialysis day and on a dialysis day and blood samples for pharmacokinetics were collected at least 10 hours following the dose. Comparison of concentration-time profiles on a non-dialysis day and during dialysis showed that the mean total clearance increased by a 2.5-fold during hemodialysis. Because the dialysis was performed 10 hours following administration of the dose, the drug-concentration time curves were not statistically significantly different for days patients were on and off of dialysis. In addition, there were no major differences in Thalix PK between patients with end-stage renal disease and healthy volunteers. Thus, no dosage adjustment is needed for patients with renal impairment or patients on dialysis.

8.7 Hepatic Impairment

No clinical studies have been conducted in patients with hepatic impairment.

9 DRUG ABUSE AND DEPENDENCE

Physical and psychological dependence has not been reported in patients taking Thalix; however, as with other tranquilizers/hypnotics, Thalix has been reported to result in habituation to its soporific effects.

10 OVERDOSAGE

Overdosages of up to 14.4 g have been reported in the literature. No fatalities have been reported and all overdosed patients recovered without sequelae. There is no specific antidote for a Thalix overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status.

11 DESCRIPTION

Thalix, α-(N-phthalimido) glutarimide, is an immunomodulatory agent. The empirical formula for Thalix is C13H10N2O4 and the gram molecular weight is 258.2. The CAS number of Thalix is 50-35-1.

Chemical Structure of Thalix

Thalix is an off-white to white, odorless, crystalline powder that is soluble at 25°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-(+). Thalix is an equal mixture of the S-(-) and R-(+) forms and, therefore, has a net optical rotation of zero.

Thalix is available in 50 mg, 100 mg, 150 mg and 200 mg capsules for oral administration. Active ingredient: Thalix. Inactive ingredients: pregelatinized starch and magnesium stearate. The 50 mg capsule shell contains gelatin, titanium dioxide, and black ink. The 100 mg capsule shell contains black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black ink. The 150 mg capsule shell contains FD&C blue #2, black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black and white ink. The 200 mg capsule shell contains FD&C blue #2, titanium dioxide, gelatin, and white ink.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of Thalix is not fully understood. Cellular activities of Thalix are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. Thalix possesses immunomodulatory, antiinflammatory and antiangiogenic properties. Available data from in vitro studies and 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 production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. For example, administration of Thalix has been reported to decrease circulating levels of TNF-α in patients with erythema nodosum leprosum (ENL); however, it has also been shown to increase plasma TNF-α levels in HIV-seropositive patients. Other anti-inflammatory and immunomodulatory properties of Thalix may include suppression of macrophage involvement in prostaglandin synthesis, and modulation of interleukin-10 and interleukin-12 production by peripheral blood mononuclear cells. Thalix treatment of multiple myeloma patients is accompanied by an increase in the number of circulating natural killer cells, and an increase in plasma levels of interleukin-2 and interferon-gamma (T cell-derived cytokines associated with cytotoxic activity). Thalix was found to inhibit angiogenesis in a human umbilical artery explant model in vitro. The cellular processes of angiogenesis inhibited by Thalix may include the proliferation of endothelial cells.

12.3 Pharmacokinetics

Absorption

Absorption of Thalix is slow after oral administration. The maximum plasma concentrations are reached approximately 2-5 hours after administration. The absolute bioavailability of Thalix from Thalix capsules has not yet been characterized in human subjects due to its poor aqueous solubility. Based on the 14C-radiolabel Thalix study in human, greater than 90% of the total radioactivity is recovered in urine suggesting good oral absorption. 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. This lack of Cmax dose proportionality, coupled with the observed increase in Tmax values, suggests that the poor solubility of Thalix in aqueous media may be hindering the rate of absorption.

