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Immunomodulators.

Several immunologic agents--adalimumab, anakinra, etanercept, three classes of interferons, and thalidomide--are classified in the general category of immunomodulators. They are used for various approved and offlabel indications: multiple sclerosis, rheumatoid arthritis, autoimmune disorders, and complications of leprosy, and for antitumor, antiviral, and antibacterial uses.

With the exception of thalidomide, these compounds are large molecules and may not reach the fetus. But their complex pharmacologic mechanisms may directly affect a number of maternal biologic processes, such as immune functions, response to infections and inflammation, cell proliferation, leukocyte migration, and prevention of cartilage degradation. Except for thalidomide, the human pregnancy experience with these agents is limited or completely lacking, making the decision about whether to use them during gestation problematic.

The tumor necrosis factor blockers adalimumab (Humira) and etanercept (Enbrel) and the interleukin-1 receptor antagonist anakinra (Kineret), which are administered subcutaneously, are approved for treating rheumatoid arthritis. All three are rated pregnancy risk category B: Animal studies have not revealed any evidence of harm to the embryo or fetus at serum levels or doses that are much higher than those used in humans.

Although this information is reassuring, the lack of pregnancy data in humans does not allow assessment of the fetal risks posed by these drugs. To help provide such information for one of these agents, the Organization of Teratology Information Services has started a Humira pregnancy registry. (Enroll patients by calling 877-311-8972.) Until pregnancy data are available, it would be prudent for women to undergo a pregnancy test before starting these drugs, but inadvertent exposure in pregnancy probably represents a low risk.

No information is available concerning the use of these agents during lactation, but since they are amino acid derivatives, they would likely be digested in the infant's gut if excreted into breast milk. Still, the safest course for a woman taking one of these agents is to avoid breast-feeding because of the potential for toxicity in the infant.

The three classes of interferons--alfa, beta, and gamma--are each rated C and administered parenterally. The interferon alfa agents include interferon alfa-2a (Roferon-A), peginterferon alfa-2a (Pegasys), interferon alfa-2b (Intron A), peginterferon alfa-2b (Peg-Intron), interferon alfacon-1 (Infergen), and interferon alfa-n3 (Alferon N).

The two "peg" products are interferons chemically bonded to polyethylene glycol and are long acting. Interferon alfa-n3 is indicated for condylomas acuminata, as is interferon alfa-2b. These interferons, with the exception of alfa-n3, are approved for various indications, including the treatment of hepatitis C, hepatitis B, hairy cell leukemia, and chronic myelogenous leukemia.

Interferon beta-1a (Avonex) and interferon beta-1b (Betaseron) are approved for multiple sclerosis; interferon gamma-1b (Actimmune) reduces the frequency and severity of infections associated with chronic granulomatous disease and delays progression of malignant osteopetrosis. With all interferons, animals given large doses have had abortions, but this does not appear to occur with doses used clinically. Miscarriages were reported in four women given interferon beta-1b in a clinical trial, but a causal relationship with the drug was not established.

With the exception of the abortifacient effects in animals, studies have not documented teratogenicity or other fetal harm in animals or humans receiving interferons. However, the potential for long-term effects in a child exposed to interferons in utero is unknown.

The addition of benzyl alcohol raises another concern. Theoretically, this preservative could cross to the fetus and cause toxicity if the mother is given a dose of a product containing benzyl alcohol immediately before delivery. It's best to avoid interferons during nursing because of the potential for serious toxicity in the infant.

Thalidomide was approved in the United States in 1999 for treating erythema nodosum leprosum, with a strict program in place to prevent pregnancy exposure. The critical period of exposure associated with congenital malformations is 34-50 days after the first day of the last menstrual period, with a critical daily dose of at least 100 mg. Thalidomide is probably excreted into breast milk, although this possibility has not been studied.

BYGERALD G. BRIGGS, B.PHARM.

GERALD G. BRIGGS is pharmacist clinical specialist, Women's Hospital, Long Beach Memorial Medical Center; clinical professor of pharmacy, University of California, San Francisco; and adjunct professor of pharmacy, University of Southern California, Los Angeles. He is also coauthor of the reference book "Drugs in Pregnancy and Lactation."
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Title Annotation:Drugs, Pregnancy, and Lactation
Author:Briggs, Gerald G.
Publication:OB GYN News
Date:Apr 15, 2004
Words:703
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