Accutane (Isotretinoin) and Other Retinoids - March of Dimes

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Accutane (Isotretinoin) and Other Retinoids
•What is Accutane?
•Who should not take isotretinoin?
•What birth defects are caused by use of isotretinoin during pregnancy
•What is nodular acne?
•What is iPLEDGE?
•What should a woman of childbearing age do before taking isotretinoin?
•What does iPLEDGE require for women who can become pregnant?
•Is it safe to breastfeed while taking isotretinoin?
•What other precautions should a woman take during treatment with isotretinoin?
•What are other iPLEDGE requirements?
•Are there safer acne medications for women of childbearing age?
•Are topical retinoids safe in pregnancy?
•Are there other retinoids that are unsafe during pregnancy?
•Can high doses of vitamin A cause birth defects?
•What is the role of the March of Dimes in the study of retinoids?
•References

What is Accutane?
Accutane (isotretinoin) is a prescription medication used to treat a severe form of acne (nodular or “cystic” acne) that has not been helped by other treatments, including oral antibiotics. Other brands of isotretinoin (Amnesteem, Claravis, Sotret) also are available.

Isotretinoin is a member of a family of drugs called retinoids, which are related to vitamin A. When taken during pregnancy, isotretinoin and other retinoids can cause miscarriage or very serious birth defects.
Who should not take isotretinoin?

Women who are pregnant, planning pregnancy, having sex without birth control or breastfeeding should not take isotretinoin.

What birth defects are caused by use of 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 (1):
•Hydrocephaly (enlargement of the fluid-filled spaces in the brain)
•Microcephaly (small head and brain)
•Mental retardation
•Ear and eye abnormalities
•Cleft palate and other facial abnormalities
•Heart defects

Isotretinoin can cause birth defects in the early weeks after conception when a woman often does not know she is pregnant. Even babies without obvious birth defects may have mental retardation or learning disabilities (1, 2). The drug also increases the risk of premature delivery and infant death (1, 2).

What is nodular acne?
Nodular acne causes many red, swollen lumps in the skin and can leave permanent scars. This form of acne sometimes does not respond to treatments other than isotretinoin. The drug clears the skin of most affected individuals for prolonged periods.

What is iPLEDGE?
All patients, including men, who take isotretinoin must participate in a risk-management program called iPLEDGE. The Food and Drug Administration (FDA) started this program in 2005 with two goals (3):
•Ensuring that no pregnant woman starts taking isotretinoin
•Ensuring that no woman taking isotretinoin becomes pregnant

The FDA approved the first form of the drug, Accutane, in 1982. Before it was approved, testing had shown that the drug 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.

Subsequently, the FDA and the manufacturers of all brands of isotretinoin implemented voluntary risk-management plans to prevent pregnant women from using the drug. These programs were not successful in preventing drug exposure during pregnancy. As a result, the FDA started iPLEDGE, a stronger, mandatory risk-management program.

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 (2, 3). In many cases, safer treatments (see below) may work to clear up acne.

If a woman decides to take isotretinoin, she must follow the steps required by iPLEDGE.

What does iPLEDGE require for women who can become pregnant?
iPLEDGE requires that women follow these steps before, during and after isotretinoin treatment:
Before treatment (3):
•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 on the Internet, and agree to follow all instructions in the iPLEDGE program

During treatment:
Each month a woman receives a 30-day supply of isotretinoin. To refill her prescription, she must:
•Have a negative pregnancy test
•Enter her two types of birth control into the iPLEDGE system (by phone or Internet)
•Answer questions about the iPLEDGE program and preventing pregnancy (by phone or Internet)

After treatment:
•Have a pregnancy test after her last dose
•Continue to use two forms of birth control for one month
•Have another pregnancy test one month after her last dose

If a woman taking isotretinoin does become pregnant, she should stop taking the drug and call her health care provider. She or her provider must report the pregnancy to the FDA at (800) FDA-1088 and to iPLEDGE (3). Reporting allows the FDA and the drug companies who make isotretinoin to monitor the success of the iPLEDGE 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 FDA provides more information about the dangers of buying isotretinoin on its Web site.

Is it safe to breastfeed while taking isotretinoin?
Women should not breastfeed while using isotretinoin and for one month after stopping the drug because it is not known whether it could harm the baby (2, 3).
What other precautions should a woman take during treatment with isotretinoin?
Most women are treated with isotretinoin for about 15 to 20 weeks (3). During this time, a woman should check with her provider before taking any other medications.

A woman should avoid certain medications while she is taking isotretinoin (2, 3):
•St. John’s wort: This herbal preparation may cause birth control pills to work less effectively and put a woman at increased risk of pregnancy.
•Tetracycline: This antibiotic can increase the risk of serious side effects when taken with isotretinoin.
•Dilantin (phenytoin): This anti-seizure medication, when taken with isotretinoin, can weaken bones.
•Corticosteroids: When taken with isotretinoin, these medicines (used to treat arthritis, severe asthma and a number of other conditions) can weaken bones.
•Progestin-only birth control pills: When taken with isotretinoin, this form of birth control may not be effective.
•Vitamin A supplements: These vitamins are related to isotretinoin and can include the risk of serious side effects.

