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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Thalidomide may be confused with flutamide, lenalidomide
Thalomid® may be confused with thiamine
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
International issues:
Thalomid® may be confused with Thilomide® which is a brand name for lodoxamide in Greece and Turkey
Pronunciation
(tha LI doe mide)
U.S. Brand Names
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of multiple myeloma; treatment and maintenance of cutaneous manifestations of erythema nodosum leprosum (ENL)
Use: Unlabeled/Investigational
Treatment of Crohn's disease; graft-versus-host reactions after bone marrow transplantation; AIDS-related aphthous stomatitis; Behçet's syndrome; Waldenström's macroglobulinemia; Langerhans cell histiocytosis
Restrictions
Thalidomide is approved for marketing only under a special distribution program. This program, called the "System for Thalidomide Education and Prescribing Safety" (STEPS® 1-888-423-5436), has been approved by the FDA. Prescribers and pharmacists must be registered with the program. No more than a 4-week supply should be dispensed. Blister packs should be dispensed intact (do not repackage capsules). Prescriptions must be filled within 7 days. Subsequent prescriptions may be filled only if fewer than 7 days of therapy remain on the previous prescription. A new prescription is required for further dispensing (a telephone prescription may not be accepted.)
Pregnancy Risk Factor
X
Pregnancy Considerations
[U.S. Boxed Warning]: Thalidomide is a known teratogen; effective contraception must be used for at least 4 weeks before initiating therapy, during therapy, and for 4 weeks following discontinuation of thalidomide for women of childbearing potential. Embryotoxic with limb defects noted from the 27th to 40th gestational day of exposure; all cases of phocomelia occur from the 27th to 42nd gestational day; fetal cardiac, gastrointestinal, bone, external ear, eye, and genitourinary tract abnormalities have also been described. Mortality at or shortly after birth has also been reported. Either abstinence or two forms of effective contraception must be used for at least 4 weeks before initiating therapy, during therapy, and for 4 weeks following discontinuation of thalidomide. A negative pregnancy test (sensitivity of at least 50 mIU/mL) within 24 hours prior to beginning therapy, weekly during the first 4 weeks, and every 4 weeks (every 2 weeks for women with irregular menstrual cycles) thereafter is required for women of childbearing potential. Males (even those vasectomized) must use a latex condom during any sexual contact with women of childbearing age. Risk to the fetus from semen of male patients is unknown. Thalidomide must be immediately discontinued and the patient referred to a reproductive toxicity specialist if pregnancy occurs during treatment. Any suspected fetal exposure to thalidomide must be reported to the FDA via the MedWatch program (1-800-FDA-1088) and to Celgene Corporation (1-888-423-5436).
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Due to the potential for serious adverse reactions in the infant, a decision should be made to discontinue nursing or discontinue treatment with thalidomide.
Contraindications
Hypersensitivity to thalidomide or any component of the formulation; neuropathy (peripheral); patient unable to comply with STEPS® program (including males); women of childbearing potential unless alternative therapies are inappropriate and adequate precautions are taken to avoid pregnancy; pregnancy
Warnings/Precautions
Boxed warnings:
• Pregnancy: See “Special populations” below.
• Thromboembolic events: See “Concerns related to adverse effects” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Bradycardia: May cause bradycardia; use with caution in patients with cardiovascular disease.
• Hypersensitivity/skin reactions: Hypersensitivity, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported; withhold therapy and evaluate with skin rashes; permanently discontinue if rash is exfoliative, purpuric, bullous or if SJS or TEN is suspected.
• Neutropenia: May cause neutropenia; discontinue therapy if absolute neutrophil count decreases to <750/mm3.
• Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients who would not tolerate transient hypotensive episodes.
• Peripheral neuropathy: Use has been associated with the development of peripheral neuropathy, which may be irreversible; use caution with other medications which may cause peripheral neuropathy. Consider immediate discontinuation (if clinically appropriate) in patients who develop neuropathy.
• Sedation: May cause sedation; patients must be warned to use caution when performing tasks which require alertness.
• Seizures: May cause seizures; use caution in patients with a history of seizures, concurrent therapy with drugs which alter seizure threshold, or conditions which predispose to seizures.
