The history behind the development of the drug, thalidomide is ironic. Used in Europe by pregnant women to treat morning sickness because of its unusual 'safety' after extensive testing,(1) thalidomide was the first medicine discovered to be highly teratogenic.(2,3) In addition, thalidomide's other marketed use was as a sedative, an action originally recognized as one of its primary side effects.(4,5)
Thalidomide was first marketed in Germany under the trade name "Contergan" in 1956,(6) then in England in 1958 under the name of "Distaval". It soon became the third largest selling drug in Europe and was sold in 48 countries.(3,6) By 1962, thalidomide was shown to be responsible for at least 8000 birth defects in 46 countries.(7) Prior to this discovery the FDA did not approve its use in the U.S. because of the potentially irreversible peripheral neuropathy.(8) Nevertheless, it was manufactured in Canada and distributed and used illegally as a sleep-inducing agent in the U.S. under the name of "Kevadon".(9)
In response to the public health disaster surrounding thalidomide, Congress enacted legislation that required drugs to be evaluated by the FDA for approval in order to be legally prescribed in the U.S.(4,7) On July 16, 1998, thalidomide was approved specifically for treating erythema nodosum leprosum (ENL) in leprosy (Hansen's Disease).(10) Thalidomide was first shown in 1965 to improve symptoms, fever, and lesions in patients with ENL within 8-48 hours.(11) ENL is a debilitating cutaneous and systemic reaction of leprosy, caused by mycobacterium lepra. These lesions represent a type II (Arthus) reaction, an acute inflammatory reaction seen mostly in lepromatous leprosy, as opposed to the type I reaction seen in tuberculoid leprosy. ENL appears clinically as inflammatory skin nodules. In addition, fevers, weight loss, arthralgias, iritis, and nephritis are also features of this condition. In double-blind, controlled clinical trials, all signs and symptoms were responsive to thalidomide in 70-80% of patients as compared to 25% of patients who were given placebo. ENL is associated with high circulating levels of tumor necrosis factor alpha (TNFalpha),(13) also referred to as cachectin, that falls when treated with thalidomide.(14)
Thalidomide is also effective in treating HIV and non-HIV patients with recurrent aphthous ulcers (RAU), a non-herpes/non-infectious ulcerative stomatitis unresponsive to acyclovir.(12) This may be related to the fact that RAU is associated with increased TNFalpha production.(15) Thalidomide has been shown to be an effective treatment for HIV-related wasting syndrome and tuberculosis-associated weight loss.(16,17) In these conditions patients consistently gained weight in response to thalidomide.(18,19) Some were found to have decreased TNFalpha and increased IFNg in response to thalidomide. Increased levels of the soluble IL-2 receptor and a concomitant increase in total lymphocyte counts and CD8+ T cell counts have been seen in patients with HIV-related wasting syndrome who are treated with thalidomide, whereas serum CD4+ counts and viral loads seemed to be unaltered. Microsporidial diarrhea in AIDS patients is associated with elevated TNFalpha. This condition has been shown to be very responsive to thalidomide by weight increase, decreasing stool frequency, improved biopsy findings, increased numbers of ultrastructurally abnormal forms of microsporidia, and a decrease in stool TNFalpha.(20,21)
Chronic graft-versus-host disease (cGVHD) after bone marrow transplantation (BMT) in 10/14 children responded to therapy with thalidomide. The benefit of thalidomide in this setting is a significant finding in view of the fact that cGVHD occurs in about 25% of children who undergo BMT. Similar benefits are also seen in adults.(22)
Case reports of beneficial results have also been described in the treatment of prurigo nodularis and pyoderma gangranosum, which are skin conditions of itching, discoloration, blistering, skin thickening, and ulcers.(7,23) Pyoderma gangranosum of the penis has reportedly responded to thalidomide and was "well tolerated".(24) Thalidomide is effective in other dermatologic conditions associated with actinic prurigo, lupus erythematosus,(25) and Behcet's syndrome.(26)
Single series or single case reports suggest that thalidomide be useful in the following disease states: Crohn's disease,(5) erythema multiforme, sarcoidosis, rheumatoid arthritis, langerhans cell histiocytosis, uremic pruritis, Jessner-Kanof disease, cold hemagglutination disease, Weber-Christian disease, ulcerative colitis, postherpetic neuralgia, AIDS-associated proctitis, bullous pemphigoid, and cicatricial pemphigoid.(6) The following disease states are associated with a rise in TNFalpha: HIV, leprosy, tuberculosis, rheumatoid arthritis, lupus, multiple sclerosis, Behcet's disease, multiple sclerosis, Sjogren syndrome, and Crohn's disease.