Women or men who use isotretinoin should not give blood while taking the drug and for one month afterward, because the drug might cause birth defects if a pregnant women receives the blood (2, 3). Individuals should never share their prescription for isotretinoin with anyone else.

What are other iPLEDGE requirements?
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.
•Pharmacists can fill a prescription only after receiving authorization from iPLEDGE.

These requirements should help ensure 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 ensure that all women of childbearing age receive continuing counseling about the safety precautions necessary to prevent fetal exposure to the drug.
A
re there safer acne medications for women of childbearing age?
Most women with acne do not have severe nodular acne. 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 even 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 provider may recommend oral treatment with antibiotics, such as erythromycin, which has not been associated with birth defects. If she is not planning pregnancy, treatment with oral contraceptives (which should not be used during pregnancy) also may be effective (5).

Are topical retinoids safe in pregnancy?
Topical retinoids are used to treat acne and sun-damaged skin. These include topical tretinoin (Retin A, Renova), adapalene (Differin) and tazarotene (Tazorac). Small amounts of these drugs may be absorbed through the skin into the bloodstream.
S
tudies suggest that topical retinoids do not cause birth defects (6). However, some questions about their safety remain, due to a few reports of birth defects in babies of women who used these preparations during pregnancy (6). 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.

Are there other retinoids that are unsafe during pregnancy?
All oral retinoids pose a risk of birth defects similar to those caused by isotretinoin and should be avoided during pregnancy. As with isotretinoin, women should have a pregnancy test before starting these drugs and another each month. Women also should use two reliable forms of birth control during treatment and for varying periods of time after discontinuing use of these drugs.
•Soriatane (acitretin): This retinoid is used to treat severe psoriasis, a chronic disfiguring skin disease. Soriatane can remain 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 (7). Women should continue to use two reliable forms of contraception for at least three years after stopping the drug (7). Women should not drink alcohol while taking the drug or for two months afterward (7). 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.
•Tegison (etretinate): This psoriasis medicine has been replaced by Soriatane and is no longer sold in the United States. Tegison stays in the body for a prolonged period. Any woman who has used Tegison should discuss with her doctor if and when it may be safe for her to attempt pregnancy.
•Vesanoid (tretinoin): This drug is used to treat a blood cancer called acute promyelocytic leukemia. Women should continue to use two forms of contraception for one month after stopping treatment (8).
•Targretin (bexarotene): This retinoid is used to treat a form of blood cancer called T-cell lymphoma. A woman should continue using two reliable forms of contraception for one month after stopping the drug (9).

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 should pay careful attention to the risks for birth defects associated with use of these drugs.

Can high doses of vitamin A cause birth defects?
Vitamin A is crucial for normal fetal growth and development. However, too much of it may cause birth defects. A 1995 study found that women who took more than 10,000 IUs (international units) of vitamin A daily in the first two months of pregnancy doubled their risk of having a baby with birth defects (10). The birth defects were similar to those seen in isotretinoin-exposed babies.
The FDA’s current daily value (DV) for vitamin A is 5,000 IUs (11). Other studies have suggested that doses less than 25,000 IU probably do not cause birth defects, but the lowest dose that can cause birth defects is unknown (6).

The body makes its own vitamin A, when needed, from vitamin A precursors, 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 5,000 IUs 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, in order to better understand how these drugs may cause birth defects, with the ultimate goal of learning how to prevent them.

References
1.iPLEDGE. About Isotretinoin: Contraindications and Warnings. Accessed 2/12/08.
2. Food and Drug Administration (FDA). Patient Information Sheet: Isotretinoin (Marketed as Accutane). Accessed 2/11/08.
3.iPLEDGE. The iPLEDGE Program Patient Introductory Brochure, effective 12/2/07.
4.Food and Drug Administration (FDA). FDA Alert for Healthcare Professionals: Isotretinoin (Marketed as Accutane), accessed 2/11/08.
5.Deitch, H.R., and Hillard, P.J.A. A Gynecologist’s Guide to Acne. Contemporary Ob/Gyn, January 2002, pages 88-93.
6.Reproductive Toxicology Center (ReproTox). Tretinoin, Adapalene, Tazarotene, Vitamin A, accessed 2/11/08.
7.Stiefel Laboratories. About Soriatane: Important Safety Information for Females. Accessed 2/12/08.
8.Roche U.S. Pharmaceuticals. Complete Product Information: Vesanoid (Tretinoin) Capsules, accessed 2/12/08.
9.Eisai, Inc. Targretin (Bexarotene) Capsules: Patient’s Instructions for Use. Accessed 2/12/08.
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.

NIH Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin A and Carotenoids. Updated 4/23/06