What is isotretinoin?
Isotretinoin is a relative of vitamin A. The Food and Drug Administration (FDA) approved the first form of the drug, Accutane, in 1982. Since then it has been widely used to treat nodular acne. Other brands of isotretinoin began to enter the market in 2002. All brands of isotretinoin pose the same risk of birth defects.
Nodular acne causes many red, swollen lumps in the skin and can leave permanent scars (1). Nodular acne sometimes does not respond to treatments other than isotretinoin. The drug clears the skin of most affected individuals for prolonged periods.
Before isotretinoin was approved by the FDA, testing had shown that it could cause birth defects in animals. The manufacturer of Accutane, Roche Pharmaceuticals (a division of Hoffmann-La Roche, Inc.), warned against its use by pregnant women, but pregnancies resulting in birth defects still occurred. As a result, the FDA and the manufacturers of Accutane and other brands of isotretinoin implemented voluntary risk-management plans to prevent pregnant women from using isotretinoin. These programs were not successful in preventing drug exposure during pregnancy, and in 2005 the FDA started a stronger, mandatory risk management program called iPLEDGE. This program aims to assure that no pregnant woman starts taking isotretinoin, and no woman taking isotretinoin becomes pregnant.
What are the risks of using isotretinoin during pregnancy?There is an extremely high risk of birth defects if a woman takes isotretinoin during pregnancy, even if she takes a small amount of the drug for a short period. Birth defects caused by isotretinoin include (2):
- Hydrocephaly (enlargement of the fluid-filled spaces in the brain)
- Microcephaly (small head and brain)
- Mental retardation
- Ear and eye abnormalities
- Cleft lip/palate and other facial abnormalities
- Heart defects
Isotretinoin can cause these birth defects in the early weeks after conception when a woman often does not know she is pregnant. Even babies without obvious malformations may have mental retardation or learning disabilities (2). The drug also increases the risk of miscarriage, premature delivery and infant death (2).
What should a woman of childbearing age do before taking isotretinoin?
A woman should discuss with a doctor who is experienced in isotretinoin treatment whether the drug is right for her. Besides causing birth defects, isotretinoin can cause serious side effects for the woman, possibly including mental health problems (1, 3). In many cases, safer treatments may work to clear up acne.
- Have two negative pregnancy tests, including one right before starting the drug
- Sign a patient information/consent form containing warnings about the risk of birth defects if the fetus is exposed to isotretinoin
- Agree to use two effective forms of birth control, which must be used at the same time (unless abstinence is the chosen method), for at least one month before and throughout treatment with the drug, and for one month after stopping the drug
- Register with iPLEDGE by phone (866-495-0654) or over the Internet, and agree to follow all instructions in the iPLEDGE program
- Have a negative pregnancy test
- Enter her two types of birth control into the iPLEDGE system (by phone or Internet)
- Sign an additional patient information/consent form
If a woman taking isotretinoin does become pregnant, she should stop taking the drug and call her doctor immediately. She or her doctor must report the pregnancy to the FDA at (800) FDA-1088 and to iPLEDGE. This notification allows the FDA and the drug companies who make isotretinoin to monitor the success of the program and to make any necessary changes to prevent pregnancy exposures.
A woman should never attempt to get isotretinoin over the Internet because she will miss out on important safeguards to protect her health. The Food and Drug Administration provides more information about the dangers of buying isotretinoin online.
What other precautions should a woman take during treatment with isotretinoin?
Most women are treated with isotretinoin for about 15 to 20 weeks (2). During this time, a woman should check with her doctor before taking any other medications, such as antibiotics or herbal preparations. For example, a woman taking isotretinoin should not use an herbal preparation called St. John's wort because it may cause birth control pills to work less effectively and put her at increased risk of pregnancy (1, 3). Taking some antibiotics, such as tetracycline, at the same time as isotretinoin can increase the risk of serious side effects (1, 3).
