* An FDA advisory committee has proposed the elimination of the five rankings (A, B, C, D, and X) describing the risks posed to fetuses of drugs taken by pregnant women.
* The five categories will be replaced by pregnancy and lactation subsections, each containing a summary of the risks posed to a fetus and newborn infant, clinical considerations, and a description of research findings.
* The agency's approval of the proposed revisions is expected by the end of 2008; implementation would begin immediately.
For the first time in 29 years the Food and Drug Administration (FDA) has proposed a major change in how drug labeling provides information on a drug's effects on the developing fetus and the breastfed infant. The changes have been proposed to help clarify what some say has been an imprecise and confusing method of imparting crucial information.
Why should all nurses understand drug risk during pregnancy? Its importance is apparent in obstetrics, but the 6 million pregnant women in the United States annually take an average of three to five prescription drugs-for existing conditions (women with hypertension and asthma often continue treatment during pregnancy), conditions worsened during pregnancy, those related to pregnancy (the onset of high blood pressure, for example), and newly acquired ones. Women of childbearing age are seen in every setting, and it's the nurse who is usually the last person to check whether a medication is appropriate for the patient. Additionally, NPs prescribe medications, and they must be thoroughly acquainted with drug labeling in order to quickly assess a drug's appropriateness.
And because it has been estimated that nearly half of all pregnancies are unplanned, nurses should be aware of the possible ramifications of the use of any drug by anyone of childbearing age. If a drug poses serious teratogenic risks, a woman must be tested for pregnancy before the drug is prescribed. Moreover, nurses are asked by patients, family members, friends, and neighbors about the safety of drug use during pregnancy and lactation.
The proposed labeling revisions are expected to be approved before the end of 2008 and will be implemented immediately in the marketing of new drugs. Because a period of several years is allowed for the revision of the labeling of drugs already on the market, there will be overlap of the two labeling formats. The following describes what the proposed changes are and why they're being made.
THE HISTORY OF THE PREGNANCY CATEGORIES
In 1979 the FDA introduced a ranking system (A, B, C, D, and X) for the purpose of classifying drug products according to the risks posed to the fetus and the benefits posed to the pregnant woman (and fetus). The descriptions of categories A and B (and to some extent, C) are based on increasing risk, while the descriptions of categories D and X (and to some extent, C) are based on a comparison of possible risk and benefit. To provide information on drug administration to providers, manufacturers have been required by law to designate the pregnancy categories in all reference materials and package inserts. But criticized as simplistic and misleading, the pregnancy categories have created much confusion. Concerns about the current categorical ranking system include the following:
* By not distinguishing fetal developmental toxicities according to severity, incidence, and type, the categories provide insufficient information for providers and patients seeking to make informed decisions about drug therapy.
* The categories imply that the degree of risk increases with each letter, which is not correct.
* All drugs within a category do not pose an equal risk of fetal developmental toxicity, as is commonly assumed.
* The criteria also permit drugs with known risks and drugs with no known risks to be placed in the same category, a problem that is especially notable in pregnancy category C (which, according to the FDA, is assigned to almost two-thirds of all categorized drugs). This category includes drugs demonstrated to have adverse effects in pregnant animals and drugs that have not been studied in animals.
* The categories do not indicate whether risks are posed in degrees, according to the dosage and the duration of use of a drug, or gestational age at the time of exposure.
* Information on the safety of drug use during lactation is not included in the current labeling format.
PREVIOUS IMPROVEMENT EFFORTS
Since September 1997 the FDA has been evaluating possible revisions to the pregnancy categories in the hope of improving them. The goal has been to devise a simple lettering or numbering classification system based on the substantial research to date that would reflect evidence-based practice and provide meaningful, clinically informative data as well as reliable differentiations in the risks posed. Despite many years' consideration of the matter, the agency was unable to accomplish that goal; determining the appropriateness of drug therapy during pregnancy is too complex to be addressed by a simple coding system. Further complicating the issue is the fact that data on how most drugs affect a developing fetus or a nursed infant aren't available because clinical trials involving pregnant and nursing women have rarely been conducted. To compensate, drug manufacturers have been gathering information during the last few years through pregnancy exposure registries, in which pregnant women taking medication for a chronic or acute condition volunteer to submit information on any complications they experience. To learn more about these registries see the FDA Office of Women's Health Web site: http://www.fda.gov%2fwomens%2fregistries. (Although not tantamount to the data derived from the findings of randomized, controlled clinical trials, the database of a pregnancy exposure registry helps to disseminate much-needed information and might be the only source of data pertaining to many drugs.)
THE PROPOSED REVISIONS
Because of the foregoing problems, the FDA has proposed that manufacturers provide narrative summaries of risks posed by drug products during pregnancy and breastfeeding as well as a discussion of the data supporting the determinations. Thereby, information on adverse drug effects during pregnancy will be presented similarly to information on other adverse effects. The agency has also proposed that manufacturers revise drug labeling by eliminating references to the pregnancy categories, and replacing them with two subsections containing information on the use of the product during pregnancy and lactation. The new Pregnancy and Lactation subsections will each have three components--a risk summary, a clinical considerations section, and a data section.
