Pregnancy and Lactation Labeling

This article details what pharmacists need to know about the FDA's new proposed rule on pregnancy and lactation labeling.

In 2006, approximately 4.3 million births occurred in the United States, which was 3% more than in 2005.¹ With an increasing number of pregnancies, of which about half are unplanned, the importance of defining and communicating information about the safe use of medications by pregnant women, breastfeeding women, and other women of childbearing potential has become even more pertinent. Many women of childbearing potential have chronic medical conditions that require ongoing or intermittent treatment with medication, and often treatment must continue during pregnancy. While medication use during pregnancy or breastfeeding may pose some potential risks to the mother and/ or her child, the risks of not properly treating the mother’s condition and the lost benefits of human milk feeding may be greater.

During pregnancy, about 64% of women are prescribed one or more medications (excluding vitamin or mineral supplements).² Because pharmacists are a primary source of medication and health information for many women, pharmacists must have a sound understanding of pregnancy and lactation drug labeling in order to provide optimal information about what is known about the effects of medication when used during pregnancy and breastfeeding. Pharmacists often refer to FDA-approved prescribing information when counseling pregnant, breastfeeding, or childbearing-aged women about using prescription medications. The 1979 federal regulation that describes the required content and format of pregnancy and nursing mothers labeling relies heavily on pregnancy categories, which define different levels of teratogenic risk, and required regulatory language. In May 2008, the FDA proposed new format and content requirements for pregnancy and lactation labeling to improve the organization and presentation of information in these subsections of labeling.

PREGNANCY CATEGORY SYSTEM

Currently, pharmacists and other health care professionals rely heavily on the pregnancy category letter system of the 5 letter designations: A, B, C, D, and X, yet the pregnancy category system has a number of shortcomings (Table 1). Many mistakenly view the pregnancy categories as grades of risk, starting with Category A, for drugs with adequate and well-controlled human studies that show no increased risk to the fetus, and ending with Category X, where use of the drug is contraindicated during pregnancy.^3,4 Both health care professionals and patients may not realize, however, that the categories address not only risk to the fetus but also take into account the balance of risks and benefits to the mother and fetus.⁵ To illustrate, many believe that Category X drugs always have the highest risk for causing harm to the fetus. Oral contraceptives are assigned Category X not because they are human teratogens, but because they offer no benefit of preventing pregnancy in a woman who is already pregnant. As defined by the regulation, the risks of using this Category X drug clearly outweigh the benefit of taking it during pregnancy.⁵

Health care professionals may also be unaware that medications with the same pregnancy category do not all have the same chance for increasing the risk of developmental abnormalities. For example, pregnancy Category C includes medications that cause adverse effects in animal studies, as well as medications with no animal or human data to evaluate adverse developmental effects. One Category C medication may cause mild and infrequent developmental abnormalities in one animal species, and another medication may cause frequent and consistent abnormalities in 2 or 3 species of animals. These 2 drugs do not have the same potential for causing developmental abnormalities in humans—the second drug has a higher potential, but both are designated Category C.

FDA’S PROPOSED RULE FOR NEW PREGNANCY AND LACTATION LABELING

Based on such concerns and misinterpretations of the current pregnancy category letter system, the FDA collected specific recommendations and ideas for designing an improved, more complete, and accessible pregnancy and lactation labeling format to better support health care professionals in selecting medications for use during pregnancy and lactation. The FDA obtained input through public hearings, focus testing with clinicians, and advisory committee meetings.

On May 29, 2008, the FDA published a proposed regulation on format and content requirements for pregnancy and lactation labeling for prescription medications (Table 2). In the proposed regulation, information for both pregnant and lactating women will be presented in 2 consecutive label subsections: “Pregnancy” and “Lactation.” The “Lactation” section will replace the current “Nursing Mothers” subsection, and the “Labor and Delivery” subsection will become part of “Pregnancy.” As proposed, all drugs approved on or after June 30, 2001, will ultimately be required to follow these requirements when a final rule publishes. In addition, pregnancy categories will be eliminated from the labeling and prescribing information.

The “Pregnancy” section will consist of 3 major subsections: Fetal Risk Summary, Clinical Considerations, and Data. Prior to the first subsection, the proposed rule requires inclusion of a general statement about the background risk of birth defects and pregnancy loss in the general population. For drugs with an enrolling pregnancy exposure registry, the labeling will include contact information for the registry. Pregnancy exposure registries are epidemiology studies that prospectively enroll pregnant women who have a particular medical condition or use a particular medication and collect information about maternal, fetal, and infant pregnancy outcomes. Data collected from a pregnancy registry may be included in medication labeling.

