Class: Biologic Response Modifiers
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
Brands: Thalomid
- 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
Mortality rate at or shortly after birth in neonates with thalidomide-induced abnormalities about 40%.1 15
- Teratogenicity Precautions
Contraindicated in pregnant women; use in females of childbearing potential only when alternative therapies considered inappropriate.1 22
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.)
Limits access to thalidomide to prescribing clinicians, pharmacies, and patients who are registered in program and mandates compliance with registration, education, and safety requirements.1 9 22
Registered prescribing clinicians must understand risks of teratogenicity if used during pregnancy and must not provide a prescription until a documented negative pregnancy test available.1 9 22
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
In selected patients, anticoagulation or aspirin may be beneficial.1
REMS:
FDA approved a REMS for thalidomide to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of thalidomide and consists of the following: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().
Introduction
Biologic response modifier; has immunomodulatory, anti-inflammatory, antiangiogenic, and sedative and hypnotic activities.1 2 3 4 7 9 53 90 112 220
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
Suggested by some clinicians as drug of choice for treatment of moderate to severe ENL reactions, especially severe, recurrent reactions.10 86 89 111
Maintenance therapy for prevention and suppression of cutaneous manifestations of ENL recurrence.1 9 10
Designated an orphan drug by FDA for treatment and maintenance of reactional lepromatous leprosy.28
Used in conjunction with corticosteroid therapy for acute treatment of ENL reactions complicated by moderate to severe neuritis.9 Should not be used as monotherapy in such patients.1 9 53 54
Undertake therapy for leprosy in consultation with an expert.10 74
Multiple Myeloma
Induction therapy (in combination with dexamethasone) in patients with newly diagnosed multiple myeloma1 9 100 161 162 163 198 199 200 201 242 (designated an orphan drug by FDA for this use).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
Has been used to treat dermatologic, mucocutaneous, and arthritic manifestations of Behcet’s syndrome†.9 49 77 93 104 125 126 128 129 130 131 132 133 134 135 136 137 215 218 219 232 237
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.)
HIV-associated Diarrhea
Has been used for treatment of HIV-associated diarrhea†.9 56 112 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.)
Mycobacterium Infections
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.)
Graft-versus-host Disease
Has been used for treatment of graft-versus-host disease† (GVHD) in bone marrow transplant recipients (designated an orphan drug by FDA for this use).28 75 101 109 151 152 153 155 218 219 232 237
Should not be used for prophylaxis of chronic GVHD.153 189
Also has been used with some success in the treatment of GVHD† in adult peripheral blood stem cell transplant recipients.236 239
Recurrent Aphthous Stomatitis
Has been used for treatment of severe aphthous oral ulcers†.9 138 139 148 149
Crohn’s Disease
Has been used for treatment of refractory Crohn’s disease† (designated an orphan drug by FDA for this use).4 28 53 133 136 157 158 159 202 206
Rheumatic Diseases
Has been used for treatment of refractory ankylosing spondylitis†98 and refractory rheumatoid arthritis†.3 4 53 112 178 179
Sarcoidosis
Has been used for treatment of sarcoidosis†.4 99 237
Thalidomide Dosage and Administration
General
ENL
Administration
Restricted Distribution
Distribution of thalidomide is restricted because of known, severe teratogenic effects.1 9 54 185 186 (See Boxed Warning and see Fetal/Neonatal Morbidity and Mortality under Cautions.)
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
STEPS program ensures appropriately timed and properly documented pregnancy testing and counseling of patients before, during, and following thalidomide therapy.1 9 17 22
Prior to initiation of therapy, females must certify that they are not pregnant or not of childbearing potential (i.e., hysterectomy, postmenopausal [no menses for ≥24 consecutive months]).1 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
Oral Administration
Administer orally with water ≥1 hour after a meal.1
Usually administer as a single daily dose, preferably at bedtime (to minimize sedative effects of drug) with water and ≥1 hour after evening meal.1 9
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
Dosage
Pediatric Patients
ENL
Oral
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
Adults
ENL
Oral
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
Multiple Myeloma
Oral
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†
Oral
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
Maintenance therapy to prevent or treat relapse: 50–100 mg daily.9 148 149
Crohn’s Disease†
Oral
50–300 mg daily has been used.157 158 159 202 203 204 205 207 208
Graft-versus-host Disease†
Oral
800 mg to 1.6 g daily for a median duration of 240 days has been used in a clinical trial.153
Prescribing Limits
Pediatric Patients
ENL
Oral
Children ≥12 years of age weighing ≥50 kg: Maximum 400 mg daily.1
Adults
ENL
Oral
Patients weighing ≥50 kg: Maximum 400 mg daily.1
Special Populations
No dosage adjustment required in patients undergoing hemodialysis.1 245
Cautions for Thalidomide
Contraindications
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.)
