Thalidomide

Pronunciation

(tha LI doe mide)

U.S. Brand Names

Thalomid®

Generic Available

Canadian Brand Names

Thalomid®

Use

Treatment and maintenance of cutaneous manifestations of erythema nodosum leprosum

Use - Unlabeled/Investigational

Treatment of Crohn's disease; treatment or prevention of graft-versus-host reactions after bone marrow transplantation; AIDS-related aphthous stomatitis; Behçet's syndrome; Waldenström's macroglobulinemia; Langerhans cell histiocytosis; may be effective in rheumatoid arthritis, discoid lupus erythematosus, and erythema multiforme

Restrictions

Thalidomide is approved for marketing only under a special distribution program. This program, called the "System for Thalidomide Education and Prescribing Safety" (STEPS™), has been approved by the FDA. Prescribing and dispensing of thalidomide is restricted to prescribers and pharmacists registered with the program. Prior to dispensing, an authorization number must be obtained (1-888-423-5436) from Celgene (write authorization number on prescription). 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.

Pregnancy Risk Factor

Pregnancy Implications

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, and genitourinary tract abnormalities have also been described. Effective contraception must be used for at least 4 weeks before initiating therapy, during therapy, and for 4 weeks following discontinuation of thalidomide. 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.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to thalidomide or any component of the formulation; neuropathy (peripheral); pregnancy or women in childbearing years unless alternative therapies are inappropriate and adequate precautions are taken to avoid pregnancy; patient unable to comply with STEPS™ program.

Warnings/Precautions

Effective contraception must be used for at least 4 weeks before initiating therapy, during therapy, and for 4 weeks following discontinuation of thalidomide. Males (even those vasectomized) must use a latex condom during any sexual contact with women of childbearing age. May cause sedation; patients must be warned to use caution when performing tasks which require alertness. Use caution in patients with renal or hepatic impairment, neurological disorders, cardiovascular disease, or constipation.

Thalidomide has been associated with the development of peripheral neuropathy, which may be irreversible. Consider immediate discontinuation (if clinically appropriate) in patients who develop neuropathy. Use caution in patients with a history of seizures, concurrent therapy with drugs which alter seizure threshold, or conditions which predispose to seizures. May cause neutropenia; discontinue therapy if absolute neutrophil count decreases to <750/mm³ . Use caution in patients with HIV infection; has been associated with increased viral loads.

May cause orthostasis and/or bradycardia; use with caution in patients with cardiovascular disease or in patients who would not tolerate transient hypotensive episodes. Thrombotic events have been reported in patients receiving thalidomide, generally in patients with other risk factors for thrombosis (neoplastic disease, inflammatory disease, or concurrent therapy with other drugs which may cause thrombosis). Safety and efficacy have not been established in children <12 years of age.

Adverse Reactions

Controlled clinical trials: ENL:

>10%:

Central nervous system: Somnolence (37.5%), headache (12.5%)

Dermatologic: Rash (20.8%)

1% to 10%:

Cardiovascular: Peripheral edema

Central nervous system: Dizziness (4.2%), vertigo (8.3%), chills, malaise (8.3%)

Dermatologic: Dermatitis (fungal) (4.2%), nail disorder (4.2%), pruritus (8.3%), rash (maculopapular) (4.2%)

Gastrointestinal (4.2%): Constipation, diarrhea, nausea, moniliasis, tooth pain, abdominal pain

Genitourinary: Impotence (8.2%)

Neuromuscular & skeletal: Asthenia (8.3%), pain (8.3%), back pain (4.2%), neck pain (4.2%), neck rigidity (4.2%), tremor (4.2%)

Respiratory (4.2%): Pharyngitis, rhinitis, sinusitis

HIV-seropositive:

General: An increased viral load has been noted in patients treated with thalidomide. This is of uncertain clinical significance - see Monitoring Parameters

>10%:

Central nervous system: Somnolence (36% to 37%), dizziness (18.7% to 19.4%), fever (19.4% to 21.9%), headache (16.7% to 18.7%)

Dermatologic: Rash (25%), maculopapular rash (16.7% to 18.7%), acne (3.1% to 11.1%)

Gastrointestinal: AST increase (2.8% to 12.5%), diarrhea (11.1% to 18.7%), nausea ( 12.5%), oral moniliasis (6.3% to 11.1%)

Hematologic: Leukopenia (16.7% to 25%), anemia (5.6% to 12.5%)

Neuromuscular & skeletal: Paresthesia (5.6% to 15.6%), weakness (5.6% to 21.9%)

