Class: Immunomodulatory Agents
ATC Class: L04AX02
VA Class: IM900
Chemical Name: (±)-2-(2,6-Dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione
Molecular Formula: C13H10N2O4
CAS Number: 50-35-1
- Teratogenic Effects
Known human teratogen; extremely high risk of severe, life-threatening birth defects if administered during pregnancy.1 2 3 4 5 11 12 15 20 21 52 53 54 Single dose (regardless of dosage strength) can cause teratogenic effects.1 2 3 4 5 15 52 1
Major human fetal abnormalities include skeletal deformities (e.g., amelia [absence of legs and/or arms],1 5 15 absence of bones,1 15 phocomelia [short legs and/or arms],1 4 5 15 54 bone hypoplasia);1 15 external ear deformities (e.g., anotia,1 15 microtia or micro pinna,1 15 small or absent auditory canals);1 5 15 facial palsy;1 15 ocular abnormalities2 5 15 (e.g., anophthalmos1 15 and microphthalmos); 1 15 congenital heart defects;1 5 15 21 renal and urinary tract malformations;15 21 genital malformations;1 15 21 and GI tract malformations.5 15
- Teratogenicity Precautions
Pregnancy must be excluded by negative pregnancy test (sensitivity to detect human serum chorionic gonadotropin [HCG] concentrations of 50 million IU/mL) ≤24 hours before treatment initiation.1 9 22 Repeat pregnancy tests throughout therapy (i.e., once weekly during first month, then monthly or every 2 weeks in women with regular or irregular menstrual cycles, respectively).1 9 22
Pregnancy must be prevented (even in females with a history of infertility) by simultaneous use of 2 forms of reliable contraception for ≥4 weeks prior to, throughout, and for 4 weeks after completion of therapy.1 9 22 (See Fetal/Neonatal Morbidity and Mortality under Cautions.) Mandatory contraception not required for females who have undergone hysterectomy, are postmenopausal and have had no menses for ≥24 consecutive months, or practice continuous abstinence from heterosexual contact.1 22
Sexually mature males (including successfully vasectomized men) must completely avoid unprotected sexual contact with women of childbearing potential (i.e., use latex condom throughout and for ≥4 weeks after thalidomide therapy) because thalidomide distributes into semen.1
Provide pregnancy tests and counseling if a patient misses her period or has abnormalities in menstrual bleeding.1
If pregnancy occurs, immediately discontinue treatment.1 Refer patient to obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling.1 Report any suspected fetal exposure to FDA MedWatch Program at 1-800-FDA-1088 and to manufacturer at 1-888-423-5436.1
- Restricted Distribution Program
Available only through restricted distribution program, the System for Thalidomide Education and Prescribing Safety (STEPS), designed to help ensure that fetal exposure does not occur.1 9 17 20 22 (See Restricted Distribution under Dosage and Administration.)
Patient or parent/legal guardian (for minors 12–18 years of age) must be capable of understanding and complying with patient registration, education, patient survey, and safety requirements, including mandatory contraceptive measures and pregnancy testing.1 22
Provide oral and written warnings of risk of possible contraceptive failure, hazards of using drug during pregnancy, exposing fetus to drug, and presence of drug in semen.1
Patient or parent/legal guardian must provide written acknowledgment of understanding of these warnings and need for mandatory contraceptive measures.1
- Venous Thromboembolism
Increased risk of venous thromboembolism (e.g., DVT, pulmonary embolism) in patients with multiple myeloma, especially when used in combination with chemotherapy, including dexamethasone.1
Monitor for signs and symptoms of thromboembolism.1
FDA approved a REMS for thalidomide to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of thalidomide and consists of the following: elements to assure safe use and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().