Population/

Single Dose


AUC0-∞

mcg·hr/mL


Cmax

mcg/mL


Tmax

(hrs)


Half‑life

(hrs)

Healthy Subjects (n=14)
50 mg 4.9 (16%) 0.62 (52%) 2.9 (66%) 5.52 (37%)
200 mg 18.9 (17%) 1.76 (30%) 3.5 (57%) 5.53 (25%)
400 mg 36.4 (26%) 2.82 (28%) 4.3 (37%) 7.29 (36%)
Patients with Hansen’s Disease (n=6)
400 mg 46.4 (44.1%) 3.44 (52.6%) 5.7 (27%) 6.86 (17%)

Coadministration of Thalix® (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 plasma, the geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-(R)- and (-)-(S)-thalidomide. In a pharmacokinetic study of Thalix in HIV-seropositive adult male subjects receiving Thalix 100 mg/day, Thalix was detectable in the semen.

Metabolism

In a 14C-radiolabel ADME study in humans, unchanged drug is the predominant circulating component. Thalix is not a substrate of the cytochrome P450 system. At therapeutic concentrations, Thalix is not an inhibitor or inducer of human cytochrome P450 enzymes in vitro. Pharmacokinetic drug-drug interactions with substrates, inhibitors or inducers of CYP450 are not anticipated.

Elimination

The mean elimination half-life of Thalix in plasma following single oral doses between 50 mg and 400 mg was 5.5 to 7.3 hours. Following a single 400 mg oral dose of radiolabeled Thalix, the total mean recovery was 93.6% of the administered dose by Day 8. The majority of the radioactive dose was excreted within 48 hours following dose administration. In humans, 14C-thalidomide is primarily excreted in urine (91.9% of the radioactive dose) mainly as hydrolytic metabolites while fecal excretion is minor (<2% of the dose). Unchanged Thalix is not eliminated by the kidney to a notable degree (<3.5% of the dose).

Effects of Weight

There is a linear relationship between body weight and estimated Thalix clearance. In MM patients with body weight from 47-133 kg, Thalix clearance ranged from approximately 6-12 L/h, representing an increase in Thalix clearance of 0.605 L/h per 10 kg body weight increase.

Effects of Age, Gender and Race

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.

While a comparative trial of the effects of gender on Thalix pharmacokinetics has not been conducted, examination of the data for Thalix does not reveal any significant gender differences in pharmacokinetic parameter values.

Pharmacokinetic differences due to race have not been studied.

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 Thalix 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 Thalix. 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.

Pediatric: No pharmacokinetic data are available in subjects below the age of 18 years.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA).

Thalix was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test.

Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral Thalix dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25-fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA).

14 CLINICAL STUDIES

14.1 Multiple Myeloma

The efficacy and safety of Thalix in patients with multiple myeloma were evaluated in two randomized, multi-center studies (Study 1 and Study 2). Study 1 was an open-label study which randomized 207 symptomatic patients with newly diagnosed MM to Thalix plus dexamethasone (N = 103) versus dexamethasone alone (N=104). The Thalix dose was 200 mg daily and the dexamethasone dose was 40 mg orally once daily on days 1-4, 9-12, and 17-20 every 28-days. Each group was treated for four 28-day cycles.

Study 2 randomized 470 newly diagnosed patients with MM to Thalix plus dexamethasone (N=235) versus placebo plus dexamethasone (N=235). In the THALOMID/dexamethasone arm, a starting dose of Thalix 50 mg was escalated to 200 mg/day (cycle 2) once daily for 28 days. Patients in both treatment groups took 40 mg of dexamethasone once daily given on days 1-4, 9-12, and 17-20 (every 28 days). Beginning with Cycle 5, the dose of dexamethasone was reduced to 40 mg once daily on Days 1 to 4 of each cycle. Treatment continued as tolerated until disease progression.

Baseline demographics for both studies are presented in Table 6 and disease characteristics for the study population are summarized in Tables 7 (Study 1) and 8 (Study 2).

