SIDE EFFECTS

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

• Teratogenicity [see BOXED WARNING, WARNINGS AND PRECAUTIONS, and PATIENT INFORMATION]
• Venous Thromboembolism [see BOXED WARNING, WARNINGS AND PRECAUTIONS, and PATIENT INFORMATION]
• Drowsiness and Somnolence [see WARNINGS AND PRECAUTIONS]
• Peripheral Neuropathy [see WARNINGS AND PRECAUTIONS]
• Dizziness and Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS]
• Neutropenia [see WARNINGS AND PRECAUTIONS]
• Increased HIV Viral Load [see WARNINGS AND PRECAUTIONS]
• Bradycardia [see WARNINGS AND PRECAUTIONS]
• Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity [see WARNINGS AND PRECAUTIONS]

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.

Clinical Trials Experience

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

Teratogenicity

The most serious toxicity associated with thalidomide is its documented human teratogenicity. The risk of severe birth defects, primarily phocomelia or death to the fetus, is extremely high during the critical period of pregnancy. The critical period is estimated, depending on the source of information, to range from 35 to 50 days after the last menstrual period. The risk of other potentially severe birth defects outside this critical period is unknown, but may be significant. Based on present knowledge, thalidomide must not be used at any time during pregnancy.

Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex or synthetic condom during any sexual contact with females of reproductive potential, even if he has undergone a successful vasectomy.

Venous thromboembolism

An increased risk of venous thromboembolism (such as deep vein thrombosis and pulmonary embolism) has been reported in patients with multiple myeloma treated with thalidomide.

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)

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)

Table 3: Grade 3/4 Adverse Drug Reactions Reported in > 2% of Patients in the THALOMID/Dexamethasone Arm (Study 2 - Safety Population; N=466)

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

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.

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.

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

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.

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.

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

Metabolic and Endocrine: Avitaminosis, bilirubinemia, dehydration, hypercholesteremia, 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 adverse reactions have been identified during post approval use of THALOMID. 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.

Cardiovascular System: Cardiac arrhythmias including atrial fibrillation, bradycardia, tachycardia, sick sinus syndrome, EKG abnormalities, myocardial infarction.

Digestive System: Intestinal perforation, gastrointestinal perforations, intestinal obstruction.

Metabolic and Endocrine: Electrolyte imbalance including hypercalcemia or hypocalcemia, hyperkalemia and hypokalemia, hyponatremia, hypothyroidism, increased alkaline phosphatase, tumor lysis syndrome.

Nervous System: Changes in mental status or mood including depression and suicide attempts, disturbances in consciousness including lethargy, syncope, loss of consciousness or stupor, seizures including grand mal convulsions and status epilepticus, , Parkinson's disease.

Skin and Appendages: Erythema multiforme, toxic epidermal necrolysis. Hemic and Lymphatic: Decreased white blood cell counts including neutropenia and febrile neutropenia, changes in prothrombin time, pancytopenia.

Respiratory System: Pleural effusion.

Reproductive System and Breast Disorders: amenorrhea, sexual dysfunction.

Immune System Disorders: Hypersensitivity, angioedema/urticaria.

Ear and Labyrinthine Disorders: Hearing impairment/deafness.

Renal and Urinary Disorders: Renal failure.

Other Adverse Events in the Published Literature or Reported from Other Sources

The following additional events have been identified either in the published literature or from spontaneous reports from other sources: acute renal failure, amenorrhea, aphthous stomatitis, bile duct obstruction, carpal tunnel, chronic myelogenous leukemia, diplopia, dysesthesia, dyspnea, enuresis, erythema nodosum, erythroleukemia, foot drop, galactorrhea, gynecomastia, hangover effect, hypomagnesemia, hypothyroidism, lymphedema, lymphopenia, metrorrhagia, migraine, myxedema, nodular sclerosing Hodgkin's disease, nystagmus, oliguria, pancytopenia, petechiae, purpura, Raynaud's syndrome, stomach ulcer, suicide attempt, interstitial lung disease and severe infections (e.g., fatal sepsis including septic shock).

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