THALIDOMIDE: 17,401 Adverse Event Reports & Safety Profile

THALOMID, α-(N-phthalimido) glutarimide, is an immunomodulatory agent. The empirical formula for thalidomide is C 13 H 10 N 2 O 4 and the gram molecular weight is 258.2. The CAS number of thalidomide is 50-35-1.

Chemical

Structure of Thalidomide Note: ∙ = asymmetric carbon atom Thalidomide 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-(+). THALOMID is an equal mixture of the S-(-) and R-(+) forms and, therefore, has a net optical rotation of zero. THALOMID is available in 50 mg, 100 mg, 150 mg and 200 mg capsules for oral administration. Active ingredient: thalidomide. 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.

Chemical

Structure

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) <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span>.

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. ( 2.2 )
• ENL: 100 to 300 mg/day for an episode of cutaneous ENL. Up to 400 mg/day for severe cutaneous ENL. ( 2.3 )

2.1 Required Baseline Testing Drug prescribing to females of reproductive potential is contingent upon initial and continued negative results of pregnancy testing <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 and 5.2) ]</span> . THALOMID must only be administered in compliance with all of the terms outlined in the THALOMID REMS program. THALOMID 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.

2.2 Recommended Dosage for Multiple Myeloma The recommended dose of THALOMID in combination with dexamethasone is 200 mg once daily (in 28-day treatment cycles) orally 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.

2.3 Recommended Dosage for Erythema Nodosum Leprosum The recommended dose of THALOMID for an episode of cutaneous ENL is 100 to 300 mg/day once daily orally with water, preferably at bedtime and at least 1 hour after the evening meal. Initiate dosing for patients weighing less than 50 kilograms at the low end of the dose range. Consider dosing in the higher dosage range for patients with a severe cutaneous ENL reaction, or in those who have previously required higher doses to control the reaction (possibly up to 400 mg/day) once daily at bedtime or in divided doses with water, at least 1 hour after meals. Consider concomitant use of corticosteroids in patients with moderate to severe neuritis associated with a severe ENL reaction. Steroid usage can be tapered and discontinued when the neuritis has ameliorated. Continue dosing with THALOMID 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.

2.4 Dosage Modifications for Adverse Reactions Interrupt THALOMID for constipation, somnolence, or peripheral neuropathy. Consider a reduced dose upon resumption of treatment. 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. Permanently discontinue THALOMID for angioedema, anaphylaxis, Grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reactions [see Warnings and Precautions (5.12 and 5.16) ] .

4 CONTRAINDICATIONS

• Pregnancy ( Boxed Warning , 4.1 , 5.1 , 5.2 , 8.1 , 17 )
• Demonstrated hypersensitivity to the drug or its components ( 4.2 , 5.16 , 6.2 )

4.1 Pregnancy THALOMID is contraindicated in females who are pregnant. THALOMID can cause fetal harm when administered to a pregnant female <span class="opacity-50 text-xs">[see Boxed Warning , Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ]</span> . THALOMID is a powerful human teratogen, inducing a high frequency of severe and life-threatening birth defects, even after a single dose <span class="opacity-50 text-xs">[see Boxed Warning ]</span> . 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 THALOMID 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.16) ]</span>.

REACTIONS The following clinically significant 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) ]
• Severe Cutaneous Reactions [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 Bristol Myers Squibb at 1-800-721-5072 or 1-888-423-5436, respectively, 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 THALOMID can be expected to experience adverse reactions.

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 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 Reactions Reported in ≥10% of Patients in the THALOMID/Dexamethasone Arm (Study 1 - Safety Population; N=204)

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 (%) * 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.

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 reactions (≥10%) that were observed.

Table

3 lists the most common Grade 3/4 adverse 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 reactions; 37% (86/234) from the THALOMID/dexamethasone arm and 15% (35/232) from the placebo/dexamethasone arm.