• Thromboembolic events: [U.S. Boxed Warning]: Thrombotic events have been reported, generally in patients with other risk factors for thrombosis (neoplastic disease, inflammatory disease, or concurrent therapy with combination chemotherapy). Use in combination with dexamethasone is associated with increased risk for deep vein thrombosis (DVT) and pulmonary embolism (PE). Monitor for signs and symptoms of thromboembolism; patients at risk may benefit from prophylactic anticoagulation or aspirin.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with cardiovascular disease.
• Constipation: Use with caution in patients with constipation.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Neurological disorders: Use with caution in patients with neurological disorders, including seizure disorder.
• Renal impairment: Use with caution in patients with renal impairment.
Concurrent drug therapy issues:
• Contraceptives: Use with caution with drugs which may decrease the efficacy of hormonal contraceptives.
Special populations:
• HIV infected patients: Use with caution in patients with HIV infection; has been associated with increased viral loads.
• Pediatrics: Safety and efficacy have not been established in children <12 years of age.
• Pregnancy: [U.S. Boxed Warning]: Thalidomide is a known teratogen; effective contraception must be used for at least 4 weeks before initiating therapy, during therapy, and for 4 weeks following discontinuation of thalidomide for women of childbearing potential.
Adverse Reactions
>10%:
Cardiovascular: Edema (57%), thrombosis/embolism (23%; grade 3: 13%, grade 4: 9%), hypotension (16%)
Central nervous system: Fatigue (79%; grade 3: 3%, grade 4: 1%), somnolence (36% to 38%), dizziness (4% to 20%), sensory neuropathy (54%), confusion (28%), anxiety/agitation (9% to 26%), fever (19% to 23%), motor neuropathy (22%), headache (13% to 19%)
Dermatologic: Rash (21% to 31%), rash/desquamation (30%; grade 3: 4%), dry skin (21%), maculopapular rash (4% to 19%), acne (3% to 11%)
Endocrine & metabolic: Hypocalcemia (72%)
Gastrointestinal: Constipation (3% to 55%), anorexia (3% to 28%), nausea (4% to 24%), weight loss (23%), weight gain (22%), diarrhea (4% to 19%), oral moniliasis (4% to 11%)
Hematologic: Leukopenia (17% to 35%), neutropenia (31%), anemia (6% to 13%), lymphadenopathy (6% to 13%)
Hepatic: AST increased (3% to 25%), bilirubin increased (14%)
Neuromuscular & skeletal: Muscle weakness (40%), tremor (4% to 26%), weakness (6% to 22%), myalgia (17%), paresthesia (6% to 16%), arthralgia (13%)
Renal: Hematuria (11%)
Respiratory: Dyspnea (42%)
Miscellaneous: Diaphoresis (13%)
1% to 10%:
Cardiovascular: Facial edema (4%), peripheral edema (3% to 8%)
Central nervous system: Insomnia (9%), nervousness (3% to 9%), malaise (8%), vertigo (8%), pain (3% to 8%)
Dermatologic: Dermatitis (fungal 4% to 9%), pruritus (3% to 8%), nail disorder (3% to 4%)
Endocrine & metabolic: Hyperlipemia (6% to 9%)
Gastrointestinal: Xerostomia (8% to 9%), flatulence (8%), tooth pain (4%)
Genitourinary: Impotence (3% to 8%)
Hepatic: LFTs abnormal (9%)
Neuromuscular & skeletal: Neuropathy (8%), back pain (4% to 6%), neck pain (4%), neck rigidity (4%)
Renal: Albuminuria (3% to 8%)
Respiratory: Pharyngitis (4% to 8%), rhinitis (4%), sinusitis (4% to 8%)
Miscellaneous: Infection (6% to 8%)
Postmarketing and/or case reports (limited to important or life-threatening): Acute renal failure, alkaline phosphatase increased, ALT increased, amenorrhea, aphthous stomatitis, arrhythmia, atrial fibrillation, bile duct obstruction, bradycardia, BUN increased, carpal tunnel, CML, creatinine clearance decreased, creatinine increased, deafness, depression, diplopia, dysesthesia, ECG abnormalities, electrolyte imbalances, enuresis, eosinophilia, epistaxis, erythema multiforme, erythema nodosum, erythroleukemia, exfoliative dermatitis, febrile neutropenia, foot drop, galactorrhea, granulocytopenia, gynecomastia, hepatomegaly, Hodgkin's