Warnings/Precautions
Warnings
Fetal/Neonatal Morbidity and Mortality
Extremely high risk of severe birth defects (possibly life-threatening) if pregnancy occurs while receiving thalidomide in any amount.1 2 3 4 5 11 12 15 20 21 52 53 54 (See Boxed Warning.)
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
Thrombotic Events
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 Consider prophylactic anticoagulation or aspirin treatment.1
DVT and pulmonary embolism also reported in patients with ENL.240
Peripheral Neuropathy
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
Correlation with cumulative thalidomide dose unclear.1 4 5 59 60 61 62
Differentiation of neuropathologic symptoms caused by thalidomide and changes caused by underlying disease (i.e., ENL, HIV infection) may be difficult.1 5 6 61 62 89 112
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
Drowsiness and somnolence occur frequently.1 34 35 42 54
Cardiovascular Effects
Possible orthostatic hypotension and dizziness.1 53 54 (See Advice to Patients.)
Hematologic 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
Increases in HIV viral load (i.e., plasma HIV-1 RNA concentrations) reported.1 12 53 54
Measure plasma HIV-1 RNA concentrations in HIV-seropositive patients after first and third months of treatment and every 3 months thereafter.1
Sensitivity Reactions
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
General Precautions
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
Bradycardia, possibly requiring medical intervention, reported; clinical importance and underlying etiology unknown.1
Seizures
Seizures, including tonic-clonic (grand mal) seizures, reported, usually in patients with predisposing risk factors.1 Epileptogenic activity of thalidomide unknown.1
Monitor patients with a history of seizures or other risk factors closely for clinical changes that could precipitate acute seizure activity.1
Specific Populations
Pregnancy
Category X.1 (See Boxed Warnings and see Fetal/Neonatal Morbidity and Mortality under Cautions.)
Lactation
Not known whether thalidomide is distributed into milk.1 Discontinue nursing or the drug.1
Pediatric Use
Safety and efficacy not established in children <12 years of age.1 75
For information on patients 12–18 years of age, see Boxed Warning.1
Geriatric Use
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
Limited hepatic metabolism;1 4 only parent compound appears to be metabolized by CYP-450 isoenzymes.4
Specific Drugs
Drug
|
Interaction
|
Comments
|
|---|
Antineoplastic agents (e.g., cisplatin, paclitaxel, vincristine)
|
Increased risk of neuropathy1 9 185 186
|
Use concomitantly with caution1 9 185 186
|
Antiretroviral agents (e.g., didanosine)
|
Increased risk of neuropathy1 9 185 186
|
Use concomitantly with caution1 9 185 186
|
CNS depressants (e.g., alcohol, barbiturates, chlorpromazine)
|
Potential additive sedative effects 1
|
|
Contraceptives, oral
|
Pharmacokinetic interaction unlikely1 78 79
|
|
Rauwolfia alkaloids (reserpine)
|
Potential additive sedative effects 1
|
|
Thalidomide Pharmacokinetics
Absorption
Bioavailability
Absolute bioavailability not determined; racemic drug has poor aqueous solubility.1 2
Slowly absorbed from GI tract;1 5 51 96 107 mean peak plasma concentrations generally attained 2.5–6 hours after oral dose.1 4 5 51 78 79 107 112 176
Food
Food decreases rate but not does not substantially affect extent of absorption.1
Special Populations
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
Distribution
Extent
Distributes into semen.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Crosses placenta i