Study 1 Study 2

Characteristic

THALOMID/

Dexamethasone

(N=103)

Dexamethasone

(N=104)

THALOMID/

Dexamethasone

(N=235)

Placebo/

Dexamethasone

(N=235)


1Missing information in Study 1 for 1 patient in the Dex alone group

2Missing information in Study 1 for 1 patient per arm

3Black/Hispanic [1 (0.4%)], Hispanic [2 (0.9%)], Hispanic/White [1 (0.4%)], Other [0 (0.0%)]

4Hispanic [1 (0.4%)], Asian/Pacific Islander [2 (0.9%)], Other [1 (0.4%)]

Age (years)
Median 65 68 65 66
Range 37 – 83 38 – 83 39 – 86 31 – 84
Gender1, N (%)
Male 53 (51) 61 (59) 118 (50) 120 (51)
Female 50 (49) 42 (40) 117 (50) 115 (49)
Race2, N (%)
Caucasian 90 (87) 90 (87) 224 (95) 221 (94)
Black 11 (11) 11 (11) 7 (3) 10 (4)
Other 1 (1) 2 (2) 4 (2)3 4 (2)4

Disease Characteristic

THALOMID/Dexamethasone

(N=103)

Dexamethasone alone

(N=104)


1 Missing information for 1 patient in Thal + Dex arm

2 Missing information for 19 patients in Thal + Dex arm and 20 patients in Dex alone arm

3 Missing information for 17 patients in Thal + Dex arm and 30 patients in Dex alone arm

4 Missing information for 16 patients in Thal + Dex arm and 11 patients in Dex alone arm

Stage (Durie-Salmon), N (%) 1
I 14 (13.6%) 17 (16.3%)
II 47 (45.6%) 44 (42.3%)
III 41 (39.8%) 43 (41.3%)
Immunoglobulin Type, N (%) 2
IgA 21 (20.4%) 22 (21.2%)
IgG 63 (61.2%) 60 (57.7%)
IgM 0 (0.0%) 1 (1.0%)
Biclonal 0 (0.0%) 1 (1.0%)
Lytic Lesions3
None 28 (27.1%) 14 (13.5%)
1-3 lesions 24 (23.3%) 19 (18.3%)
>3 lesions 34 (33.0%) 41 (39.4%)
Serum Light Chain4
Kappa 59 (57.3%) 53 (51.0%)
Lambda 28 (27.2%) 40 (38.5%)

Disease Characteristic

THALOMID/ Dexamethasone

(N=235)

Placebo/

Dexamethasone

(N=235)


KEY: ECOG=Eastern Cooperative Oncology Group

Baseline MM Stage (Durie-Salmon), n (%)
I 2 (1) 2 (1)
II 76 (32) 88 (37)
III 157 (69) 145 (62)
ECOG Performance Status, n (%)
0 40 (17) 54 (23)
1 124 (53) 112 (48)
2 70 (30) 68 (29)
3 0 (0) 1 (<1)
Missing 1 (<1) 0 (0)
Lytic Bone Lesions, n (%)
Present 185 (79) 188 (80)
Absent 49 (21) 46 (20)
Missing 1 (<1) 1 (<1)
Bone Marrow Aspirate/Biopsy Cellularity, n (%)
Normal 102 (43) 108 (46)
Hyperplasia 77 (33) 76 (32)
Hypoplasia 53 (23) 50 (21)
Missing 3 (1) 1 (<1)
Baseline β-2 Microglobulin, n (%)
≤ 2.5 mg/L 33 (14) 35 (15)
> 2.5 mg/L 200 (85) 199 (85)
Missing 2 (1) 1 (<1)

In Study 1, response rate was the primary endpoint. Response rates based on serum or urine paraprotein measurements were significantly higher in the combination arm (52% vs. 36%). The primary efficacy endpoint in Study 2 was time to progression (TTP), defined as the time from randomization to the first documentation of disease progression, based on the myeloma response criteria. A preplanned interim analysis for Study 2 demonstrated that the combination of Thalix plus dexamethasone was superior to placebo plus dexamethasone with respect to TTP (Table 9).

Thalidomide/Dexamethasone

(N=235)

Placebo/

Dexamethasone

(N=235)


a The 95% confidence intervals about the median overall TTP, or median overall survival. CI: confidence interval; NR: not reached.

b Based on a proportional hazards model comparing the hazard functions associated with treatment groups (thalidomide/dexamethasone:placebo/dexamethasone).

c P-value based on the interim analysis was compared with the nominal significance level of 0.0027. Based on a one-sided unstratified log rank test of survival curve differences between treatment groups.

d Disease response assessments were determined according to the Bladé criteria. Response is the highest assessment of response during the treatment phase of the study.