Table

2: Adverse Reactions Reported in ≥10% of Patients in the THALOMID/Dexamethasone Arm (Study 2 - Safety Population; N=466)

Body System Adverse Reaction

Thal/Dex (N=234)* n (%) Placebo/Dex (N=232)* n (%) *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. 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 Reactions Reported in >2% of Patients in the THALOMID/Dexamethasone Arm (Study 2 - Safety Population; N=466)

Body System Adverse

Reaction THALOMID/Dex (N=234)* n (%) Placebo/Dex (N=232)* n (%) * 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. 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

Reactions in Multiple Myeloma Controlled Clinical Trials In Study 2, THALOMID in combination with dexamethasone in patients with multiple myeloma, the following adverse 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 Reactions (ARs) Reported in Controlled Clinical Trials All ARs Reported in Patients with ENL ARs Reported in ≥3 HIV-seropositive Patients Body System/ Adverse Reaction THALOMID 50 to 300 mg/day (N=24) n (%) THALOMID 100 mg/day (N=36) n (%) THALOMID 200 mg/day (N=32) n (%) Placebo (N=35) n (%) Blood and Lymphatic 0 8 (22) 13 (41) 10 (29)

Anemia

0 2 (6) 4 (13) 3 (9)

Leukopenia

0 6 (17) 8 (25) 3 (9)

Lymphadenopathy

0 2 (6) 4 (13) 3 (9) Body as a Whole 16 (67) 18 (50) 19 (59) 13 (37) Abdominal pain 1 (4) 1 (3) 1 (3) 4 (11) Accidental injury 1 (4) 2 (6) 0 1 (3)

Asthenia

2 (8) 2 (6) 7 (22) 1 (3) Back pain 1 (4) 2 (6) 0 0 Chills 1 (4) 0 3 (9) 4 (11) Facial edema 1 (4) 0 0 0 Fever 0 7 (19) 7 (22) 6 (17)

Headache

3 (13) 6 (17) 6 (19) 4 (11)

Infection

0 3 (8) 2 (6) 1 (3)

Malaise

2 (8) 0 0 0 Neck pain 1 (4) 0 0 0 Neck rigidity 1 (4) 0 0 0 Pain 2 (8) 0 1 (3) 2 (6)

Digestive System

5 (21) 16 (44) 16 (50) 15 (43)

Anorexia

0 1 (3) 3 (9) 2 (6)

Constipation

1 (4) 1 (3) 3 (9) 0 Diarrhea 1 (4) 4 (11) 6 (19) 6 (17) Dry mouth 0 3 (8) 3 (9) 2 (6)

Flatulence

0 3 (8) 0 2 (6) Liver function tests multiple abnormalities 0 0 3 (9) 0 Nausea 1 (4) 0 4 (13) 1 (3) Oral moniliasis 1 (4) 4 (11) 2 (6) 0 Tooth pain 1 (4) 0 0 0 Metabolic and Endocrine Disorders 1 (4) 8 (22) 12 (38) 8 (23) Edema peripheral 1 (4) 3 (8) 1 (3) 0 Hyperlipidemia 0 2 (6) 3 (9) 1 (3) SGOT increased 0 1 (3) 4 (13) 2 (6)

Nervous System

13 (54) 19 (53) 18 (56) 12 (34)

Agitation

0 0 3 (9) 0 Dizziness 1 (4) 7 (19) 6 (19) 0 Insomnia 0 0 3 (9) 2 (6)

Nervousness

0 1 (3) 3 (9) 0 Neuropathy 0 3 (8) 0 0 Paresthesia 0 2 (6) 5 (16) 4 (11)

Somnolence

9 (38) 13 (36) 12 (38) 4 (11)

Tremor

1 (4) 0 0 0 Vertigo 2 (8) 0 0 0 Respiratory System 3 (13) 9 (25) 6 (19) 9 (26)

Pharyngitis

1 (4) 3 (8) 2 (6) 2 (6)

Rhinitis

1 (4) 0 0 4 (11)

Sinusitis

1 (4) 3 (8) 1 (3) 2 (6) Skin and Appendages 10 (42) 17 (47) 18 (56) 19 (54)

Acne

0 4 (11) 1 (3) 0 Dermatitis fungal 1 (4) 2 (6) 3 (9) 0 Nail disorder 1 (4) 0 1 (3) 0 Pruritus 2 (8) 1 (3) 2 (6) 2 (6)

Rash

5 (21) 9 (25) 8 (25) 11 (31) Rash maculopapular 1 (4) 6 (17) 6 (19) 2 (6)

Sweating

0 0 4 (13) 4 (11)

Urogenital System

2 (8) 6 (17) 2 (6) 4 (11)

Albuminuria

0 3 (8) 1 (3) 2 (6)

Hematuria

0 4 (11) 0 1 (3)

Impotence

2 (8) 1 (3) 0 0 Other Adverse Reactions 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 reactions, 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 THALOMID. 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 Reactions

Observed in HIV-seropositive Patients In addition to controlled clinical trials, THALOMID has been used in uncontrolled studies in 145 patients. Less frequent adverse reactions 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 reactions 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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&apos;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 including anaphylaxis, solid organ transplant rejection. Infections and infestations: Severe infections (e.g., fatal sepsis including septic shock), viral infections (including varicella zoster virus, cytomegalovirus, and hepatitis B virus reactivation) and progressive multifocal leukoencephalopathy (PML). 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 (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), purpura, petechiae.