Miscellaneous: Diaphoresis ( 12.5%), lymphadenopathy (5.6% to 12.5%)

1% to 10%:

Cardiovascular: Peripheral edema (3.1% to 8.3%)

Central nervous system: Nervousness (2.8% to 9.4%), insomnia ( 9.4%), agitation ( 9.4%), chills ( 9.4%), neuropathy (up to 8% in HIV-seropositive patients)

Dermatologic: Dermatitis (fungal) (5.6% to 9.4%), nail disorder ( 3.1%), pruritus (2.8% to 6.3%)

Gastrointestinal: Anorexia (2.8% to 9.4%), constipation (2.8% to 9.4%), dry mouth (8.3% to 9.4%), flatulence (8.3% to 9.4%), multiple abnormalities LFTs ( 9.4%), abdominal pain (2.8% to 3.1%)

Neuromuscular & skeletal: Back pain ( 5%), pain ( 3.1%)

Respiratory: Pharyngitis (6.3% to 8.3%), sinusitis (3.1% to 8.3%)

Miscellaneous: Accidental injury ( 5.6%), infection (6.3% to 8.3%)

Postmarketing and/or case reports (limited to important or life-threatening): Acute renal failure, arrhythmia, bradycardia, CML, dyspnea, electrolyte imbalances, erythema multiforme, erythema nodosum, Hodgkin's disease, hypersensitivity, hyperthyroidism, intestinal perforation, lethargy, lymphopenia, mental status changes, myxedema, neutropenia, orthostatic hypotension, pancytopenia, paresthesia, peripheral neuritis, photosensitivity, pleural effusion, psychosis, Raynaud's syndrome, seizure, Stevens-Johnson syndrome, suicide attempt, syncope, thrombosis, toxic epidermal necrolysis, tumor lysis syndrome

Drug Interactions

Anakinra: Thalidomide may be associated with increased risk of serious infection when used in combination with anakinra.

CNS depressants: Thalidomide may enhance the sedative activity of other drugs such as ethanol, barbiturates, reserpine, and chlorpromazine

Drugs which may cause peripheral neuropathy: Use with caution in patients receiving thalidomide.

Drugs which may decrease the efficacy of hormonal contraceptives: Women using any drug which may decrease the serum concentrations and/or efficacy of hormonal contraceptives must use 2 other methods of contraception or abstain from heterosexual contact.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase sedation).

Herb/Nutraceutical: Avoid cat's claw (has immunostimulant properties).

Stability

Store at 15°C to 30°C (50°F to 86°F). Protect from light. Keep in original package.

Mechanism of Action

A derivative of glutethimide; mode of action for immunosuppression is unclear; inhibition of neutrophil chemotaxis and decreased monocyte phagocytosis may occur; may cause 50% to 80% reduction of tumor necrosis factor - alpha

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: 2-6 hours

Excretion: Urine (<1%)

Dosage

Oral:

Cutaneous ENL:

Initiate dosing at 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 previously requiring high dose may be initiated at 400 mg/day; doses may be divided, but taken 1 hour after meals

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

Discoid lupus erythematosus (unlabeled use): 100-400 mg/day; maintenance dose: 25-50 mg

Administration

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

WBC with differential; 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 is required within 24 hours of 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 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. You may experience postural hypotension (use caution when rising from lying or sitting position); sleepiness; dizziness; 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; back, neck, or muscle pain or stiffness; numbness or pain in extremities; skin rash or eruptions; increased nervousness, anxiety, 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. 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

Dosage Forms

Capsule: 50 mg

References

Beckman DA and Brent RL, "Mechanism of Known Environmental Teratogens: Drugs and Chemicals," Clin Perinatol , 1986, 13(3):649-87.

Gunzler V, "Thalidomide in Human Immunodeficiency Virus (HIV) Patients. A Review of Safety Considerations," Drug Saf , 1992, 7(2):116-34.

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.

Levien T, Baker DE, and Ballasiotes AA, "Reviews of Dexrazoxane and Thalidomide," Hosp Pharm , 1996, 31(5):487-8, 493-4, 499-500, 504, 508, 510.

Schuler U and Ehninger G, "Thalidomide: Rationale for Renewed Use in Immunological Disorders," Drug Saf , 1995, 12(6):364-9.

"Thalidomide," Med Lett Drugs Ther , 1998, 40(1038):103-4.

International Brand Names

Thalix® (IN); Thalomid® (CA)

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