Uses for Thalidomide
Erythema Nodosum Leprosum
Acute treatment of cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL) reactions (lepra type 2 reactions);1 9 10 13 34 35 39 44 76 86 89 111 113 114 218 220 232 233 234 235 237 238 (designated an orphan drug by FDA for this use).28
Designated an orphan drug by FDA for treatment and maintenance of reactional lepromatous leprosy.28
Combination therapy with dexamethasone more effective than dexamethasone monotherapy in achieving partial response (decreased concentrations of monoclonal immunoglobulins [e.g., myeloma or Bence-Jones proteins] in serum or urine) in patients with newly diagnosed multiple myeloma.1 242 243 Effect of combination therapy on survival in such patients not established.1
Other Neoplastic Diseases
Has also been used for treatment of melanoma†,9 175 232 237 ovarian cancer†,9 myelodysplastic syndrome (MDS)†,229 advanced pancreatic cancer†,229 primary brain tumors† (designated an orphan drug by FDA for this use),9 28 29 169 174 175 229 androgen-independent prostate cancer†,9 168 and renal carcinoma†.9 175
Inflammatory and/or Dermatologic Disorders
Has been used for treatment of a variety of severe, refractory (e.g., unresponsive to other appropriate agents [e.g., corticosteroids]),9 93 156 186 inflammatory and/or dermatologic disorders (e.g., erosive lichen planus†,9 104 127 215 219 232 erythema multiforme†,181 182 215 218 219 232 237 lupus erythematosus†,3 4 9 53 59 104 110 121 122 123 124 196 215 218 219 220 229 237 prurigo nodularis†,9 59 60 94 104 117 118 215 219 229 232 actinic prurigo†,104 119 cutaneous Langerhans cell histiocytosis†,4 104 183 184 232 uremic pruritus†,104 180 215 237 237 porphyria cutanea tarda†,195 215 and pyoderma gangrenosum†).4 5 9 53 104 125 126 219 232 237
HIV-associated Aphthous Ulcers
Has been used for treatment of HIV-associated aphthous ulcers†.9 48 112 142 143 144 146 147 221 223 237 However, increases in HIV viral load reported.1 12 53 54 (See Effects on HIV Viral Load under Cautions.)
May be effective in patients with recurrent ulcers refractory to other therapies (e.g., corticosteroids).55 142 143 144 147 221 Recommended as alternative therapy; not a drug of first choice.55 102 186
HIV-associated Wasting Syndrome
Has been used for treatment of HIV-associated wasting syndrome†9 11 41 48 50 112 140 141 224 (designated an orphan drug by FDA for this use).28 However, increases in HIV viral load reported.1 12 53 54 (See Effects on HIV Viral Load under Cautions.)
AIDS-related Kaposi’s Sarcoma
Has been used for treatment of AIDS-related Kaposi’s sarcoma†9 30 48 115 170 227 (designated an orphan drug by FDA for this use).28 However, increases in HIV viral load reported.1 12 53 54 (See Effects on HIV Viral Load under Cautions.)
Has been used as an adjunct to anti-infective agents in treatment of mycobacterial infections†, including Mycobacterium tuberculosis† and M. avium complex† (MAC) infections, in HIV-infected patients.40 42 53 However, increases in HIV viral load reported.1 12 53 54 (See Effects on HIV Viral Load under Cautions.)
Recurrent Aphthous Stomatitis
Thalidomide Dosage and Administration
In patients with moderate to severe neuritis associated with severe ENL reactions receiving concomitant corticosteroid therapy, taper corticosteroid dosage and discontinue when neuritis has subsided.1
A special restricted distribution program, called STEPS, for thalidomide was approved by FDA.1 9 54 185 186 The program requires registration of clinicians, pharmacies, and patients; all must agree to accept specific responsibilities (e.g., mandatory contraceptive measures, pregnancy testing) designed to minimize pregnancy exposures in order to prescribe, dispense, or use thalidomide.1 9 22
To facilitate pregnancy testing and counseling in accordance with STEPS program, prescribe and dispense ≤28-day supply of drug.9 1 Refills require new prescription and another authorization from STEPS program; automatic refills not allowed.1 9 22
Registering pharmacist must agree to inform all staff pharmacists of dispensing procedures for drug.1 9 22 Before dispensing thalidomide, activate authorization number on every prescription by calling Celgene Customer Care Center at 1-888-423-5436 and obtaining a confirmation number; write confirmation number on thalidomide prescription.1 Verify that each prescription was written within ≤7 days.1 9 Dispense blister packs containing drug intact (i.e., drug cannot be repackaged).1
Administer orally with water ≥1 hour after a meal.1
May administer a high daily dosage (e.g., ≤400 mg daily) as a single dose at bedtime or, alternatively, in divided doses with water ≥1 hour after meals.1