The Fetal Risk Summary subsection characterizes any increased risk of developmental abnormalities in humans as well as other relevant risks. Risk conclusions will be based on human and/or animal data. The Clinical Considerations subsection provides clinically useful information to support clinical care and management decisions by health care professionals with their patients. It will provide information on known maternal and fetal risks from the mother’s underlying condition, recommended dosing adjustments, and documented adverse reactions. The Data subsection presents more detailed data that support the information in the Fetal Risk Summary and Clinical Considerations. Here, human and animal data will be presented separately, with human data listed first.⁵

The “Lactation” section will also have sections entitled Risk Summary, Clinical Considerations, and Data. As proposed, the Risk Summary must state whether the medication is present in breast milk and, if so, in what concentration. The Risk Summary must describe any expected adverse effects on the breastfed infant and on milk production. The Clinical Considerations subsection will provide information to help minimize medication exposure to the infant and any recommended dosing adjustments, if known. Finally, the Data subsection presents more detailed data that support information in the Risk Summary and Clinical Considerations.⁵

MOVING FORWARD

After the proposed rule was published, there was a 90-day public comment period. The FDA received many substantial and helpful comments on the proposed rule. A summary of the comments received by the FDA from health care providers, pharmacists, industry, academia, medical organizations, and consumers can be found in Table 3. Many of these responses were favorable, and suggestions for improvement were offered.

When the final rule publishes, it will include responses to all of the issues raised in the public comments, and it may include changes to the regulation in response to these comments. It will also include an implementation plan that will describe which drugs are affected by the new regulation and how these new labeling requirements will go into effect. Rewriting and restructuring labeling is a large job for both drug manufacturers and the FDA, and the new pregnancy and lactation format will be phased in gradually for previously approved drugs. When the FDA finishes writing the final rule, it will pass through a routine, multilayered clearance process before it publishes.

Prescribing decisions are complex and highly individualized, especially for women who are pregnant, lactating, or of childbearing potential. Medication labeling should be a clearly written communication tool for health care professionals to support informed prescribing for and counseling with patients. The FDA developed these proposed labeling requirements for pharmacists, other health care professionals, and their female patients of childbearing potential to improve the safe and effective use of medications during pregnancy and breastfeeding.

No official support or endorsement of this article by the FDA is intended or should be inferred. The views presented in this article do not necessarily reflect those of the FDA.

Dr. Miller is the safety regulatory project manager, Office of New Drugs, Center for Drug Evaluation and Research (CDER), at the FDA, in Silver Spring, Maryland. Dr. Birch-Smith was a labeling reviewer in the Office of Pharmaceutical Science, Office of Generic Drugs, CDER, at the FDA in Rockville, Maryland. Dr. McKinnon is a regulatory project manager, Division of Special Pathogen and Transplant Products, Office of Antimicrobial Products, Office of New Drugs, CDER, at the FDA in Silver Spring, Maryland. Dr. Borders-Hemphill is a drug utilization data analyst, Division of Epidemiology, Office of Surveillance and Epidemiology, CDER, at the FDA in Silver Spring, Maryland. Dr. Flowers was a director health promotion officer, Division of Training and Development, Office of Training and Communications, CDER, at the FDA in Rockville, Maryland. Soim Kim was a sixth-year PharmD student at the University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania.

Table 1

FDA Pregnancy Categories (1979 regulation)

Category

Definition

A

AWC studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters).

B

Animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no AWC studies in pregnant women, OR animal studies demonstrate a risk and AWC studies in pregnant women have failed to demonstrate a risk in any trimester.

C

Animal reproduction studies have shown an adverse effect on the fetus, there are no AWC studies in humans, AND the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. OR animal studies have not been conducted and there are no AWC studies in humans.

D

There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, BUT the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks (eg, if the drug is needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective).

X

Studies in animals or humans have demonstrated fetal abnormalities, OR there is positive evidence of fetal risk based on adverse reaction reports from investigational or marketing experience, or both, AND the risk of the use of the drug in a pregnant woman clearly outweighs any possible benefit (for example, safer drugs or other forms of therapy are available).

AWC = adequate and well-controlled.

Table 2

Model of New Labeling

General Information

Contact information if active pregnancy registry available.

“All pregnancies have a background risk of birth defects, lost, or other adverse outcome, regardless of drug exposure.”

Pregnancy

Fetal Risk Summary

For systemically absorbed drugs:

• When there are human data, there is a statement about the likelihood of increased risk followed by a description of findings.
• When there are only animal data, there is a standard statement about the likelihood of increased risk but no description.

For drugs not absorbed systemically:

• Label states that maternal use is not expected to result in fetal exposure

Clinical Considerations

• Known or predicted risk to the fetus from inadvertent exposure to drug early in pregnancy.
• Any known risk to the pregnant woman and fetus from disease or condition the drug is intended to treat.
• Dosing adjustments during pregnancy.
• Maternal adverse reactions unique to pregnancy or increased in pregnancy.
• Effects of dose, timing, and duration of exposure to drug during pregnancy. Potential neonatal complications and needed interventions.

Data

Description of Studies

• Type of study
• Drug exposure information (dose, duration, timing)
• Limitations of data

Describe nature of any identified fetal/neonatal developmental abnormality or adverse effect.

For human data, includes positive and negative experiences, number of subjects, and duration of study.

For animal data, includes species studied and describe doses in terms of human dose equivalents and include the basis for those calculations.

