National Toxicology Program

Overview

In the 1960s the drug thalidomide was used by some pregnant women in Europe and Canada to treat morning sickness. Women who took the drug in early pregnancy gave birth to children with severe birth defects such as missing or shortened limbs. Shortly after the birth defects were observed, thalidomide was banned worldwide. It has recently been discovered that thalidomide is effective in treating symptoms of diseases such as leprosy and possibly AIDS. The state of California has identified thalidomide as a developmental hazard, which means there is proof that it may harm unborn children. However, thalidomide was approved in 1998 by the U.S. Food and Drug Administration (FDA) to treat leprosy. In order to avoid tragic birth defects, the FDA has established several restrictions. Doctors prescribing and pharmacists dispensing thalidomide are required to participate in a program sponsored by the drug's manufacturer, and patients must also be educated about the drug's effects. Female patients must be tested for pregnancy before and while taking the drug and must use two forms of birth control if sexually active. Men taking thalidomide must also practice birth control because it is not known if thalidomide can produce defects in the children they conceive. Donating of blood or semen and breast feeding are prohibited while taking the drug.

History of birth defects

In Europe and Canada during the early 1960s, thalidomide was prescribed to treat morning sickness in pregnant women. At that time, it was not approved in the United States because Dr. Frances Kelsey from the Food and Drug Administration (FDA) stated there was insufficient proof of the drug’s safety in humans. Thalidomide was soon banned worldwide when it was discovered that it caused tragic birth defects. According to the March of Dimes (MOD, November 1998), "More than 10,000 children around the world were born with major malformations, many missing arms and legs, because their mothers had taken the drug during early pregnancy. Mothers who had taken the drug when arms and legs were beginning to form had babies with a widely varying but recognizable pattern of limb deformities. The most well-known pattern, absence of most of the arm with the hands extending flipper-like from the shoulders, is called phocomelia. Another frequent arm malformation called radial aplasia was absence of the thumb and the adjoining bone in the lower arm. Similar limb malformations occurred in the lower extremities. The affected babies almost always had both sides affected and often had both the arms and the legs malformed. In addition to the limbs, the drug caused malformations of the eyes and ears, heart, genitals, kidneys, digestive tract (including the lips and mouth), and nervous system. Thalidomide was recognized as a powerful human teratogen (a drug or other agent that causes abnormal development in the embryo or fetus). Taking even a single dose of thalidomide during early pregnancy may cause major birth defects."

New Therapeutic Uses

In 1998 the Food and Drug Administration (FDA) approved thalidomide for use in treating leprosy symptoms (FDA Talk Paper: July 16, 1998). Studies are also being conducted to determine the effectiveness of thalidomide in treating symptoms associated with AIDS, Behchet disease, lupus, Sjogren syndrome, rheumatoid arthritis, inflammatory bowel disease, macular degeneration, and some cancers (MOD, November 1998).

Government regulation and safeguards

The California Environmental Protection Agency (Cal/EPA) has added thalidomide to its Proposition 65 list of developmental toxins. This means there is evidence that the compounds can be harmful to unborn children (Cal/EPA Proposition 65 List).

The Food and Drug Administration (FDA) approved thalidomide for treatment of leprosy symptoms in 1998 (FDA Talk Paper: July 16, 1998). The approval was based upon the establishment of strict safeguards to prevent the occurrence of birth defects. The March of Dimes has summarized the FDA restrictions and the following information comes from their web site (MOD, November 1998):

To prevent fetal exposure to thalidomide, the drug’s manufacturer has developed the System for Thalidomide Education and Prescribing Safety (STEPS) program. Only physicians who are registered may prescribe thalidomide to patients and those patients—both male and female—must comply with mandatory contraceptive measures, patient registration and patient surveys.

Thalidomide may be dispensed only by licensed pharmacists who are registered in the S.T.E.P.S. program and have been educated to understand the risk of severe birth defects if thalidomide is used during pregnancy.

In addition, female patients’ prescriptions will not be filled without a physician’s written report of a negative pregnancy test that has been conducted within 24 hours of starting thalidomide therapy. Pregnancy testing will continue to be required weekly during the first month of use, then monthly thereafter in women with regular cycles, or every two weeks if cycles are irregular. Prescriptions are only for one month’s supply. A female patient must abstain from sexual intercourse or use two highly effective methods of birth control at the same time for at least one month before receiving thalidomide and continue their use until one month after the last thalidomide dose. All patients must participate in a mandatory registry that will provide follow-up to detect any adverse effects of using thalidomide and will hopefully identify areas in which safeguards need to be improved, if problems occur.

The FDA reminds female patients that no method of birth control is completely reliable, except for having no sexual intercourse at all (abstinence). Women being treated with thalidomide should refrain from any other activities that could result in pregnancy, such as assisted fertilization methods. Breast feeding a baby and donating blood are also prohibited.

Male patients must abstain from sexual intercourse or use a condom during intercourse while taking thalidomide and for one month after, because it is not known if thalidomide in semen is a hazard. Donating sperm or blood is also prohibited.

It is vital that each patient understands that thalidomide is prescribed for him or her alone and must not be shared with, or given to, others.

Current research

The following information about thalidomide research comes from the March of Dimes web site (MOD, November 1998):

One of the manufacturers of thalidomide has an ongoing program to develop and study the effectiveness of thalidomide analogs – chemical compounds that may have thalidomide’s benefits without its toxic and teratogenic effects. Some of these compounds should be ready for clinical testing soon.

March of Dimes has recently supported thalidomide research on the stubborn question of how the drug causes a wide range of birth defects, depending greatly on just when a woman takes it during her pregnancy. Learning how its mechanisms work should give us insight into the major processes of normal development and how drugs or other chemicals can disrupt it.

Links to useful information

US Food & Drug Administration - Center for Drug Evaluation and Research: Thalidomide Information

BBC News (UK) - "Fresh Start for Notorious Drug"

Thalidomide - Contergan^® - Detailed information on thalidomide and a collection of links to interesting web resources.