Children ≥12 years of age weighing <50 kg: Initially, administer at lower end of dosage range (e.g., 100 mg daily).1
Children ≥12 years of age weighing ≥50 kg: Initially, 100–300 mg once daily.1 For treatment of severe cutaneous reactions or in patients who previously required high dosages to control a reaction, may initiate at ≤400 mg once daily at bedtime or in divided doses.1
Continue therapy until signs and symptoms of active ENL reaction have subsided (usually ≥2 weeks).1 Gradually taper daily dosage in 50-mg decrements every 2–4 weeks until drug withdrawn or recurrence of ENL occurs.1
Maintenance therapy in patients who have recurrence of ENL during tapering and those who have a documented history of recurrences: Institute minimum dosage as required to control ENL reaction.1 Attempt gradual decrease (i.e., 50-mg decrements every 2–4 weeks) and withdrawal every 3–6 months.1
Patients weighing <50 kg: Initially, administer at lower end of dosage range (e.g., 100 mg daily).1
Patients weighing ≥50 kg: Initially, 100–300 mg once daily.1 For treatment of severe cutaneous reactions or in patients who previously required high dosages to control a reaction, may initiate at ≤400 mg once daily at bedtime or in divided doses.1
Continue until signs and symptoms of active ENL reaction have subsided (usually ≥2 weeks).1 Gradually taper daily dosage in 50-mg decrements every 2–4 weeks until drug withdrawn or recurrence of ENL occurs.1
Maintenance therapy in patients who have recurrence of ENL during tapering and those who have a documented history of recurrences: Institute minimum dosage as required to control ENL reaction.1 Attempt gradual decrease (i.e., 50-mg decrements every 2–4 weeks) and withdrawal every 3–6 months.1
Induction therapy: 200 mg once daily combined with dexamethasone 40 mg daily on days 1–4, 9–12, and 17–20 of a 28-day cycle, with cycles repeated at 28-day intervals.1
Reduce dosage or temporarily discontinue if adverse effects such as constipation, oversedation, or peripheral neuropathy occur.1 Once adverse effects subside, reinitiate at lower or previous dosage, based on clinical judgment.1
Recurrent Aphthous Stomatitis†
100–300 mg daily for 1–6 weeks has been used.9 148 149 150 May be necessary to use higher dosages (e.g., 400–600 mg daily).9 148 149 150 Optimal duration of therapy unknown; may relapse following discontinuance of drug.9 148 149
800 mg to 1.6 g daily for a median duration of 240 days has been used in a clinical trial.153
Children ≥12 years of age weighing ≥50 kg: Maximum 400 mg daily.1
Patients weighing ≥50 kg: Maximum 400 mg daily.1
Cautions for Thalidomide
Pregnant women.1 (See Boxed Warning and see Fetal/Neonatal Morbidity and Mortality under Cautions.)
Females of childbearing potential and sexually mature males, unless they comply with all special conditions required by manufacturer and STEPS program.1 22 (See Boxed Warning and see Fetal/Neonatal Morbidity and Mortality under Cautions.)
Known hypersensitivity to thalidomide or any ingredient in formulation.1 (See Sensitivity Reactions under Cautions.)
Fetal/Neonatal Morbidity and Mortality
High risk of severe teratogenicity (e.g., phocomelia, death to the fetus) especially during critical period of pregnancy (i.e., 35–50 days after the last menstrual period); potentially significant risk outside this critical period.1
Contraindicated in female patients who are or who may become pregnant.1
Women of childbearing potential must use 2 forms of effective contraception ≥4 weeks prior to, throughout, and following completion of therapy.1 22 Use a highly effective birth control method (intrauterine device [IUD]; oral, injectable, or implanted hormonal contraceptives; tubal ligation; vasectomized partner) and effective barrier method (latex condom, diaphragm, cervical cap).1 22 If either IUD or hormonal contraceptive use contraindicated, may use another highly effective method or 2 simultaneous effective barrier methods.1
Thalidomide distributes into semen;1 risk to fetus from semen of male patients receiving thalidomide unknown.1 Sexually mature males (including those who have successfully undergone vasectomy) receiving thalidomide must use a latex condom each time they have sexual contact with a woman of childbearing potential during therapy and for 4 weeks following completion of therapy.1
If clinician not available, information about emergency contraception (including information regarding clinicians who provide emergency contraceptive services) can be obtained by calling 1-888-668-2528 or by using other sources (e.g., ).1 24
Increased risk of venous thromboembolism (e.g., DVT, pulmonary embolism) in patients with multiple myeloma, especially when used in combination with chemotherapy, including dexamethasone.1