Special

Senses: Diplopia, nystagmus

AND PRECAUTIONS

• Ischemic heart disease (including myocardial infarction) and stroke have been observed in patients treated with THALOMID in combination with dexamethasone. ( 5.3 )
• Increased Mortality: Observed in patients with MM when pembrolizumab was added to dexamethasone and a thalidomide analogue. ( 5.4 )
• Drowsiness and Somnolence: Instruct patients to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness. ( 5.5 )
• Peripheral Neuropathy: Monitor patients for signs or symptoms of peripheral neuropathy during treatment. Discontinue THALOMID if symptoms of drug-induced peripheral neuropathy occur, if clinically appropriate. ( 5.6 )
• Dizziness and Orthostatic Hypotension: Advise patients to sit upright for a few minutes prior to standing up from a recumbent position. ( 5.7 )
• Neutropenia and Thrombocytopenia: Patients may require dose interruption and/or dose reduction. ( 5.8 , 5.9 )
• Increased HIV Viral Load: Measure viral load during treatment. ( 5.10 )
• Bradycardia: Monitor patients for bradycardia and possible syncope. Dose reduction or discontinuation may be required. ( 5.11 )
• Severe Cutaneous Reactions: Discontinue THALOMID for severe reactions. ( 5.12 )
• Seizures: Monitor patients with a history of seizures or other risk factors for acute seizure activity. ( 5.13 )
• Tumor Lysis Syndrome: Monitor patients at risk (e.g., those with high tumor burden prior to treatment) and take appropriate precautions. ( 5.14 )
• Hypersensitivity: Monitor patients for potential hypersensitivity. Discontinue THALOMID for angioedema and anaphylaxis. ( 5.16 )

5.1 Embryo-Fetal Toxicity THALOMID 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 THALOMID provided adequate precautions are taken to avoid pregnancy. THALOMID is only available through the THALOMID REMS program <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . Oral ingestion is the only type of maternal THALOMID 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 THALOMID; however, females of reproductive potential should avoid contact with THALOMID Capsules.

Thalomid

Capsules should be stored in blister packs until ingestion. If there is contact with non-intact THALOMID capsules or the powder contents, the exposed area should be washed with soap and water. If healthcare providers or other care givers are exposed to body fluids from patients receiving THALOMID, the exposed area should be washed with soap and water. Appropriate precautions should be utilized, such as wearing gloves to prevent the potential cutaneous exposure to THALOMID. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning THALOMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with THALOMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of THALOMID therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing THALOMID therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles or every 2 weeks in females with irregular menstrual cycles [see Use in Specific Populations (8.3) ].

Males

Thalidomide is present in the semen of patients receiving THALOMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking THALOMID and for up to 4 weeks after discontinuing THALOMID, even if they have undergone a successful vasectomy. Male patients taking THALOMID must not donate sperm [see Use in Specific Populations (8.3) ] .

Blood Donation

Patients must not donate blood during treatment with THALOMID 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 THALOMID.

5.2 THALOMID REMS Program Because of the embryo-fetal risk <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>, THALOMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the THALOMID REMS program. Required components of the THALOMID REMS program include the following:

• Prescribers must be certified with the THALOMID REMS program by enrolling and complying with the REMS requirements.
• Patients must sign a Patient-Physician Agreement Form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3) ] and males must comply with contraception requirements [see Use in Specific Populations (8.3) ].
• Pharmacies must be certified with the THALOMID REMS program, must only dispense to patients who are authorized to receive THALOMID and comply with REMS requirements. Further information about the THALOMID REMS program is available at www.thalomidrems.com or by telephone at 1-888-423-5436.

5.3 Venous and Arterial Thromboembolism The use of THALOMID in patients with MM results in an increased risk of venous thromboembolism, such as deep venous thrombosis and pulmonary embolism. This risk increases significantly when THALOMID 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 THALOMID in combination with dexamethasone compared to 4.9% in patients receiving dexamethasone alone (p = 0.002). Ischemic heart disease (11.1%), including myocardial infarction (1.3%), and stroke (cerebrovascular accident, 2.6%) have also occurred in patients with previously untreated MM treated with THALOMID and dexamethasone compared to placebo and dexamethasone (4.7%, 1.7%, and 0.9%, respectively) in one clinical trial <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Consider thromboprophylaxis based on an assessment of individual patients&apos; 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 <span class="opacity-50 text-xs">[see Boxed Warning ]</span> . Agents that also may increase the risk of thromboembolism should be used with caution in patients receiving THALOMID <span class="opacity-50 text-xs">[see Drug Interactions (7.7) ]</span>.