Women should avoid breastfeeding while using isotretinoin and for one month after stopping the drug because it is not known whether it could harm the baby (1). Women or men who use isotretinoin also should avoid giving blood while taking the drug and for one month afterward, because the drug might cause birth defects if a pregnant women receives the blood (1). Individuals should never share their prescription for isotretinoin with anyone else.
What are iPLEDGE requirements?
The FDA requires that all manufacturers of isotretinoin use iPLEDGE. This should help eliminate any confusion resulting from having several voluntary risk-management programs.
All patients, including men, must register with iPLEDGE before starting isotretinoin. All doctors who prescribe the drug and pharmacists who sell it also must register with iPLEDGE (4). Each must agree to certain responsibilities for preventing pregnant women from taking the drug. For example, doctors are responsible for counseling women about birth control and the risks of isotretinoin, explaining the iPLEDGE program and documenting in iPLEDGE a negative pregnancy test for women taking the drug each month. The pharmacist can fill a prescription only after receiving authorization from iPLEDGE (4). These requirements should help assure that each woman has had an appropriately timed negative pregnancy test before starting the drug, and each month before she refills her prescription. The requirements also should help assure that all women of childbearing age receive continuing counseling about the safety precautions necessary to prevent fetal exposures to the drug.
Are there safer acne medications for women of childbearing age?
Most women with acne do not have severe nodular acne, and their skin problems often respond to safe topical (applied to the skin) or oral medications. Topical preparations of the antibiotics erythromycin or clindamycin are safe choices during pregnancy, as is benzoyl peroxide, an antibacterial agent that also dries the skin (5).
If topical preparations do not clear the skin, a woman's doctor may recommend other treatments. These include oral treatment with antibiotics such as erythromycin, which has not been associated with birth defects, or, if she is not planning pregnancy, with oral contraceptives (which should not be used during pregnancy) (5).
Topical retinoids also are used to treat acne. However, these medications have not been proven safe for use during pregnancy. Small amounts of these drugs may be absorbed through the skin into the bloodstream, so it's best to avoid them during pregnancy.
Are there other retinoids that are unsafe during pregnancy?
All oral retinoids pose a risk of birth defects and should be avoided during pregnancy. Women also should avoid pregnancy for varying periods of time after discontinuing use of such a drug.
Soriatane (acitretin) is a retinoid that is used to treat severe psoriasis, a chronic disfiguring skin disease. Like isotretinoin, this drug can cause serious birth defects, including craniofacial and heart defects, spina bifida and limb defects. This drug remains in the body for an extended period. It should not be used by any woman who plans to become pregnant within three years after stopping the drug (6).
As with isotretinoin, two negative pregnancy tests are recommended before starting Soriatane. Women also should use two reliable forms of contraception during treatment and for at least three years after stopping the drug (6).
Soriatane replaces (and is closely related to) another psoriasis drug called Tegison (etretinate), which stays in the body for a prolonged period. Some doctors recommend that women avoid pregnancy indefinitely after taking Tegison. Any woman who has used Tegison should discuss with her doctor if and when it may be safe for her to attempt pregnancy. Women who take Soriatane should not drink alcoholic beverages while taking the drug or for two months afterward. This combination causes the body to turn Soriatane into etretinate (the active ingredient in Tegison), which may remain in the body for many years after treatment ends (6).
Other retinoids used to treat certain cancers of the blood also pose a risk of birth defects. These include Vesanoid (tretinoin), used to treat acute promyelocytic leukemia, and Targretin (bexarotene), used to treat a form of T-cell lymphoma. A pregnancy test before starting treatment and each month, and two reliable forms of contraception during treatment and for one month after stopping the drugs, are recommended (7, 8).
Topical versions of tretinoin (Retin-A and Renova) and other retinoids called adapalene (Differen) and tazarotene (Tazorac) are available to treat acne and sun-damaged skin. Studies suggest that topical retinoids do not cause birth defects (9). However, some questions about their safety in pregnancy remain, due to a few reports of birth defects in babies of women who used these preparations during pregnancy (9). Until more is known about the safety of topical retinoids during pregnancy, it's best for women who are pregnant or planning pregnancy to avoid them.
