Consultant PharmacistForum

As we prepare for thalidomide’s comeback, we must also review its history. The comeback will be somewhat cautious because of the drug’s devastating early problems.

Thalidomide was originally marketed as a sedative. It was introduced in West Germany in 1956 and in numerous other countries soon thereafter. It became extremely popular because it did not impair coordination or respiratory function. By 1961, however, there were mounting reports of severe congenital abnormalities associated with the maternal use of thalidomide, and it was withdrawn from the market and its use highly restricted. A few years later, thalidomide was found useful in dermatology after it was reported that leprosy patients with erythema nodosum leprosum (ENL) demonstrated rapid and dramatic improvement on taking it as a sedative. Additional data quickly appeared in the literature to confirm its efficacy in ENL, indicating thalidomide as the drug of choice for this condition.

The History

The historical time line went something like this:

• In 1959, thalidomide was marketed as a sedative and sold in 48 countries. Physicians in West Germany reported 12 cases of children with truncated limbs born to women using thalidomide.
• In 1960, the William S. Merrell Company of Cincinnati asked the Food and Drug Administration (FDA) to approve thalidomide under the trade name Kavadon as a sedative because it was already being used in Europe and Canada. Fortunately, because of the skepticism of the FDA and its medical officer, Frances Kelsey, MD, PhD, it was never approved in the United States.
• By 1961, evidence linking thalidomide to birth defects mounted. The most devastating defect was phocomelia, an anomaly consisting of hands and feet being directly connected to the trunk in a "flipper-like" fashion. Other defects included malformations of the limbs, eyes, ears, heart, genitals, kidneys, digestive tract, and nervous system.¹
• By 1962, thalidomide was off the market. An estimated 10,000–12,000 infants around the world had been born with missing or malformed limbs, facial deformities, or defective organs. About half of the victims died as infants, and regulators in Europe and the United States began changing rules for drug safety testing.
• The thalidomide story picks up again in 1994 at the Tenth International Conference on AIDS, where researchers from Mexico and Thailand reported that thalidomide helps prevent weight loss and infections in patients with AIDS.
• In 1996, Celgene Corporation in Warren, New Jersey, sought approval from the FDA for use of the drug in healing inflamed lesions in individuals diagnosed with leprosy. Researchers were also reviewing it as a treatment to reduce rejection problems related to organ transplants, and for macular degeneration and cancer.
• In 1997, the results of the first clinical trials showing that thalidomide was effective against painful AIDS- related sores were published. The Thalidomide Victims Association of Canada (TVAC)² reported that 5,000 individuals are alive who were born with thalidomide-linked birth defects in the 1950s and 1960s. This included 15 in the United States, 125 in Canada, and 400 in the United Kingdom.

Future Prospects

In the 1960s, when it was prescribed for pregnant women, it was found that thalidomide had some anti-inflammatory effects. In 1964, a patient presented to an Israeli physician with ENL. This complication of leprosy causes a disfiguring skin disorder that involves a loss of sensation and leads to paralysis. After thalidomide was used in that patient, the nodules and accompanying fever dissipated.³

Early use of thalidomide in leprosy led to the conclusion that it was not destroying the bacteria associated with leprosy, but was working by limiting the body’s immunologic and inflammatory attack on the pathogen. This opened the door for further investigation for other disorders that involve aberrant immune and inflammatory reactions. Consequently, thalidomide was suggested for use in Behcet’s disease, Crohn’s disease, lupus, and rheumatoid arthritis, and it has demonstrated moderating effects on these disorders.²

Possibly the most cited new use for thalidomide is for the treatment of cachexia in cancer patients. Tumor necrosis factor (TNF)-alpha has a prominent role in the pathogenesis of anorexia and cachexia in chronic diseases. Thalidomide has been useful in treatment of weight loss associated with human immunodeficiency virus (HIV) disease and TB.

Other uses include aphthous stomatitis, actinic prurigo, prurigo nodularis, dermatologic conditions associated with HIV infection, idiopathic esophageal ulceration, Kaposi’s sarcoma, night sweats in advanced malignant disease, and refractory chronic graft-versus-host disease after bone marrow transplants in children.

Mechanism of Action

Another recent discovery is thalidomide’s ability to inhibit the growth of new blood vessels, or angiogenesis. Thalidomide appears to inhibit the movement and migration of cells that are needed for the formation and extension of new vessels. This is a necessary process under normal conditions for fetal development, childhood growth and development, and wound healing. However, there are conditions such as cancer, diabetic retinopathy, and osteoporosis in which inhibition of angiogenesis is beneficial.³

Thalidomide Today

Precautions have been taken to prevent the adverse effects of thalidomide with Celgene Corporation’s controlled distribution system, the "System for Thalidomide Education and Prescribing Safety (STEPS)" program. Physicians and pharmacists must be registered in the STEPS program if they are to prescribe or dispense it. All patients— both males and females— must comply with patient registration, surveys, and mandatory contraceptive measures. Females must have a negative pregnancy test within 24 hours of starting therapy, weekly tests during the first four weeks, and monthly thereafter. Two forms of contraception are also required. Males receive written and oral warnings of the risk of contraceptive failure, since it is not known whether thalidomide is present in sperm or semen. They are instructed to use condoms when having intercourse with women of childbearing capacity.³

Celgene designed the STEPS program in conjunction with input from the FDA, the Centers for Disease Control and Prevention (CDC), and TVAC.⁵

Other Adverse Effects

Other side effects include dizziness, drowsiness, dry mouth, and constipation.⁶

Conclusion

The STEPS program reminds us of the restrictions with Clozaril (clozapine)—is this a trend that some critically needed drugs will have to be coupled with restrictions or a monitoring system? I guess we will have to stay tuned to find the answer. Obviously, with us groping for treatments for some critical diseases, we may have to accept the risk-to-benefit ratio that comes with them.

Perhaps thalidomide will provide some new hope for patients with ENL and lead to future indications for patients with AIDS and other wasting diseases.

Phyllis M. Parks-Veal, BS Pharm, PharmD
Milledgeville, Georgia