The fetal risk summary in the Pregnancy subsection will describe the likelihood of fetal developmental abnormalities attributable to drug exposure and whether the determination is based on animal or human data, or both. If human data are available, the summary will include information on the specific developmental abnormality and the incidence, severity, and reversibility of it.
The clinical considerations section will present information on prescribing, education, and counseling, including the advisability of drug treatment, the effect of the untreated disease for which the drug is prescribed on the woman and the fetus, dose adjustment in pregnancy, and alternative treatments. Information on inadvertent fetal exposure will also be included to assist women who have taken a drug prior to realizing they were pregnant.
The data section will provide a detailed analysis of clinical trial findings and other sources of information (postmarketing data) that support the fetal risk summary and clinical considerations section. The Pregnancy subsection will also include information on pregnancy exposure registries and how to contact and enroll in one and a general statement concerning the known risks of birth defects, miscarriage, or other adverse outcomes of pregnancy ("background risk") that exist in the population as a whole regardless of drug exposure, to provide a context for the risks identified in the use of a drug. A sample of the drug labeling Pregnancy subsection can be seen at the FDA Web site: http://www.fda.gov%2fcder%2fregulatory%2f pregnancy_labeling/example_ http://pregnancy.pdf. (Note that the drugs cited in the sample labeling are fictitious.)
If applicable, a statement will be included in the risk summary of the Lactation subsection that the use of the drug has been determined to be "compatible with breastfeeding." Otherwise, the Lactation risk summary will include the effect of the drug on milk production, its transmissibility through breast milk, and the estimated daily dose transmitted and its possible adverse effects on the breastfed infant. Information provided in the clinical considerations section will include ways of minimizing drug exposure to a breastfed child, suggestions for assessing for and responding to possible adverse effects of the drug on the child, and any dosing adjustment recommended during lactation. The data section will provide an overview of findings similar to that in the Pregnancy subsection. A sample of the Lactation subsection can be seen at the FDA Web site: http://www.fda.gov%2fcder%2fregulatory%2fpregnancy%26%2395%3blabeling%2fexample%.
Drug manufacturers will be required to keep the data sections up-to-date, and the FDA will monitor accordingly to ensure their currency. Drug labeling changes most recently submitted to the FDA and in current use can be found within 24 hours of their approval at Daily Med, a Web site sponsored by the National Library of Medicine: http://dailymed.nlm.nih.gov. In addition to searching for new information on the site, one can sign up for notification of changes made to drug labeling as they are introduced, a free-of-charge service that might be a more efficient way to learn of such revisions.
For more on the proposed revisions see http://www.fda.gov%2fcder%2fregulatory%2fpregnancy%26%2395%3blabeling.
Update: Immunosuppressants and Birth Risks
* Mycophenolate mofetil (CellCept) and mycophenolic acid (Myfortic) have been found to cause serious birth defects and spontaneous abortion if used for either approved or off-label indications during the first trimester of pregnancy.
The Food and Drug Administration (FDA) has issued an alert to health care providers concerning the teratogenic effects that mycophenolate mofetil (CellCept) and mycophenolic acid (Myfortic) can have if taken during the first trimester of pregnancy and the possibility that they can also heighten the risk of spontaneous abortion during that time.
CellCept is used to prevent the rejection of transplanted hearts, livers, and kidneys, and Myfortic is approved to prevent the rejection of kidney transplants. Additionally, CellCept is used off label to treat the immune-mediated diseases and conditions systemic lupus erythematosus, rheumatoid arthritis, and erythema multiforme. In response to postmarketing data derived from published and unpublished reports of infants with serious congenital malformations (microtia, cleft lip, and cleft palate) and anomalies of the heart, esophagus, distal limbs, and kidney after exposure to CellCept in utero (see Drug Watch, March) the FDA mandated revision of the labeling of both CellCept and Myfortic in November 2007 to change the pregnancy category from C to D (evidence of risks posed to the human fetus, but the possible benefits of drug use might outweigh them).
An FDA alert has been issued to raise awareness among health care providers in an effort to decrease the occurrence of adverse effects. A pregnancy test should be performed within the week before starting either drug, and nurses and physicians should provide pertinent education to all women of childbearing age who are prescribed these medications, including girls in puberty and perimenopausal women. These patients should be informed of the risks of serious birth defects and of spontaneous abortion if CellCept or Myfortic is taken during the first trimester of pregnancy. The importance of using two forms of contraception while taking either drug should also be emphasized. Use of the dual contraception should begin four weeks before starting the immunosuppressive drug therapy and continue for six weeks after stopping it. (Abstinence can be substituted for contraception, according to the same schedule.) Routine follow-up education on the importance of using contraception while taking either CellCept or Myfortic should be provided at each clinical visit during treatment.
Center for Drug Evaluation and Research. FDA alert: Information for healthcare professionals. Mycophenolate mofetil (marketed as CellCept) and mycophenolic acid (marketed as Myfortic). Rockville, MD: U.S. Food and Drug Administration; 2008 May 16. http://www.fda.gov%2fcder%2fdrug%2fInfoSheets%2fHCP%2fmycophelolateHCP.htm.