Data from FDA - Curated by EPG Health - Last updated 31 December 2017

Indication(s)

1 INDICATIONS AND USAGE THALOMID in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma (MM). (1.1) THALOMID is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). THALOMID is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis. THALOMID is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence. (1.2) 1.1 Multiple Myeloma THALOMID in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma (MM) [see Clinical Studies (14.1)]. 1.2 Erythema Nodosum Leprosum THALOMID is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). THALOMID is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis. THALOMID is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence [see Clinical Studies (14.2)].

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Advisory information

contraindications
4 CONTRAINDICATIONS Pregnancy (Boxed Warning, 4.1, 5.1, 5.2, 8.1, 17) Demonstrated hypersensitivity to the drug or its components (4.2, 5.15, 6.2) 4.1 Pregnancy [see Boxed Warning] THALOMID can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. Thalidomide is contraindicated in females who are pregnant. Thalidomide is a powerful human teratogen, inducing a high frequency of severe and life-threatening birth defects, even after a single dose [see Boxed Warning]. Mortality at or shortly after birth has been reported in about 40% of infants. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus. If pregnancy occurs during thalidomide treatment, the drug should be discontinued immediately. 4.2 Hypersensitivity THALOMID is contraindicated in patients who have demonstrated hypersensitivity to the drug or its components [see Warnings and Precautions (5.16)].
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: Teratogenicity [see Boxed Warning, Warnings and Precautions (5.1, 5.2), and Patient Counseling Information (17)] Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.3), and Patient Counseling Information (17)] Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone [see Warnings and Precautions (5.4)] Drowsiness and Somnolence [see Warnings and Precautions (5.5)] Peripheral Neuropathy [see Warnings and Precautions (5.6)] Dizziness and Orthostatic Hypotension [see Warnings and Precautions (5.7)] Neutropenia [see Warnings and Precautions (5.8)] Thrombocytopenia [see Warnings and Precautions (5.9)] Increased HIV Viral Load [see Warnings and Precautions (5.10)] Bradycardia [see Warnings and Precautions (5.11)] Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis [see Warnings and Precautions (5.12)] Seizures [see Warnings and Precautions (5.13)] Tumor Lysis Syndrome [see Warnings and Precautions (5.14)] Hypersensitivity [see Warnings and Precautions (5.16)] MM: The most common adverse reactions (≥ 20%) are fatigue, hypocalcemia, edema, constipation, neuropathy-sensory, dyspnea, muscle weakness, leukopenia, neutropenia, rash/desquamation, confusion, anorexia, nausea, anxiety/agitation, asthenia, tremor, fever, weight loss, thrombosis/embolism, neuropathy-motor, weight gain, dizziness, and dry skin. (6.1) ENL: The most common adverse reactions (≥ 10%) are somnolence, rash, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS or embryo-fetal exposure: contact Celgene Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 thalidomide can be expected to experience adverse reactions. Teratogenicity: The most serious toxicity associated with thalidomide is its documented human teratogenicity. The risk of severe birth defects, primarily phocomelia or death to the fetus, is extremely high during the critical period of pregnancy. The critical period is estimated, depending on the source of information, to range from 35 to 50 days after the last menstrual period. The risk of other potentially severe birth defects outside this critical period is unknown, but may be significant. Based on present knowledge, thalidomide must not be used at any time during pregnancy. Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex or synthetic condom during any sexual contact with females of reproductive potential, even if he has undergone a successful vasectomy. Venous and Arterial Thromboembolism: An increased risk of venous thromboembolism (such as deep vein thrombosis and pulmonary embolism), ischemic heart disease (including myocardial infarction), and stroke have been reported in patients with multiple myeloma treated with thalidomide [see Warnings and Precautions (5.3)]. Peripheral Neuropathy: Peripheral neuropathy is a very common, potentially severe, adverse reaction of treatment with thalidomide that may result in irreversible damage. Peripheral neuropathy generally occurs following chronic use over a period of months. However, reports following relatively short-term use also exist. Incidence of neuropathy events leading to discontinuation, dose reduction or interruption increases with cumulative dose and duration of therapy. Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all. Somnolence, dizziness, and rash are the most commonly observed adverse reactions associated with the use of thalidomide. Adverse event profiles from clinical trials are summarized in the sections that follow. Adverse Reactions in Multiple Myeloma Controlled Clinical Trials 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. Table 1: Adverse Drug Reactions Reported in ≥10% of Patients in the THALOMID/Dexamethasone Arm (Study 1 - Safety Population; N=204) *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. Table 2: Adverse Drug Reactions Reported in ≥10% of Patients in the THALOMID/Dexamethasone Arm (Study 2 - Safety Population; N=466) *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) Table 3: Grade 3/4 Adverse Drug Reactions Reported in >2% of Patients in the THALOMID/Dexamethasone Arm (Study 2 - Safety Population; N=466) *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, THALOMID 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. Table 4: Summary of Adverse Events (AEs) Reported in Celgene-sponsored Controlled Clinical Trials Body System/Adverse Event All AEs Reported in Patients with ENL AEs Reported in ≥3 HIV-seropositive Patients Thalidomide 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 THALOMID 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 THALOMID 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 thalidomide. 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, THALOMID has been used in uncontrolled studies in 145 patients. Less frequent adverse events that have been reported in these HIV-seropositive patients treated with THALOMID 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 THALOMID and are not already included in Clinical Trials Experience [see Adverse Reactions (6.1)]. 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