disease, hypercalcemia, hyper-/hypokalemia, hypersensitivity, hypertension, hyper-/hypothyroidism, hyperuricemia, hypomagnesemia, hyponatremia, hypoproteinemia, intestinal obstruction, intestinal perforation, interstitial pneumonitis, LDH increased, lethargy, leukocytosis, lymphedema, lymphopenia, mental status changes, metrorrhagia, migraine, myxedema, nystagmus, oliguria, orthostatic hypotension, pancytopenia, paresthesia, petechiae, peripheral neuritis, photosensitivity, pleural effusion, prothrombin time changes, psychosis, pulmonary embolus, pulmonary hypertension, purpura, Raynaud's syndrome, seizure, status epilepticus, Stevens-Johnson syndrome, stomach ulcer, stupor, suicide attempt, syncope, tachycardia, thrombocytopenia, toxic epidermal necrolysis, tumor lysis syndrome
Drug Interactions
Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Canakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased. Risk X: Avoid combination
Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Risk X: Avoid combination
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Olopatadine, Ophthalmic. Risk C: Monitor therapy
Dexamethasone: May enhance the dermatologic adverse effect of Thalidomide. Dexamethasone may enhance the thrombogenic effect of Thalidomide. Risk D: Consider therapy modification
Dexamethasone, Systemic: May enhance the dermatologic adverse effect of Thalidomide. Dexamethasone, Systemic may enhance the thrombogenic effect of Thalidomide. Risk D: Consider therapy modification
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Pamidronate: Thalidomide may enhance the nephrotoxic effect of Pamidronate. Risk C: Monitor therapy
Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live virus vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Zoledronic Acid: Thalidomide may enhance the adverse/toxic effect of Zoledronic Acid. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase sedation).
Herb/Nutraceutical: Avoid cat's claw and echinacea (have immunostimulant properties; consider therapy modifications).
Storage
Store at 15°C to 30°C (50°F to 86°F). Protect from light. Keep in original package.
Mechanism of Action
Has immunomodulatory and antiangiogenic characteristics. Immunologic effects may vary based on conditions; may suppress excessive tumor necrosis factor-alpha production in patients with ENL, yet may increase plasma tumor necrosis factor-alpha levels in HIV-positive patients. In multiple myeloma, thalidomide is associated with an increase in natural killer cells and increased levels of interleukin-2 and interferon gamma. Other proposed mechanisms of action include suppression of angiogenesis, prevention of free-radical-mediated DNA damage, increased cell mediated cytotoxic effects, and altered expression of cellular adhesion molecules.
Pharmacodynamics/Kinetics
Distribution: Vd: 120 L
Protein binding: 55% to 66%
Metabolism: Nonenzymatic hydrolysis in plasma; forms multiple metabolites
Half-life elimination: 5-7 hours
Time to peak, plasma: 3-6 hours
Excretion: Urine (<1% as unchanged drug)
Dosage
Oral:
Multiple myeloma: 200 mg once daily (with dexamethasone 40 mg daily on days 1-4, 9-12, and 17-20 of a 28-day treatment cycle)
Cutaneous ENL:
Initial: 100-300 mg/day taken once daily at bedtime with water (at least 1 hour after evening meal)
Patients weighing <50 kg: Initiate at lower end of the dosing range
Severe cutaneous reaction or patients previously requiring high dose may be initiated at 400 mg/day; doses may be divided, but taken 1 hour after meals
Maintenance: Dosing should continue until active reaction subsides (usually at least 2 weeks), then tapered in 50 mg decrements every 2-4 weeks
Patients who flare during tapering or with a history or requiring prolonged maintenance should be maintained on the minimum dosage necessary to control the reaction. Efforts to taper should be repeated every 3-6 months, in increments of 50 mg every 2-4 weeks.
