The most serious toxicity associated with thalidomide is its documented human teratogenicity. (See BOXED WARNINGS and CONTRAINDICATIONS.) 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 condom during any sexual contact with women of childbearing potential.

Thalidomide is associated with drowsiness/somnolence, peripheral neuropathy, dizziness/orthostatic hypotension, neutro-penia, and HIV viral load increase. (See WARNINGS)

Hypersensitivity to THALOMID® (thalidomide) and bradycardia in patients treated with thalidomide have been reported. (See PRECAUTIONS)

Somnolence, dizziness, and rash are the most commonly observed adverse events associated with the use of thalidomide. Thalidomide has been studied in controlled and uncontrolled clinical trials in patients with multiple myeloma and ENL and in people who are HIV-seropositive. In addition, thalidomide has been administered investigationally for more than 20 years in numerous indications. Adverse event profiles from these uses are summarized in the sections that follow.

Other Adverse Events

Due to the nature of the longitudinal data that form the basis of this product's safety evaluation, no determination has been made of the causal relationship between the reported adverse events listed below and thalidomide. These lists are of various adverse events noted by investigators in patients to whom they had administered thalidomide under various conditions. The use of thalidomide may not limit disease progression and/or death.

Adverse Events in Multiple Myeloma Controlled Clinical Trial

The safety analysis was conducted on 204 patients who received study drug in the randomized trial. Table 6 lists the most common treatment-emergent signs and symptoms (occurring at ≥ 10%) that were observed. The most frequently reported adverse events were constipation, sensory neuropathy, confusion, hypocalcemia, edema, dyspnea, thrombosis/ embolism, and rash/desquamation (occurring in ≥ 20% of patients and with a frequency of ≥ 10% in patients treated with THALOMID® (thalidomide)/dexamethasone compared with dexamethasone alone).

Twenty-three percent of patients (47/204) discontinued due to adverse events; thirty percent (31/102) from the THALOMID® (thalidomide)/dexamethasone arm and sixteen percent (16/102) from the dexamethasone alone arm.

Table 6: Treatment-Emergent Adverse Events in ≥ 10% of All Patients Adverse Event (Safety Population; N=204)

Incidence in ENL Controlled Clinical Trials

Table 7 lists treatment-emergent signs and symptoms that occurred in THALOMID® (thalidomide)-treated patients in controlled clinical trials in ENL. Doses ranged from 50 to 300 mg/day. All adverse events were mild to moderate in severity, and none resulted in discontinuation. Table 7 also lists treatment-emergent adverse events that occurred in at least three of the THALOMID® (thalidomide)-treated HIV-seropositive patients who participated in an 8-week, placebo-controlled clinical trial. Events that were more frequent in the placebo-treated group are not included. (See WARNINGS, PRECAUTIONS, and DRUG INTERACTIONS)

Table 7: Summary of Adverse Events (AEs) Reported in Celgene-sponsored Controlled Clinical Trials

Other Adverse Events Observed in ENL Patients

Thalidomide 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. As mentioned previously, no causal relationship between thalidomide 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 thick-ening, 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® (thalidomide) 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® (thalidomide) 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.

Other Adverse Events Observed in Post-Marketing Use

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

Digestive System: Intestinal perforation.

Metabolic and Endocrine: Electrolyte imbalance including hypercalcemia or hypocalcemia, hyperkalemia and hypo-kalemia, hyponatremia, hypothyroidism, and 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 epilepicus.

Skin and Appendages: Erythema multiforme.

Hemic and Lymphatic: Decreased white blood cell counts including neutropenia and febrile neutropenia, changes in pro-thrombin time.

Respiratory System: Pleural effusion.

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 myelog-enous 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, and suicide attempt.

Drug Abuse And Dependence

Physical and psychological dependence has not been reported in patients taking thalidomide. However, as with other tranquilizers/hypnotics, thalidomide too has been reported to create in patients habituation to its soporific effects.

Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine.

Peripheral Neuropathy

Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide.

Oral Contraceptives

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

Important Non-Thalidomide Drug Interactions

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 and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide.

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