Another potential use for thalidomide is in the treatment of diabetic retinopathy and macular degeneration because of its ability to block angiogenesis.(27)
Thalidomide can produce dysgenesis of fetal organs when the fetus is exposed to this drug 20-36 days after conception, which is during the organogenic period (days 21-56) of human development.(28) This results in phocomelia (shortening of limbs) and amelia (absence of one or more limbs), kidney and heart dysgenesis, brain dysfunction, and death. Although there is a question as to whether thalidomide is a mutagen also, there are no data to substantiate this.(29) Thalidomide serves as a substrate for the fetal xenobiotic-metabolizing cytochrome P450 system (CYP), which is probably extrahepatic at this stage of development. One theory is that during the organogenic period of human development, the CYP enzymes are activated to form dysmorphogenic endogenous cellular ligands that serve as teratogenic intermediates to affect the regulation of cell growth, differentiation, and angiogenesis.(30) Phocomelia is thought to be a result of thalidomideÕs blunting the growth of long bones by its actions preventing angiogenesis.(27) The timing of exposure to thalidomide during fetal development correlates with specific fetal damage. The upper limbs are affected earlier in gestation than the lower ones. If other structures are affected, such as the ear or cranial nerves, this indicates that thalidomide was given during the fourth week of development.
The Arthus type phenomenon in ENL includes antigen-specific T cell activities, elevated TNF and IL-1. Thalidomide is thought to selectively degrade the mRNA of TNFalpha. One recent report showed that stimulated monocytes, in vitro, had decreased TNFa in a dose response fashion when treated with incremental concentrations of thalidomide.(31) This has been shown in vivo also in a dose response manner, where both TNFa and interleukin gamma (IL-g) serum levels were elevated in ENL and decreased in response to thalidomide.(14) Other studies have confirmed this by showing that serum TNFalpha is elevated along with a decrease in IFN-g in patients with ENL and these two cytokines are significantly decreased and increased, respectively, after thalidomide treatment.(32)
Other recent studies suggest that TNFalpha is not alone in the pathogenesis of ENL and that thalidomide may act in other ways. It can be an immunostimulator of T cells,(33) for CD8+ T cells and of interferon-g production.(34) Serum T-helper cells and IgM concentrations are decreased in response to thalidomide. In addition, intradermal polymorphonuclear leukocytes, T cells, and keratinocyte intercellular adhesion molecules (MHC-II) are decreased by thalidomide in patients with ENL.(6)
The FDA mandates that physicians prescribing thalidomide be registered in the System for Thalidomide Education and Prescribing Safety (STEPS) program.(35) Registration packets can be obtained through Celgene by calling 1-888-423-5436. All patients taking thalidomide are required to comply with the following measures: to be informed about the risks verbally and in writing, given the opportunity to watch a video, give signed consent, submit their name and address, and complete a questionnaire for a national registry. Women of childbearing age (except women who have had a hysterectomy or no periods for at least two years) must agree in writing to have no heterosexual intercourse from 4 weeks before to 4 weeks after duration of treatment, or if intercourse is undertaken, to use two methods of birth control. A physician must receive a written report of a negative pregnancy test within 24 hours of treatment with thalidomide. Then a pregnancy test needs to be performed once a week for the first four weeks, then monthly thereafter (if menstrual cycles are irregular, every two weeks and contact provider). Although it is unknown whether thalidomide is carried in the sperm, men need to comply with using latex condoms during sexual intercourse with a woman of childbearing age, even in the face of having had a vasectomy.(36)
Thalidomide is marketed by the brand name Thalomide® by Celgene Corporation located in Warren, N.J. The dosage forms are 50mg capsules. The usual dose is 3-6mg/kg/d in one to four divided doses taken with water at least 1h after mealtime and preferably at bedtime. The dose can be increased as needed for resolution of symptoms.