Behçet's syndrome (unlabeled use): 100-400 mg/day
Graft-vs-host reactions (unlabeled use): 100-1600 mg/day; usual initial dose: 200 mg 4 times/day for use up to 700 days
AIDS-related aphthous stomatitis (unlabeled use): 200 mg twice daily for 5 days, then 200 mg/day for up to 8 weeks
Dosage: Combination Regimens
Multiple myeloma:
Bortezomib-Melphalan-Prednisone-Thalidomide
DTPACE
Melphalan-Prednisone-Thalidomide
Thalidomide-Dexamethasone
Prostate cancer: Docetaxel-Thalidomide
Administration: Oral
Administer with water, preferably at bedtime once daily on an empty stomach, at least 1 hour after the evening meal. Doses >400 mg/day may be given in 2-3 divided doses. Avoid extensive handling of capsules; capsules should remain in blister pack until ingestion. If exposed to the powder content from broken capsules or body fluids from patients receiving thalidomide, the exposed area should be washed with soap and water.
Monitoring Parameters
CBC with differential, platelets; signs of neuropathy monthly for the first 3 months, then periodically during treatment; consider monitoring of sensory nerve application potential amplitudes (at baseline and every 6 months) to detect asymptomatic neuropathy. In HIV-seropositive patients: viral load after 1 and 3 months, then every 3 months. Pregnancy testing (sensitivity of at least 50 mIU/mL) is required within 24 hours prior to initiation of therapy, weekly during the first 4 weeks, then every 4 weeks in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles.
Reference Range
Therapeutic plasma thalidomide levels in graft-vs-host reactions are 5-8 mcg/mL, although it has been suggested that lower plasma levels (0.5-1.5 mcg/mL) may be therapeutic; peak serum thalidomide level after a 200 mg dose: 1.2 mcg/mL
Dietary Considerations
Should be taken at least 1 hour after the evening meal.
Patient Education
You will be given oral and written instructions about the necessity of using two methods of contraception and the necessity of keeping return visits for pregnancy testing. Do not donate blood while taking this medicine. Male patients should not donate sperm. Avoid extensive handling of capsules; capsules should remain in blister pack until ingestion. If exposed to the powder content from broken capsules or body fluids from patients receiving thalidomide, the exposed area should be washed with soap and water. Avoid alcohol. You may experience postural hypotension (use caution when rising from lying or sitting position); sleepiness; dizziness; fatigue; fever; headaches; lack of concentration (use caution when driving, climbing stairs, or engaging in tasks requiring alertness until response to drug is known); nausea or vomiting or loss of appetite (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation or diarrhea; oral thrush (frequent mouth care is necessary); or sexual dysfunction (reversible). Report any of the above if persistent or severe. Report chest pain or palpitations or swelling of extremities; respiratory difficulty; back, neck, muscle pain, muscle weakness, or stiffness; numbness or pain in extremities; significant weight loss or gain; skin rash or eruptions; increased nervousness, anxiety, confusion, or insomnia; or any other symptom of adverse reactions. Pregnancy/breast-feeding precautions: Do not get pregnant (females) or cause pregnancy (males) during treatment. The use of two forms of contraception are required for 1 month prior to therapy, during therapy, and for 1 month following discontinuation of therapy. Pregnancy tests will be routinely conducted during therapy. Consult prescriber if you suspect you might be pregnant. This drug should not be used in the 2nd or 3rd trimester of pregnancy. Do not breast-feed while taking this medication or for 1 month following discontinuation.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Oral moniliasis (HIV-seropositive patients), toothache, xerostomia (normal salivary flow resumes upon discontinuation), and aphthous stomatitis.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Sedation is common; may cause dizziness, nervousness, insomnia, agitation, abnormal thinking, amnesia, anxiety, confusion, depression, euphoria, and psychosis
Mental Health: Effects on Psychiatric Treatment
May cause leukopenia; use caution with clozapine and carbamazepine; concurrent use with other psychotropics may produce additive sedation
Nursing: Physical Assessment/Monitoring
Patient must be capable of complying with STEPS® program. Instruct patient on risks of pregnancy, appropriate contraceptive measures, and necessity for frequent pregnancy testing (schedule pregnancy testing at time of dispensing and give patient schedule in writing). Assess other medications patient may be taking for possible interactions. Monitor for signs of fluid retention, weight gain, and blood pressure. Monitor closely for signs of neuropathy, neutropenia, and CNS depression. Instruct patient on signs and symptoms to report, and appropriate interventions for adverse reactions.