Lactation

Risk Summary

For systemically absorbed drugs: Lack of data acknowledged OR

• Impact on milk production
• Presence of drug in human milk Drug concentration in milk Estimated infant daily dose Age-related absorption and metabolism
• If the drug is used in the pediatric population, then exposure compared with pediatric exposure.
• If the drug has not been labeled for pediatric use, then exposure in terms of percentage of maternal doses.
• Effects of the drug on breastfed child
• If data shows that the drug does not affect the quantity and quality of breast milk and there is reasonable certainty that either the drug is not detectable in breast milk or will not adversely affect the breast-fed child, then: “The use of (name of drug) is compatible with breastfeeding”

For drugs not absorbed systemically:

• Standard statement that states that maternal use is not expected to result in infant exposure

Clinical Considerations

• Ways to minimize exposure of the breastfed infant
• Dosage adjustments during lactation
• Potential drug effects in the breastfed child
• Consideration of benefits of breastfeeding or risks of not breastfeeding

Data

Overview of data to support risk summary and clinical considerations.

Table 3

Summary of Comments to the New Proposed Pregnancy Labeling Rule Proposal

Pros

Cons

Suggestions

Health Care Providers

(15 comments)

• The current system A, B, C, D, X drug category labeling is unclear.
• There is a lack of useful information in the current system.

• The labeling is verbose and not clinically useful.
• The proposed rule makes it difficult for the average physician to counsel pregnant patients.
• The standardized risk statements (no, low, moderate, or high) are ambiguous and subjective and should be avoided.

• As new information becomes available, this system should be updated.
• There should be inclusion of an online reference which includes updated information.
• The new proposal should be incorporated with the current A, B, C, D, X categories.
• The labeling should also explain the risks of not breastfeeding.
• Keep the letter designations.

Pharmacists

(2 comments)

• The proposed rule would be more helpful when counseling patients.

• Keep the letter designations for quick reference and incorporate the new information.
• Make the labeling user-friendly.

Industry

(8 comments)

• The proposed rule provides clear and complete information to enable informed benefit/risk determinations for pregnant women.
• The proposed rule is particularly useful for pregnancy.

• There is a high cost with establishing a postapproval registry.
• By dropping the A, B, C, D, X categories, FDA would discontinue a longstanding and familiar system that provides a quick and simple reference.
• The use of “low,” “moderate,” and “high” to classify risks can be subjective and confusing.
• Pregnant women are usually excluded from clinical trials, so obtaining pertinent human data will be quite a challenge.

• The agency should provide incentive to the industry similar to the “Pediatric Exclusivity Rule.”
• The proposed rule should not be overly complex or confusing for prescribing physicians and patients.

Academia

(4 comments)

• The proposed labeling rule will allow practitioners to make more informed decisions.

• The proposed labeling is written for someone with a more sophisticated medical background.

• Category X should be maintained even if the other categories are done away with.
• Additional risk information should include short- and long-term side effects if a woman chooses not to take a necessary chronic drug for the duration of her pregnancy.
• The data should be updated annually in a more user-friendly format.

Medical Organizations

(18 Comments)

• The proposed labeling format is more professional and useful for physicians.
• The proposed labeling format provides for more clarity, especially for drugs now listed in Category C.

• The new system does not adequately address inadvertent drug exposures.
• The new system fails to create a useful format for decision making as the current labeling system.
• Applications approved prior to June 29, 2001, do not have to implement proposed labeling format.
• “Low, moderate, high” will create similar problems to the current A, B, C, D, X categories.

• The proposed labeling should be made simple for patients to understand.
• Maintain an “X”-like category.
• Supplemental information should be available electronically.
• The agency should develop educational campaigns for health care professionals and patients regarding the changes.

Other

(7 comments)

• The proposed changes lay the groundwork for improved health outcomes among pregnant and lactating women.

• Applications approved prior to June 29, 2001, do not have to implement proposed labeling format.
• More clarity is needed for inadvertent fetal exposure prior to a woman knowing she is pregnant.

• The risk categories “low, moderate, and high” are confusing and subject to variable interpretations.
• A new section titled “Clinician Summary” should be included to allow physicians to make efficient clinical decisions.
• The language should be made understandable to the average woman.

References:

1. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, et al. Births: Final Data for 2006. National vital statistics report; vol 57 no 7. Hyattsville, MD: National Center for Health Statistics. 2009. Accessed athttp://www.cdc.gov/nchs/data/nvsr/nvsr57/nvsr57_07.pdf, December 16, 2009.

2. Andrade SE, Gurwitz JH, Davis RL, et al.Prescription drug use in pregnancy. Am J Obstet Gynecol. 2004 Aug;191(2):398-407.

3. Hecht A. 1979. Drug Safety labeling for doctors. FDA Consum 13:12-13.

4. Code of Federal Regulations.2001.21CFR201.57, available at http://www.access.gpo.gov/nara/cfr/waisidx_01/21cfr201_01.html, last accessed December 16, 2009.

5. Kweder SL. Drugs and Biologics in Pregnancy and Breastfeeding: FDA in the 21^st Century. Birth Defects Res A Clin Mol Teratol. 2008 Sep;82(9):605-9.