Time to Progression
Progressed – n (%) 72 (31) 126 (54)
Median (Weeks) (95% CIa) 97.7 (61.86, NR) 28.3 (27.71, 36.43)
Hazard Ratio (95% CI)b 0.43 (0.32, 0.58)
P-valuec <0.0001
Overall Survival
Death – n (%) 57 (24) 68 (29)
Median (Weeks) (95% CIa) NR (112.14, NR) 128.6 (113.43, NR)
Hazard Ratio (95% CI)b 0.82 (0.57, 1.16)
Myeloma Response Rated – n (%)
Complete Response (CR) 18 (8) 6 (3)
Partial Response (PR) 130 (55) 102 (43)
Overall Response (CR + PR)

95% CI (%)

148 (63)

(56, 69)

108 (46)

(39, 53)


The Kaplan-Meier plot of the time to progression by treatment group is presented in Figure 1.

Figure 1: Kaplan-Meier Plot of Time to Disease Progression

KEY: Placebo/Dex=placebo/dexamethasone; Thal/Dex=THALOMID/dexamethasone

14.2 Erythema Nodosum Leprosum

The primary data demonstrating the efficacy of Thalix 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 Thalix (four times daily) or control. Dosage was lower for patients under 50 kg in weight.

Reference No. of Patients No. Treatment Courses* Percent Responding**

* In patients with cutaneous lesions

**Iyer: Complete response or lesions absent

**Sheskin: Complete improvement + “striking” improvement (i.e., >50% improvement)

Iyer et al.

Bull World Health

Organization 1971;45:719

92 204 Thalix

75%

Aspirin

25%

Sheskin et al.

Int J Lep 1969;37:135

52 173 Thalix

66%

Placebo

10%


Waters 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 Thalix or placebo (three times daily). All patients also received dapsone. The primary endpoint was reduction in weekly steroid dosage.

Reference Duration of Treatment No. of Patients Number Responding
Thalix Placebo
Waters 4 weeks 9 4/5 0/4
Lep Rev 1971;42:26 6 weeks

(crossover)

8 8/8 1/8

Data on the efficacy of Thalix 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 Thalix 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 Thalix, 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 Thalix.

15 REFERENCES


16 HOW SUPPLIED/STORAGE AND HANDLING


16.1 How Supplied

50 mg capsules [white opaque], imprinted “Celgene/50 mg” with a “Do Not Get Pregnant” logo.

Individual blister packs of 1 capsule (NDC 59572-205-17).

Individual blister packs of 28 capsules (NDC 59572-205-14).

100 mg capsules [tan], imprinted “Celgene/100 mg” with a “Do Not Get Pregnant” logo.

Individual blister packs of 28 capsules (NDC 59572-210-15).

150 mg capsules [tan and blue], imprinted “Celgene/150 mg” with a “Do Not Get Pregnant” logo.

Individual blister packs of 28 capsules (NDC 59572-215-13).

200 mg capsules [blue], imprinted “Celgene/200 mg” with a “Do Not Get Pregnant” logo.

Individual blister packs of 28 capsules (NDC 59572-220-16).

16.2 Storage

This drug must not be repackaged.

Store at 20°C- 25°C ; excursions permitted to 15-30° C (59-86° F).. Protect from light.

16.3 Handling and Disposal

Care should be exercised in handling of Thalix. Thalix capsules should not be opened or crushed. If powder from Thalix contacts the skin, wash the skin immediately and thoroughly with soap and water. If Thalix contacts the mucous membranes, flush thoroughly with water.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published1.

Rx only and only able to be prescribed and dispensed under the terms of the Thalix REMS Restricted Distribution Program.

17 PATIENT COUNSELING INFORMATION

See FDA-approved Patient labeling (Medication Guide)

Embryo-Fetal Toxicity

Advise patients that Thalix is contraindicated in pregnancy and can cause serious birth defects or death to a developing baby .