Pregnancy risk factor X: Pregnancy test is required within 24 hours prior to beginning therapy, weekly during first month of therapy, and monthly thereafter for all women of childbearing age. Effective contraception with at least two reliable forms of contraception must be used for 1 month prior to beginning therapy, during therapy, and for 1 month following discontinuance of therapy. Women who have undergone a hysterectomy or have been postmenopausal for at least 24 consecutive months are the only exception. Do not prescribe, administer, or dispense to women of childbearing age or males who may have intercourse with women of childbearing age unless both female and male are capable of complying with contraceptive measures. Even males who have undergone vasectomy must acknowledge these risks in writing, and must use a latex condom during any sexual contact with women of childbearing age. Oral and written warnings concerning contraception and the hazards of thalidomide must be conveyed to females and males and they must acknowledge their understanding in writing. Parents or guardians must consent and sign acknowledgment for patients between 12 and 18 years of age following therapy. Breast-feeding is contraindicated.
Oncology: Emetic Potential
Very low (<10%)
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule:
Thalomid®: 50 mg, 100 mg, 150 mg, 200 mg
References
Antonioli E, Nozzoli C, Gianfaldoni G, et al, “Pulmonary Hypertension Related to Thalidomide Therapy in Refractory Multiple Myeloma,” Ann Oncol, 2005, 16(11):1849-50.
Bessmertny O and Pham T, "Thalidomide Use in Pediatric Patients," Ann Pharmacother, 2002, 36(3):521-5.
Diggle GE, "Thalidomide: 40 years On," Int J Clin Pract, 2001, 55(9):627-31.
Eriksson T, Bjorkman S, and Hoglund P, "Clinical Pharmacology of Thalidomide," Eur J Clin Pharmacol, 2001, 57(5):365-76.
Franks ME, Macpherson GR, and Figg WD, "Thalidomide," Lancet, 2004, 363(9423):1802-11.
Hamuryudan V, Mat C, Saip S, et al, “Thalidomide in the Treatment of the Mucocutaneous Lesions of the Behçet Syndrome. A Randomized, Double-Blind, Placebo-Controlled Trial,” Ann Intern Med, 1998, 128(6):443-50.
Jacobson JM, Greenspan JS, Spritzler J, et al, “Thalidomide for the Treatment of Oral Aphthous Ulcers in Patients With Human Immunodeficiency Virus Infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group,” N Engl J Med, 1997, 336(21):1487-93.
Kyle RA and Rajkumar SV, “Multiple Myeloma,” N Engl J Med, 2004, 351(18): 1860-73.
Onozawa M, Hashino S, Sogabe S, et al, “Side Effects and Good Effects from New Chemotherapeutic Agents. Case 2. Thalidomide-Induced Interstitial Pneumonitis,” J Clin Oncol, 2005, 23(10):2425-6.
Rajkumar SV, Blood E, Vesole D, et al, “Phase III Clinical Trial of Thalidomide Plus Dexamethasone Compared With Dexamethasone Alone in Newly Diagnosed Multiple Myeloma: A Clinical Trial Coordinated by the Eastern Cooperative Oncology Group,” J Clin Oncol, 2006, 24(3):431-6.
Teo SK, Colburn WA, Tracewell WG, et al, "Clinical Pharmacokinetics of Thalidomide," Clin Pharmacokinet, 2004, 43(5):311-27.
Uhl K, Cox E, Rogan R, et al, “Thalidomide Use in the US: Experience With Pregnancy Testing in the S.T.E.P.S.® Programme,” Drug Saf, 2006, 29(4):231-9.
International Brand Names
Lexi-Comp.com
Last full review/revision January 2010
Content last modified January 2010
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