Monitor for signs and symptoms of thromboembolism (e.g., shortness of breath, chest pain, arm or leg swelling).1
Carefully assess multiple myeloma patients receiving thalidomide for risk factors for thromboembolism; base decisions regarding use of thromboprophylaxis and appropriate thromboprophylaxis regimens (e.g., aspirin, anticoagulant) on patient’s risk.251 252 253 254
International Myeloma Working Group (IMWG) recommends aspirin for thalidomide-treated multiple myeloma patients with ≤1 individual and/or myeloma-related risk factor and a low molecular weight heparin (LMWH) for those with ≥2 such risk factors.253 IMWG also recommends that thromboprophylaxis with an LMWH be considered in patients receiving thalidomide with high-dose dexamethasone, doxorubicin, or multiple antineoplastic agents, independent of additional risk factors.253 IMWG states full-dose warfarin (INR 2–3) is an alternative to LMWHs, but clinical experience is limited.253
ASCO recommends pharmacologic thromboprophylaxis for multiple myeloma patients receiving thalidomide with dexamethasone or antineoplastic agents.254 Those at lower risk for thromboembolism may receive aspirin or an LMWH; those at higher risk should receive an LMWH.254
DVT and pulmonary embolism also reported in patients with ENL.240
Potentially severe and irreversible nerve damage (i.e., polyneuritis or peripheral neuropathy);1 3 4 5 20 41 53 54 57 59 60 61 62 generally reported with chronic use,1 53 60 but has occurred with relatively short-term use1 58 61 62 and after discontinuance of therapy.1
Evaluate patients for signs and symptoms of peripheral neuropathy (e.g., numbness, tingling, pain or a burning sensation in the hands and feet), and counsel and question patients regularly during therapy (i.e., monthly for first 3 months of thalidomide treatment, and periodically thereafter).1 4
Consider using electrophysiologic testing, consisting of sensory nerve action potential (SNAP) amplitude measurement at baseline and every 6 months thereafter to detect asymptomatic neuropathy.1
If manifestations of peripheral neuropathy develop, discontinue therapy immediately (if clinically appropriate) to minimize further damage.1 Usually, resume treatment only if manifestations of neuropathy return to baseline.1
Use concomitantly with drugs known to be associated with peripheral neuropathy with caution.1 (See Specific Drugs under Interactions.)
Other Nervous System Effects
Decreased leukocyte counts, including neutropenia, reported.1 34 53 54 Do not initiate therapy in patients with ANC <750/mm3.1 Routinely monitor leukocyte and differential counts, especially in those prone to neutropenia (e.g., HIV-infected patients).1 If ANC decreases to <750/mm3, reevaluate drug regimen.1 20 If neutropenia persists, consider withholding drug if clinically appropriate.1 20
Effects on HIV Viral Load
Measure plasma HIV-1 RNA concentrations in HIV-seropositive patients after first and third months of treatment and every 3 months thereafter.1
Hypersensitivity reactions (e.g., erythematous macular rash associated with fever, tachycardia, hypotension) reported.1 Discontinue if signs and symptoms of hypersensitivity are severe.1 If therapy resumed and reaction recurs, permanently discontinue.1
Severe, potentially fatal skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, reported.1 197 212 214 217 Discontinue if rash occurs; resume therapy only after appropriate clinical evaluation.1 Do not resume therapy if rash is exfoliative, purpuric, or bullous, or if Stevens-Johnson syndrome or toxic epidermal necrolysis suspected.1
Environmental Exposure of Patients and Health-care Providers
Potential risks of birth defects from environmental exposure through cutaneous absorption or inhalation of drug powder by sexually mature females unknown.1 Birth defects reported only following oral ingestion of thalidomide.1
Do not extensively handle or open drug capsules; maintain storage in blister packs until ingestion.1 If accidental skin contact with opened capsules or drug powder occurs, wash affected area with soap and water.1
Thalidomide present in serum and semen of patients receiving drug.1 When treating patients receiving drug, use precautions (e.g., use of gloves, wash skin exposed to body fluids) to minimize exposure to patient’s body fluids.1
Bradycardia, possibly requiring medical intervention, reported; clinical importance and underlying etiology unknown.1
Monitor patients with a history of seizures or other risk factors closely for clinical changes that could precipitate acute seizure activity.1
Category X.1 (See Boxed Warnings and see Fetal/Neonatal Morbidity and Mortality under Cautions.)