Thalix REMS Program

Because of the risk of embryo-fetal toxicity, Thalix is only available through a restricted program called the Thalix REMS program .



Pregnancy Exposure Registry

Inform females there is a Pregnancy Exposure Registry that monitors pregnancy outcomes in females exposed to Thalix during pregnancy and that they can contact the Pregnancy Exposure Registry by calling 1-888-423-5436 .

Venous and Arterial Thromboembolism

Inform patients of the potential risk of developing venous thromboembolism (such as DVT and PE), ischemic heart disease (including myocardial infarction), and stroke, and discuss the need for appropriate prophylactic treatment .

Drowsiness and Somnolence

Inform patients of the risk of drowsiness and somnolence with the drug and to avoid situations where drowsiness or somnolence may be a problem and not to take other medications that may cause drowsiness or somnolence without adequate medical advice .

Peripheral Neuropathy

Inform patients of the risk of peripheral neuropathy and report the signs and symptoms associated with this event to their health care provider for further evaluation .

Dizziness and Orthostatic Hypotension

Inform patients of the risk of dizziness and orthostatic hypotension with the drug. Inform patients to sit upright for a few minutes prior to standing .

Neutropenia

Inform patients on the risk of developing neutropenia and the need to monitor their white blood cell count .

Thrombocytopenia

Inform patients of the risk of developing thrombocytopenia and the need to monitor their platelet count .

Increased HIV Viral Load

Inform HIV seropositive patients of the risk of increased viral load and the need to monitor viral load .

Bradycardia

Inform patients of the risk of bradycardia and report signs and symptoms associated with this event to their healthcare provider for evaluation .

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Inform patients of the potential risk for Stevens Johnson syndrome and toxic epidermal necrolysis and report any signs and symptoms associated with these events to their healthcare provider for evaluation .

Seizures

Inform patients of the risk of seizures and report any seizure while taking Thalix .

Tumor Lysis Syndrome

Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation .

Contraceptive Risks

Inform patients that some contraceptive methods may pose a higher risk of adverse effects or may be medically contraindicated in some patients treated with Thalix .

Hypersensitivity

Inform patients of the potential for a hypersensitivity reaction to Thalix if they have had such a reaction in the past to Revlimid .

Manufactured for Celgene Corporation

86 Morris Avenue

Summit, NJ 07901

1-(888)-423-5436

Thalix® and Thalix REMS® are registered trademarks of Celgene Corporation.

Pat. http://www.celgene.com/therapies

©1998-2017 Celgene Corporation. All Rights Reserved.

THALPLYPI.021/MG.021 01/17 CG

MEDICATION GUIDE

Thalix® (tha-lo-mid)

(thalidomide)

capsules

What is the most important information I should know about Thalix?

Before you begin taking Thalix, you must read and agree to all of the instructions in the Thalix REMS® program. Before prescribing Thalix, your healthcare provider will explain the Thalix REMS program to you and have you sign the Patient-Physician Agreement Form.

Thalix can cause serious side effects including:

  • Severe and life-threatening human birth defects (deformed babies) or death of an unborn baby. Females who are pregnant or who plan to become pregnant must not take Thalix.

    Females must not get pregnant:

    • For at least 4 weeks before starting Thalix
    • While taking Thalix
    • During any breaks (interruptions) in your treatment with Thalix
    • For at least 4 weeks after stopping Thalix

    Females who can become pregnant:

    • Will have pregnancy tests weekly for 4 weeks, then every 4 weeks if your menstrual cycle is regular, or every 2 weeks if your menstrual cycle is irregular.
    • If you miss your period or have unusual bleeding, you will need to have a pregnancy test and receive counseling.
    • Must agree to use two acceptable forms of birth control at the same time, for at least 4 weeks before, while taking, during any breaks (interruptions) in your treatment, and for at least 4 weeks after stopping Thalix.
    • Talk with your healthcare provider to find out about options for acceptable forms of birth control that you may use to prevent pregnancy before, during, and after treatment with Thalix.
    • Stop taking Thalix and call your healthcare provider right away if you have unprotected sex or if you think your birth control has failed.