Thalidomide follows first order kinetics. Absorption is variable, but t1/2 is about 1-2h and elimination t1/2 is about 9h. Volume of distribution is about 122 liters. Total body clearance is about 10L/h. Although clearance is predominantly non-renal (less than 1% found in the urine), thalidomide is usually detectable in the urine.(6) Thalidomide is metabolized in the liver to EM-12 and supidimide, the teratogenic and non-teratogenic analogs, respectively.(37) Although the cytochrome P450 system is implicated in the metabolism of thalidomide, it does not induce directly the enzyme complex; however, it may interfere with other medications that induce cytochrome P450.(18) Thalidomide can be measured by liquid chromatography.(38)
The most notorious effect of thalidomide is teratogenicity. Thalidomide has been associated with neuropathy (characterized as distal lower extremity painful paraesthesia, anesthesia and/or delayed motor weakness, which can be irreversible. This effect seems to be unrelated to the duration and dose. The patients with the highest risk for this effect are females and the elderly, according to at least one report.(39) Smoking may have a protective effect in this regard.(40)
Universally, sedation or drowsiness and constipation are known side-effects of thalidomide, regardless of the application of the drug. Some patients are more sensitive to these effects than others. Endocrine abnormalities that have been described include a hypothyroid effect, hypoglycemia, and increasing ACTH and prolactin levels.(6) Neutropenia is also a reported side effect. (15) There is a case report of toxic pustuloderma secondary to thalidomide in a patient treated for nodular prurigo.(41) Other less common clinical side effects include allergic vasculitis, brittle fingernails, decreased libido, dizziness, exfoliative reaction, erythrodermic reaction, face/limb edema, galactorrhea, increased appetite, menstruation abnormalities, mood changes, nausea, pruritis, red palms, thrombocytopenic purpura, and xerostomia.(6)
Toxicities in patients with HIV disease treated with thalidomide commonly include rashes and fevers (33% of patients), and less commonly neuropathic pain, mood changes.(17) Hypersensitivity reactions, although uncommon, may be more common in patients with AIDS.(6)
Ipecac would not be used in a thalidomide overdose because its only potentially serious acute toxicity in a non-pregnant acute ingestion is sedation. If, however, a pregnant woman in her first trimester of pregnancy ingested thalidomide within one hour, the risks of ipecac probably do not outweigh the benefit of its administration. Gastric lavage is indicated within one-hour post ingestion to retrieve any pill fragments that might be left in the stomach as long as the patient's airway is protected. Although there are no studies of activated charcoal (AC) use in thalidomide poisoning, it is recommended. Treatment is otherwise symptomatic and supportive. Seizures can be controlled by the usual medications such as a benzodiazepine. Hypotension can be treated with IV fluid boluses, dopamine, or if necessary, norepinephrine.
Thalidomide therapy should be discontinued if pearaesthesias or pallor of extremities, ataxia, or nocturnal muscle cramps occur. Nerve conduction studies should be performed before and during treatment of thalidomide, to ensure early detection of peripheral neurophathy.(40)
If a pregnant woman ingests any amount of thalidomide, counseling would be indicated because of the high risk of teratogenicity associated in the first trimester. In addition, this occurrence should be reported to the FDA.(10)
Jay R. Bernstein, M.D.
Department of Emergency Medicine
Boston Medical Center
Clinical Toxicology Review, Vol. 21, No. 5 (1999)
Copyright © 1999 by Massachusetts Poison Control System