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION MM: 200 mg orally once daily. The recommended dose of dexamethasone is 40 mg/day on days 1-4, 9-12, and 17-20 every 28 days. (2.1) ENL: 100 to 300 mg/day for an episode of cutaneous ENL. Up to 400 mg/day for severe cutaneous ENL. (2.2) 2.1 General Considerations THALOMID (thalidomide) must only be administered in compliance with all of the terms outlined in the THALOMID REMS program. THALOMID (thalidomide) may only be prescribed by prescribers certified with the THALOMID REMS program and may only be dispensed by pharmacists certified with the THALOMID REMS program. Drug prescribing to females of reproductive potential is contingent upon initial and continued negative results of pregnancy testing [see Warnings and Precautions (5.1 and 5.2)]. 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 THALOMID is administered in combination with dexamethasone in 28-day treatment cycles. The dose of THALOMID is 200 mg administered orally once daily with water, preferably at bedtime and at least 1 hour after the evening meal. The dose of dexamethasone is 40 mg daily administered orally on days 1-4, 9-12, and 17-20 every 28 days. Patients who develop adverse reactions such as constipation, somnolence, or peripheral neuropathy may benefit by either temporarily discontinuing the drug or continuing at a lower dose. With the abatement of these adverse reactions, the drug may be started at a lower dose or at the previous dose based on clinical judgment. 2.3 Erythema Nodosum Leprosum For an episode of cutaneous ENL, THALOMID dosing should be initiated at 100 to 300 mg/day, administered once daily with water, preferably at bedtime and at least 1 hour after the evening meal. Patients weighing less than 50 kilograms should be started at the low end of the dose range. In patients with a severe cutaneous ENL reaction, or in those who have previously required higher doses to control the reaction, THALOMID dosing may be initiated at higher doses up to 400 mg/day once daily at bedtime or in divided doses with water, at least 1 hour after meals. In patients with moderate to severe neuritis associated with a severe ENL reaction, corticosteroids may be started concomitantly with THALOMID. Steroid usage can be tapered and discontinued when the neuritis has ameliorated. Dosing with THALOMID should usually continue until signs and symptoms of active reaction have subsided, usually a period of at least 2 weeks. Patients may then be tapered off medication in 50 mg decrements every 2 to 4 weeks. Patients who have a documented history of requiring prolonged maintenance treatment to prevent the recurrence of cutaneous ENL or who flare during tapering should be maintained on the minimum dose necessary to control the reaction. Tapering off medication should be attempted every 3 to 6 months, in decrements of 50 mg every 2 to 4 weeks.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. (8.2) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to THALOMID during pregnancy as well as female partners of male patients who are exposed to THALOMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to THALOMID 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 [see Clinical Pharmacology (12.1)], human and animal data [see Data], THALOMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy [see Boxed Warning, Contraindications (4.1), and Warnings and Precautions (5.1)]. THALOMID 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 THALOMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436. Thalidomide crossed the placenta after administration to pregnant hamsters [see Data]. 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 thalidomide concentrations in milk ranged from 22 to 36 mcg per mL). In a study conducted in pregnant rabbits, thalidomide 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, thalidomide 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 thalidomide in human milk, the effects of THALOMID on the breastfed infant, or the effects of THALOMID on milk production. Thalidomide is excreted in the milk of lactating rabbits [see Data]. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from THALOMID, advise women not to breastfeed during treatment with THALOMID. Data Animal Data In lactating female rabbits at an oral dose of 150 mg/kg/day, the average thalidomide concentrations in milk ranged from 22 to 36 mcg per mL. In the study of lactating female rabbits, high concentrations of thalidomide (7741 – 71425 ng per mL) 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 thalidomide doses, respectively; thalidomide, 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 THALOMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Verify the pregnancy status of females of reproductive potential prior to initiating THALOMID therapy and during therapy. Advise females of reproductive potential that they must avoid pregnancy 4 weeks before therapy, while taking THALOMID, during dose interruptions and for at least 4 weeks after completing therapy. Females of reproductive potential must have 2 negative pregnancy tests before initiating THALOMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing THALOMID. 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. THALOMID 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 THALOMID, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of THALOMID 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 Thalidomide is present in the semen of males who take THALOMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking THALOMID, during dose interruptions and for up to 28 days after discontinuing THALOMID, even if they have undergone a successful vasectomy. Male patients taking THALOMID must not donate sperm. Infertility Based on findings in animals, male fertility may be compromised by treatment with THALOMID [see Nonclinical Toxicology (13.1)]. 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 (52%) of 336 patients treated with THALOMID 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 THALOMID 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, thalidomide (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 thalidomide 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.