    If you become pregnant while taking Thalix, stop taking it right away and call your healthcare provider. If your healthcare provider is not available, you should call Celgene Customer Care Center at 1-888-423-5436. Healthcare providers and patients should report all cases of pregnancy to:

    • FDA MedWatch at 1-800-FDA-1088, and
    • Celgene Corporation at 1-888-423-5436
    There is a pregnancy exposure registry that monitors the outcomes of females who take Thalix during pregnancy, or if their male partner takes Thalix and they are exposed during pregnancy. You can enroll in this registry by calling Celgene Corporation at the phone number listed above.

    Thalix can pass into human semen:

    • Males, including those who have had a vasectomy, must always use a latex or synthetic condom during any sexual contact with a pregnant female or a female that can become pregnant while taking Thalix, during any breaks (interruptions) in your treatment with Thalix, and for up to 4 weeks after stopping Thalix.
    • Do not have unprotected sexual contact with a female who is or could become pregnant. Tell your healthcare provider if you do have unprotected sexual contact with a female who is or could become pregnant.
    • Do not donate sperm while taking Thalix, during any breaks (interruptions) in your treatment, and for 4 weeks after stopping Thalix. If a female becomes pregnant with your sperm, the baby may be exposed to Thalix and may be born with birth defects.
    Men, if your female partner becomes pregnant, you should call your healthcare provider right away.
  • Blood clots. People with multiple myeloma (MM) who take Thalix may have an increased risk for blood clots in their arteries, veins, and lungs. This risk is even higher if you take the medicine dexamethasone with Thalix to treat your MM. Heart attacks and strokes may also happen if you take Thalix with dexamethasone.

    Before taking Thalix, tell your healthcare provider about all the medicines you take. Certain other medicines can also increase your risk for blood clots.

    Call your healthcare provider or get medical help right away if you get any of the following during treatment with Thalix:

    • Signs or symptoms of a blood clot in the lung, arm, or leg may include: shortness of breath, chest pain, or arm or leg swelling
    • Signs or symptoms of a heart attack may include: chest pain that may spread to the arms, neck, jaw, back, or stomach area (abdomen), feeling sweaty, shortness of breath, feeling sick or vomiting
    • Signs or symptoms of stroke may include: sudden numbness or weakness, especially on one side of the body, severe headache or confusion, or problems with vision, speech, or balance

What is Thalix?

Thalix is a prescription medicine used

  • to treat people who have been newly diagnosed with multiple myeloma (MM) in combination with the medicine dexamethasone.
  • to treat people who have moderate to severe new lesions of leprosy. Thalix is not used by itself to treat the skin lesions when there is moderate to severe nerve pain.
  • as maintenance treatment to prevent and keep the skin lesions of leprosy from coming back (recurring).

It is not known if Thalix is safe and effective in children under 12 years of age.


Who should not take Thalix?

Do not take Thalix if you:

  • are pregnant, plan to become pregnant, or become pregnant during treatment with Thalix. See “What is the most important information I should know about Thalix?”
  • are allergic to Thalix or any of the ingredients in Thalix. See the end of this Medication Guide for a complete list of ingredients in Thalix.

What should I tell my healthcare provider before taking Thalix?

Before you take Thalix, tell your healthcare provider about all of your medical conditions, including if you:

  • have a history of seizures
  • drink alcohol
  • plan to have surgery
  • are breastfeeding. Thalix must not be used by females who are breastfeeding. It is not known if Thalix passes into your breast milk and can harm your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Thalix and other medicines may affect each other, causing serious side effects. Talk with your healthcare provider before taking any new medicines. Certain medicines can affect the way that birth control pills, injections, patches, or implants work. You could become pregnant. See “What is the most important information I should know about Thalix?”

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist.


How should I take Thalix?