5.4 Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone In two randomized clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

5.5 Drowsiness and Somnolence THALOMID 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span>. 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.

5.6 Peripheral Neuropathy THALOMID is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common (≥10%) and potentially severe adverse reaction of treatment with THALOMID 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 THALOMID 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 THALOMID treatment. However, the inability clinically to differentiate THALOMID neuropathy from the neuropathy often seen in ENL makes it difficult to determine accurately the incidence of THALOMID-related neuropathy in patients with ENL treated with THALOMID. Patients should be examined at monthly intervals for the first 3 months of THALOMID 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, THALOMID should be discontinued immediately to limit further damage, if clinically appropriate. Usually, treatment with THALOMID 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 THALOMID <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span>.

5.7 Dizziness and Orthostatic Hypotension Patients should also be advised that THALOMID 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.

5.8 Neutropenia Decreased white blood cell counts, including neutropenia, have been reported in association with the clinical use of THALOMID. Treatment should not be initiated with an absolute neutrophil count (ANC) of &lt;750/mm 3 . 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/mm 3 while on treatment, the patient&apos;s medication regimen should be re-evaluated and, if the neutropenia persists, consideration should be given to withholding THALOMID if clinically appropriate.

5.9 Thrombocytopenia Thrombocytopenia, including Grade 3 or 4 occurrences, has been reported in association with the clinical use of THALOMID. 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.

5.10 Increased HIV Viral Load In a randomized, placebo-controlled trial of thalidomide in an HIV-seropositive patient population, plasma HIV RNA levels were found to increase (median change = 0.42 log 10 copies HIV RNA/mL, p = 0.04 compared to placebo). A similar trend was observed in a second, unpublished study conducted in patients who were HIV-seropositive. The clinical significance of this increase is unknown. Both studies were conducted prior to availability of highly active antiretroviral therapy. Until the clinical significance of this finding is further understood, in HIV-seropositive patients, viral load should be measured after the first and third months of treatment and every 3 months thereafter.

5.11 Bradycardia Bradycardia in association with THALOMID 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 THALOMID-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 THALOMID <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span>.

5.12 Severe Cutaneous Reactions Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with THALOMID use. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These events can be fatal. THALOMID interruption or discontinuation should be considered for Grade 2-3 skin rash. Discontinue THALOMID for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN, or DRESS, and do not resume therapy <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> .

5.13 Seizures Although not reported from pre-marketing controlled clinical trials, seizures, including grand mal convulsions, have been reported during post-approval use of THALOMID in clinical practice. Because these events are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. Most patients had disorders that may have predisposed them to seizure activity, and it is not currently known whether THALOMID has any epileptogenic influence. During therapy with THALOMID, 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.

5.14 Tumor Lysis Syndrome Monitor patients at risk of tumor lysis syndrome (e.g., patients with high tumor burden prior to treatment) and take appropriate precautions.

5.15 Contraceptive Risks Some contraceptive methods may pose a higher risk of adverse effects or may be medically contraindicated in some patients treated with THALOMID. Because some patients may develop sudden, severe neutropenia and/or thrombocytopenia, use of an intrauterine device (IUD) or implantable contraception in these patients may carry an increased risk for infection or bleeding either at insertion, removal or during use. Treatment with THALOMID, the presence of an underlying malignancy, and/or use of an estrogen-containing contraceptive can each increase the risk of thromboembolism. It is not known if these risks of thromboembolism are additive. However, they should be taken into consideration when choosing contraceptive methods.

5.16 Hypersensitivity Hypersensitivity, including angioedema and anaphylactic reactions to THALOMID has been reported. Signs and symptoms have included the occurrence of erythematous macular rash, possibly associated with fever, tachycardia, and hypotension, and if severe, may necessitate interruption of therapy. If the reaction recurs when dosing is resumed, THALOMID should be discontinued. Do not resume THALOMID treatment after angioedema and anaphylaxis <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> .

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. ( 5.15 , 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 THALOMID 200 mg/day at steady state levels. The single dose of digoxin had no effect on the pharmacokinetic profile of THALOMID. 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 THALOMID 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 THALOMID 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&apos;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 THALOMID.

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 THALOMID with dexamethasone <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span>.