For information on patients 12–18 years of age, see Boxed Warning.1
No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1
Possibility exists of greater sensitivity to the drug in some geriatric individuals.1
Common Adverse Effects
Somnolence, dizziness, rash.1
Interactions for Thalidomide
Antineoplastic agents (e.g., cisplatin, paclitaxel, vincristine)
Antiretroviral agents (e.g., didanosine)
CNS depressants (e.g., alcohol, barbiturates, chlorpromazine)
Potential additive sedative effects 1
Rauwolfia alkaloids (reserpine)
Potential additive sedative effects 1
Food decreases rate but not does not substantially affect extent of absorption.1
Pharmacokinetics similar in HIV-infected patients and in healthy individuals.1
Pharmacokinetics not established in pediatric and adolescent patients (<18 years of age).1
Bioavailability may be greater in patients with leprosy than in healthy individuals.1
Distributes into semen.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Plasma Protein Binding
Averages approximately 5–7 hours in healthy individuals.1
In patients with severe renal impairment, accumulation of drug does not occur.2 6 92 Mean total clearance increased 2.5-fold in patients undergoing hemodialysis.1 245 (See Special Populations under Dosage and Administration.)
25°C (may be exposed to 15–30°C); protect from light.1
Induces down-modulation of selected cell surface adhesion molecules involved in leukocyte migration,1 2 6 14 45 248 resulting in decreased dermal infiltrations of leukocytes (e.g., neutrophils) in ENL lesions.2 14 44
In multiple myeloma patients, inhibits TNF-α expression by bone marrow stromal cells, resulting in inhibition of growth of multiple myeloma cells.248 Enhances T cell activation, releasing cytokines IL-2 and interferon-γ.1 248 These cytokines activate natural killer cells causing lysis of multiple myeloma cells.1 243 248
Impairs angiogenesis in bone marrow by decreasing fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) production.243
Suppresses production of prostaglandins by macrophages.1
Advice to Patients
Importance of warning women of childbearing potential not to take drug if pregnant, breast-feeding, or able to get pregnant (e.g., not using required methods of birth control).1
Necessity of advising women of childbearing potential to avoid pregnancy by using mandatory contraceptive measures, unless she abstains from heterosexual contact.1 9 22 (See Boxed Warning and see Fetal/Neonatal Morbidity and Mortality under Cautions.)
Importance of immediately discontinuing therapy if pregnancy suspected.1
Importance of women of childbearing potential informing clinicians of pregnancy, suspected pregnancy, missed menstrual period, unusual menstrual bleeding, or cessation of using contraceptive measures.1
Importance of informing patient how to obtain information about emergency contraception (including information regarding clinicians who provide emergency contraceptive services) if clinician not available.1 24 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Importance of informing sexually mature male patients (including those who have undergone a vasectomy) of necessity using a latex condom when engaging in sexual contact with a woman of childbearing potential or a pregnant women.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Importance of male patients informing clinician of unprotected heterosexual sexual contact during therapy and first 4 weeks after drug discontinuance.1 Importance of male patients informing clinician of suspected pregnancy of their sexual partner.1
Importance of avoiding extensive handling or opening of drug capsules.1 Importance of maintaining storage of drug capsules in blister packs until ingestion.1 (See Environmental Exposure of Patients and Health-care Providers under Cautions.)
Importance of keeping thalidomide out of reach of children and from women of childbearing potential, unless part of STEPS program.1
Risk of drowsiness and somnolence; importance of avoiding situations where such drowsiness could create a problem.1 Risk of impaired ability to perform tasks that require mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).1 Importance of warning patients not to take any other drugs or alcohol that may cause drowsiness without consulting their clinician.1 (See Specific Drugs under Interactions.)
Importance of immediately reporting initial symptoms (e.g., numbness, tingling, pain or a burning sensation in hands and feet) of peripheral neuropathy to clinician.1
Importance of contacting clinician if symptoms of thromboembolism (e.g., shortness of breath, chest pain, arm or leg swelling) develop.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription or OTC drugs and herbal supplements, as well as concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Because thalidomide is a known human teratogen and can cause severe, life-threatening birth defects if administered during pregnancy, commercially available thalidomide must be obtained through a restricted distribution program, the System for Thalidomide Education and Prescribing Safety (STEPS), designed to help ensure that fetal exposure to the drug does not occur. See Restricted Distribution Program under Dosage and Administration.
AHFS DI Essentials. © Copyright, 2004-2016, Selected Revisions November 1, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
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- Other brands: Thalomid