DESCRIPTION
Mechanism of Action
• Mechanism of action is not fully characterized.
• Inhibition of TNF-α synthesis and down-modulation of selected cell
surface adhesion molecules.
• May exert an antiangiogenic effect through inhibition of BFGF and
VEGF as well as through as yet undefined mechanisms.
Mechanism of Resistance
None well characterized to date.
Absorption
Oral bioavailability of thalidomide is not known due to poor aqueous
solubility. Slowly absorbed from the GI tract with peak plasma levels reached
3–6 hours after oral administration.
Distribution
The extent of binding to plasma proteins is not known. Remains unclear
whether thalidomide is present in the ejaculate of males.
Metabolism
Nonenzymatic hydrolysis appears to be the principal mechanism of
thalidomide breakdown. However, the exact metabolic pathway(s) has not
been fully characterized. The precise route of drug excretion is not well
defined.
Indications
1. FDA-approved in combination with dexamethasone for the treatment
of newly diagnosed multiple myeloma.
2. FDA-approved for the treatment of the cutaneous manifestations of
erythema nodosum leprosum (ENL).
3. Thalidomide has activity in MDS and in a broad range of solid tumors.
Dosage Range
No standard dose recommendations for use in cancer patients have been
established. When used in combination with chemotherapy, doses are typically
titrated up to 400 mg PO daily given as a single bedtime dose. As a
single agent, doses have been in the range of 100 mg to 1200 mg daily.
Drug Interaction 1
Barbiturates, chlorpromazine, and reserpine—Sedative effect of thalidomide
is enhanced with concurrent use of these medications.
Drug Interaction 2
Alcohol—Sedative effect of thalidomide is enhanced with concurrent use
of alcohol.
Special Considerations
1. Pregnancy category X. Severe fetal malformations can occur if even
one capsule is taken by a pregnant woman. All women should have a
baseline β-human chorionic gonadotropin before starting therapy
with thalidomide. All women of childbearing potential should practice
two forms of birth control throughout treatment with thalidomide:
one highly effective (intrauterine device, hormonal contraception,
partner’s vasectomy) and one additional barrier method (latex condom,
diaphragm, cervical cap). It is strongly recommended that these
precautionary measures begin 4 weeks before initiation of therapy,
that they continue while on therapy, and continue for at least 4 weeks
after therapy is discontinued.
2. Breastfeeding while on therapy should be avoided given the potential
for serious adverse reactions from thalidomide in nursing
infants. It remains unknown whether thalidomide is excreted in
human milk.
3. Men taking thalidomide must use latex condoms for every sexual
encounter with a woman of childbearing potential, since thalidomide
may be present in semen.
4. Patients with AIDS should have their HIV mRNA levels monitored
after the first and third months after treatment initiation with
T thalidomide, then every 3 months thereafter, as HIV mRNA levels
may be increased while on thalidomide.
5. Instruct patients to avoid operating heavy machinery or driving a car
while on thalidomide, as the drug can cause drowsiness.
6. Patients who develop a skin rash during therapy with thalidomide
should have prompt medical evaluation. Serious skin reactions,
including Stevens-Johnson syndrome, which may be fatal, have been
reported.
7. There is an increased risk of thromboembolic complications, including
DVT and PE, and prophylaxis with low-molecular weight heparin,
warfarin, or aspirin can help to prevent and/or reduce the
incidence.
Toxicity 1
Teratogenic effect is most serious toxicity. Severe birth defects or death to
an unborn fetus. Manifested as absent or defective limbs, hypoplasia or
absence of bones, facial palsy, absent or small ears, absent or shrunken eyes,
congenital heart defects, and GI and renal abnormalities.
Toxicity 2
General neurologic-related events that occur frequently include fatigue,
orthostatic hypotension, and dizziness. Specific peripheral neuropathy in the
form of numbness, tingling, and pain in the feet or hands does not appear
to be dose- or duration-related. Prior exposure to neurotoxic agents increases
the risk of occurrence.
Toxicity 3
Constipation is most common GI toxicity.
Toxicity 4
No known direct myelosuppressive effects. Certain patient populations
(ENL and HIV) have reported a higher incidence of abnormalities in blood
counts.
Toxicity 5
Skin toxicity in the form of maculopapular skin rash, urticaria, and dry
skin. Serious dermatologic reactions, including Stevens-Johnson syndrome,
have been reported. Patients who develop a skin rash during therapy
with thalidomide should discontinue therapy. Therapy can be restarted
with caution if the rash was not exfoliative, purpuric, or bullous, or otherwise
suggestive of a serious skin condition.
Toxicity 6
Daytime sedation or fatigue following an evening dose often associated
with larger initial doses. Doses can be reduced until the patient accommodates
to the effect.
Toxicity 7
Increased risk of thromboembolic complications, including DVT and PE.
SPECIFICATION
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