A number of new retinoids are being tested for their effectiveness in treating and, in some cases, preventing various forms of cancer, including breast, ovarian and lung cancer. These drugs appear to cause cancer cells to behave like normal cells, possibly leading to remission of some cancers. If these drugs prove successful, women and their doctors will need to pay careful attention to the risks for birth defects associated with use of these drugs.
Can high doses of vitamin A cause birth defects?
While vitamin A is crucial for normal fetal growth and development, too much of it may cause birth defects. A 1995 study found that women who took more than 10,000 IU (international units) of vitamin A daily—twice the FDA's current Daily Value (DV)—in the first two months of pregnancy had more than double the risk of having a baby with birth defects similar to those seen in isotretinoin-exposed babies (10). Other studies have suggested that doses under 25,000 IU probably do not cause birth defects, but the lowest dose that can cause birth defects is unknown (11).
The body is able to make its own vitamin A, when needed, from substances such as beta carotene, which is found in yellow and green vegetables and some multivitamins. This form of the vitamin is believed to be completely safe during pregnancy. However, much of the vitamin A we consume is the preformed vitamin which, in excessive amounts, can cause birth defects. Preformed vitamin A is found in many vitamin supplements and some foods, including meats (especially liver), eggs, dairy products and fortified breakfast cereals.
A pregnant woman should be sure that her multivitamin or prenatal supplement contains no more than the DV#5,000 IU#of preformed vitamin A, and she should not take any vitamin A supplements beyond that amount. She also should limit the amount of liver she eats.
What is the role of the March of Dimes in the study of retinoids?
The March of Dimes has supported research on isotretinoin and was instrumental in bringing to public attention the need for more stringent guidelines concerning its use. The March of Dimes continues to support research on the role of retinoids in both normal and abnormal fetal development. This research may lead to a better understanding of how these drugs may cause birth defects, with the ultimate goal of learning how to prevent them.
For more information
Read the fact sheet provided by the Organization for Teratology Information Services (OTIS).
References
1. Roche Laboratories, Inc. Medication Guide: Accutane. Revised August 2005.
2. Roche Laboratories, Inc. Accutane (Isotretinoin) Capsules: Prescribing Information (Accutane Label). Updated August 2005.
3. Food and Drug Administration (FDA). Patient Information Sheet: Isotretinoin (marketed as Accutane).
4. Food and Drug Administration (FDA). FDA Announces Strengthened Risk Management Program to Enhance Safe Use of Isotretinoin (Accutane) for Treating Severe Acne. August 12, 2005.
5. Deitch, H.R., and Hillard, P.J.A. A Gynecologist's Guide to Acne. Contemporary Ob/Gyn, January 2002, pages 88-93.
6. Connetics Corporation. Once-a-Day Oral Soriatane: Important Information for Female Patients. Accessed 6/13/05.
7. Roche U.S. Pharmaceuticals. Our Products: Complete Product Information: Vesanoid (Tretinoin) Capsules. Updated 7/19/04.
8. Ligand Pharmaceuticals, Inc. Targretin (Bexarotene) Capsules: Patient's Instructions for Use. Accessed 9/6/05.
9. Reproductive Toxicology Center (ReproTox). Tretinoin, Adapalene, and Tazarotene, accessed 5/05.
10. Rothman, K.J., et al. Teratogenicity of high doses of vitamin A intake. The New England Journal of Medicine, volume 333, number 21, November 23, 1995, pages 1365-1373.
11. Briggs, G. G., et al. Vitamin A, in Drugs in Pregnancy and Lactation, 7th Edition, Lippincott, Williams & Wilkins, Philadelphia, 2005, pages 1717-1724.
October 2005 (R 4-07)