  • Take Thalix exactly as prescribed and follow all the instructions of the Thalix REMS program.
  • Keep Thalix in the blister pack until you take your daily dose.
  • Swallow Thalix capsules whole with water.
  • Thalix is taken 1 time each day, at least 1 hour after your evening meal. Bedtime is the preferred time to take Thalix.
  • Do not open or crush Thalix capsules or handle them any more than needed.
    • If powder from the Thalix capsule comes in contact with your skin, wash the skin right away with soap and water.
    • If powder from the Thalix capsule comes in contact with the inside of your eyes, nose, and mouth, flush well with water.
  • If you miss a dose of Thalix and it has been less than 12 hours since your regular time, take it as soon as you remember. If it has been more than 12 hours, just skip your missed dose. Do not take 2 doses at the same time.
  • If you take too much Thalix, call your healthcare provider right away.
What should I avoid while taking Thalix?

  • See “What is the most important information I should know about Thalix?”
  • Females: Do not get pregnant and do not breastfeed while taking Thalix.
  • Males: Do not donate sperm.
  • Do not share Thalix with other people. It may cause birth defects and other serious problems.
  • Do not donate blood while you take Thalix, during any breaks (interruptions) in your treatment, and for 4 weeks after stopping Thalix. If someone who is pregnant gets your donated blood, her baby may be exposed to Thalix and may be born with birth defects.
  • Thalix can cause drowsiness and sleepiness. Avoid drinking alcohol, operating machinery, and driving a car when taking Thalix. Avoid taking other medicines that may cause drowsiness without talking to your healthcare provider first.

What are the possible side effects of Thalix?

Thalix can cause serious side effects, including:

  • See “What is the most important information I should know about Thalix?”
  • Drowsiness and sleepiness. See “What should I avoid while taking Thalix?”
  • Nerve damage. Nerve damage is common with Thalix. If the nerve damage is severe, it may not go away. Stop taking Thalix and call your healthcare provider right away if you have any of these early symptoms of nerve damage in your hands, legs, or feet:
    • numbness
    • tingling
    • pain
    • burning sensation
  • Dizziness and decreased blood pressure when changing positions. Thalix may cause a decrease in your blood pressure, and you may feel dizzy when you go from a lying down or sitting position to standing up. When changing positions, sit upright for a few minutes before standing to help prevent this.
  • Decreased white blood cell count. Thalix can cause decreased white blood cell counts, including neutrophils. Neutrophils are a type of white blood cell that is important in fighting bacterial infections. Your healthcare provider should check your white blood count before and regularly while you take Thalix. If your neutrophils are too low you should not start Thalix and if they are low during treatment, your dose of Thalix may need to be changed.
  • Decreased platelet count. Thalix can cause decreased platelet counts. Your healthcare provider should check your platelet count before and regularly while you take Thalix. If your platelets are too low, your healthcare provider may lower your dose, delay your dose, or completely stop treatment. Tell your healthcare provider if you have signs and symptoms of bleeding such as:
    • small red or purple spots on your body
    • unusual bleeding or bruising
    • nosebleeds
    • bright red or tar like stools
    • vomiting or coughing up blood
  • Increased HIV virus in the blood. If you are HIV positive, your healthcare provider should check your viral load after one month and three months of treatment, then every 3 months after that.
  • Slow heartbeat (bradycardia). Tell your healthcare provider if you have a slow heartbeat, fainting, dizziness or shortness of breath.
  • Serious skin reactions. Serious skin reactions can happen with Thalix and may cause death. Call your healthcare provider right away if you have any skin reaction while taking Thalix.
  • Seizures. Tell your healthcare provider right away if you have a seizure while taking Thalix.
  • Tumor Lysis Syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure and sometimes death. Your healthcare provider may do blood tests to check you for TLS.
  • Birth control risks. Certain birth control methods may pose a higher risk of serious side effects and should not be used in some females. These risks include severe decreased white blood cell counts, low platelet counts, and blood clots. Use of an intrauterine device (IUD) or implantable birth control may also increase your risk of infection or bleeding during insertion, removal or during use of the device.
  • Allergic reaction. Allergic reactions can happen with Thalix and may be severe. Call your healthcare provider or get medical help right away if you have any of these symptoms of allergic reaction:
    • a red, itchy rash
    • fever
    • fast heartbeat
    • feel dizzy or faint

Your healthcare provider may tell you to decrease your dose, temporarily stop or permanently stop taking Thalix if you develop certain serious side effects during treatment with Thalix.

