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In 1998, the Food and Drug Administration (FDA) approved the drug thalidomide (Thalomid) as a treatment for a severe skin disorder (1). In 2006, the FDA also approved it to treat a form of cancer (2). Thalidomide can cause severe birth defects and death of a baby. The March of Dimes wants all women who could become pregnant to be aware of this drug's danger.

What is the history of thalidomide?

Doctors in Europe first prescribed thalidomide in the late 1950s to treat anxiety, insomnia and, in pregnant women, morning sickness. It was marketed in Europe as well as in Japan, Australia and Canada. It was withdrawn from the market in the early 1960s when doctors learned that it caused devastating birth defects. About 10,000 children around the world were born with major malformations because their mothers had taken the drug during early pregnancy (3).

Until 1998, thalidomide was not approved in the United States. This was largely due to the skepticism of FDA medical officer Frances Kelsey, MD, PhD (4). Dr. Kelsey wanted proof that thalidomide was safe for humans, particularly for the embryo. By late 1961, the drug's unique ability to cause serious human malformations was becoming clear.

The worldwide thalidomide tragedy changed the way drugs are developed, tested and regulated in the United States, significantly broadening FDA authority. Dr. Kelsey often is credited with sealing the FDA's reputation as the world's premier authority on food and drug safety.

What birth defects does thalidomide cause?

In 1961, doctors in Germany, Australia and Great Britain noted a significant increase in the number of babies born with severely malformed or missing arms and legs. These birth defects were traced to the use of thalidomide during early pregnancy, when a baby's arms and legs begin to form.

The most well-known defect, a severe shortening of the arms or legs with flipper-like hands or feet, is called phocomelia. Affected babies almost always have defects on both sides and often have both the arms and legs malformed. In especially severe cases, the babies have complete absence of limbs. The drug also causes malformations of the eyes and ears, heart, genitals, kidneys and digestive tract (including the lips and mouth) (3, 5). About 40 percent of babies exposed to the drug die before or soon after delivery (5).

Thalidomide is one of the most powerful human teratogens (drugs or other agents that cause abnormal development in the embryo or fetus). Taking even a single dose of thalidomide during early pregnancy may cause major birth defects (1). Women should never take thalidomide if they could become pregnant or if they are pregnant.

What disorders is thalidomide approved to treat?

In 1998, the FDA approved thalidomide for the treatment of erythema nodosum leprosum (ENL), a complication of leprosy (1). This disfiguring skin disorder affects about 6,500 persons in the United States (6).

In 2006, the FDA approved thalidomide for treatment of multiple myeloma, a bone marrow cancer (2). Each year, about 15,000 people in the United States are diagnosed with multiple myeloma (7).

Now that the drug has been approved for ENL and multiple myeloma, providers can prescribe it for people with other conditions. Because thalidomide may become available to women capable of having children, they need to be warned about the serious risks of birth defects.

What other disorders might be treated with thalidomide?

Thalidomide is being used experimentally to treat a number of serious disorders. The drug is showing promise in treating severe ulcers of the mouth and throat in individuals with AIDS, and ulcers of the mouth and genitals in individuals with Behcet disease. These ulcerous sores are large, deep and painful. The mouth ulcers may lead to malnutrition because they interfere with eating. Studies suggest that thalidomide may improve weight gain in AIDS and cancer patients suffering from a severe weight loss, called wasting (3, 5).

Researchers are studying the effectiveness of thalidomide in treatment of rheumatoid arthritis, lupus erythematosus, Sjogren syndrome, inflammatory bowel disease (Crohn's disease) and in a number of cancers, including Kaposi's sarcoma (seen mainly in AIDS patients), melanoma, and kidney and brain cancers (3, 5).

What other risks does thalidomide pose?

Thalidomide can cause severe nerve damage (peripheral neuropathy) that may not go away after a patient stops taking the drug. Symptoms include a burning sensation or numbness or tingling in the arms, hands, legs or feet (1). Other side effects may include drowsiness, dizziness and reduced ability to think clearly (1). Thalidomide can interfere with the ability to drive a car or operate machinery. Thalidomide also appears to increase the risk of blood clots in individuals being treated for multiple myeloma (2).

What safeguards are in place to prevent use of thalidomide in pregnancy?

Because of thalidomide's danger to a developing baby, the FDA requires special safeguards. To prevent fetal exposure to thalidomide, the drug's manufacturer has developed the System for Thalidomide Education and Prescribing Safety (STEPS) program (1). Only physicians and pharmacists who are registered in the program may prescribe and dispense thalidomide to patients. Patients, both male and female, must agree in writing to important actions to prevent pregnancy.

Female patients must (1):

• Use two methods of birth control beginning 4 weeks before starting thalidomide and continuing until 4 weeks after the last dose, or abstain from sexual contact during this time period. One of the birth control methods must be highly effective, such as birth control pills.
• Have a negative pregnancy test within 24 hours of starting treatment. The doctor must see a written report of a negative pregnancy test before prescribing thalidomide.
• Have a pregnancy test every week during the first month of treatment. For the remainder of treatment, women with regular cycles must have a pregnancy test every 28 days, and women with irregular cycles, every 2 weeks. Prescriptions are for a 4-week supply.

Male patients must agree in writing to use a latex condom any time they have sexual contact with a woman of childbearing age because thalidomide may be present in semen (1).

All patients must participate in a mandatory registry that provides follow-up to detect adverse effects of using thalidomide. This follow-up helps identify areas in which safeguards need to be improved. Women and men being treated with thalidomide should not donate blood, and men should not donate sperm (1). Patients on thalidomide should never share or give the drug to others (1). Individuals should never buy thalidomide over the Internet because they miss out on the important drug safety program (1).

Is it safe for a woman to breastfeed while taking thalidomide?

No. A woman should not breastfeed her baby while taking thalidomide because of possible side effects in her baby (1).

What research is being done on thalidomide?

Scientists continue to develop chemical compounds that may have thalidomide's benefits without the risk of birth defects and nerve damage. One of these compounds, lenalidomide (Revlimid), was approved by the FDA in 2005 for the treatment of advanced multiple myeloma and another bone marrow disorder (myelodysplastic syndrome) (8). Studies are evaluating the risk of birth defects with this drug (8). Because lenalidomide has the potential to cause birth defects, it is prescribed under a risk management plan similar to the STEPS program. Women who are pregnant or could become pregnant should not take lenalidomide.

For more information

Read the fact sheet provided by the Organization of Teratology Information Services.

References

1. Food and Drug Administration (FDA). Thalidomide Information. Accessed 6/12/08.
2. Food and Drug Administration (FDA). FDA Approves Thalomid (thalidomide) to Treat Multiple Myeloma. Updated 7/20/06.
3. Franks, M.E., et al. Review: Thalidomide. The Lancet, volume 363, May 29, 2004, pages 1802-1811.
4. National Library of Medicine. Biography: Dr. Frances Kathleen Oldham Kelsey. Accessed 6/13/08.
5. Perri, A.J., and Hsu, S. A Review of Thalidomide's History and Current Dermatologic Applications. Dermatology Online Journal, volume 3, number 5, 2003.
6. U.S. Health Resources and Services Administration (HRSA). National Hansen's Disease (Leprosy) Program. Accessed 6/13/08.
7. National Cancer Institute. What You Need To Know About Multiple Myeloma. Accessed 6/16/08.
8. Food and Drug Administration (FDA). FDA Approves New Treatment for Myelodysplastic Syndrome (MDS). December 28, 2005.

August 2008