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THALOMID SIDE EFFECTS

  • Generic Name: thalidomide
  • Brand Name: Thalomid
  • Drug Class: Antineoplastics, Angiogenesis Inhibitor
Last updated on MDtodate: 10/12/2022

SIDE EFFECTS

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

  • Teratogenicity
  • Venous and Arterial Thromboembolism
  • Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone
  • Drowsiness and Somnolence
  • Peripheral Neuropathy
  • Dizziness and Orthostatic Hypotension
  • Neutropenia
  • Thrombocytopenia
  • Increased HIV Viral Load
  • Bradycardia
  • Severe Cutaneous Reactions
  • Seizures
  • Tumor Lysis Syndrome
  • Hypersensitivity

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 (%)
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)
* 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.

 

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 (%)
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)
NOS = not otherwise specified.
* 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.

 

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 (%)
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)
NOS = not otherwise specified.
* 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.

 

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 reported1:

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

1All 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 Celgene-sponsored 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.

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. 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 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.

 

SRC: NLM .

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