The most common side effects of Thalix for treatment of multiple myeloma include:

  • tiredness
  • decreased calcium levels
  • swelling of the hands and feet
  • constipation
  • numbness or tingling
  • shortness of breath
  • muscle weakness
  • low blood counts
  • skin rash or peeling
  • confusion
  • decreased appetite
  • nausea
  • anxiety
  • decreased energy or strength
  • tremor
  • fever
  • weight loss
  • blood clots
  • muscle twitching and cramping
  • weight gain
  • dizziness
  • dry skin

The most common side effects of Thalix for treatment of leprosy include:

  • sleepiness
  • rash
  • headache

These are not all the possible side effects of Thalix.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.


How should I store Thalix?

  • Store Thalix at room temperature between 68°F to 77°F (20°C to 25°C).
  • Protect from light.
  • Return any unused Thalix to Celgene or your healthcare provider.

Keep Thalix and all medicines out of the reach of children.


General information about the safe and effective use of Thalix

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take Thalix for conditions for which it was not prescribed. Do not give Thalix to other people, even if they have the same symptoms you have. It may harm them and may cause birth defects. You can ask your healthcare provider or pharmacist for information about Thalix that is written for health professionals.

What are the ingredients in Thalix?

Active ingredient: Thalix

Inactive ingredients: pregelatinized starch and magnesium stearate.

The 50 mg capsule shell contains gelatin, titanium dioxide and black ink.

The 100 mg capsule shell contains black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black ink.

The 150 mg capsule shell contains FD&C blue #2, black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black and white ink.

The 200 mg capsule shell contains FD&C blue #2, titanium dioxide, gelatin, and white ink.

Manufactured for: Celgene Corporation, Summit, NJ 07901

Thalix® and Thalix REMS® are registered trademarks of Celgene Corporation.

Pat. http://www.celgene.com/therapies © 1998-2017 Celgene Corporation All rights reserved. THALPLYMG.021 01/2017

For more information, call 1-888-423-5436 or go to www. CelgeneRiskManagement.com or www.celgene.com/therapies.

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: January 2017

Package Label - Principal Display Panel – 50 mg Blister Pack

Package Label - Principal Display Panel – 50 mg Carton

Package Label - Principal Display Panel – 50 mg - Single Unit Blister Pack

Package Label - Principal Display Panel – 50 mg - Single Unit Carton

Package Label - Principal Display Panel – 100 mg Blister Pack

Package Label - Principal Display Panel – 100 mg Carton

Package Label - Principal Display Panel – 150 mg Blister Pack

Package Label - Principal Display Panel – 150 mg Carton

Package Label - Principal Display Panel – 200 mg Blister Pack

Package Label - Principal Display Panel – 200 mg Carton

Thalix pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Thalix available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Thalix destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Thalix Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Thalix pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."THALOMID (THALIDOMIDE) CAPSULE [CELGENE CORPORATION]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Cancer.Net."Angiogenesis and Angiogenesis Inhibitors to Treat Cancer". http://www.cancer.net/navigating-ca... (accessed August 28, 2018).
  3. Dailymed."THALIDOMIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Thalix?

Depending on the reaction of the Thalix after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Thalix not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Thalix addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Thalix, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Thalix consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

Visitor reported frequency of use

No survey data has been collected yet

Two visitors reported doses

What is the dose of Thalix drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 101-200mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
101-200mg2
100.0%

Visitor reported time for results

No survey data has been collected yet

One visitor reported administration

The drugs are administered in various routes, like oral or injection form. They are administered before food or after food. How are you taking Thalix drug, before food or after food?
Click here to find out how other users of our website are taking it. For any doubts or queries on how and when the medicine is administered, contact your health care provider immediately.
Visitors%
Before food1
100.0%

Visitor reported age

No survey data has been collected yet

Visitor reviews


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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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