Interactions

7 DRUG INTERACTIONS Use caution if other drugs which have sedative and hypnotic properties, slow cardiac conduction and/or cause peripheral neuropathy must be used. (7.1, 7.2, 7.3) It is not known whether concomitant use of hormonal contraceptives further increases the risk of thromboembolism with THALOMID. (5.14, 7.4) Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thromboembolism. (7.7) 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 THALOMID 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 THALOMID 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 (e.g., famotidine, cimetidine), 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 thalidomide 200 mg/day at steady state levels. The single dose of digoxin had no effect on the pharmacokinetic profile of thalidomide. The safety of long-term concomitant use of THALOMID 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 THALOMID. 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 thalidomide 200 mg/day to steady-state levels. 7.5 Warfarin In 13 healthy men, the pharmacokinetic profile and international normalized ratio (INR) of prothrombin time for warfarin, following a single oral dose of 25 mg, were similar with and without the coadministration of thalidomide 200 mg/day at steady-state levels. The single dose of warfarin had no effect on the pharmacokinetic profile of thalidomide. 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 thalidomide. 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 thalidomide with dexamethasone [see Warnings and Precautions (5.3)].

More information

Category Value
Authorisation number NDA020785
Agency product number 4Z8R6ORS6L
Orphan designation No
Product NDC 59572-215,59572-220,59572-205,59572-210
Date Last Revised 07-12-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 200390
Storage and handling 16.2 Storage This drug must not be repackaged. Store at 20°C- 25°C (68°F -77°F); excursions permitted to 15-30° C (59-86° F). [See USP Controlled Room Temperature]. Protect from light.
Marketing authorisation holder Celgene Corporation
Warnings WARNING: EMBRYO-FETAL TOXICITY AND VENOUS THROMBOEMBOLISM EMBRYO-FETAL TOXICITY If thalidomide is taken during pregnancy, it can cause severe birth defects or embryo-fetal death. Thalidomide should never be used by females who are pregnant or who could become pregnant while taking the drug. Even a single dose [1 capsule (regardless of strength)] taken by a pregnant woman during her pregnancy can cause severe birth defects. Because of this toxicity and in an effort to make the chance of embryo-fetal exposure to THALOMID® (thalidomide) as negligible as possible, THALOMID® (thalidomide) is approved for marketing only through a special restricted distribution program: THALOMID REMS® program, approved by the Food and Drug Administration. You can get the information about THALOMID and the THALOMID 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 THALOMID® (thalidomide) in multiple myeloma results in an increased risk of venous thromboembolism, such as deep venous thrombosis and pulmonary embolism. This risk increases significantly when thalidomide is used in combination with standard chemotherapeutic agents including dexamethasone. In one controlled trial, the rate of venous thromboembolism was 22.5% in patients receiving thalidomide in combination with dexamethasone compared to 4.9% in patients receiving dexamethasone alone (p = 0.002). Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Instruct patients to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Consider thromboprophylaxis based on an assessment of individual patients’ underlying risk factors. WARNING: EMBRYO-FETAL TOXICITY AND VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning. EMBRYO-FETAL TOXICITY If thalidomide is taken during pregnancy, it can cause severe birth defects or embryo-fetal death. Thalidomide should never be used by females who are pregnant or who could be pregnant while taking the drug. Even a single dose [1 capsule (regardless of strength)] taken by a pregnant woman during her pregnancy can cause severe birth defects. Pregnancy must be excluded before start of treatment. Prevent pregnancy thereafter by the use of two reliable methods of contraception. (5.1, 8.3) THALOMID® (thalidomide) is only available through a restricted distribution program, the THALOMID REMS® program (5.2). VENOUS THROMBOEMBOLISM Significant increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma receiving THALOMID® (thalidomide) with dexamethasone (5.3).