Changes to U.S. Drug Labeling – Pregnancy Language Requirements

By Darren Scheer, MPH, Dr. Catherine E. Patterson, and Mikel Alberdi, MPH   01/22/2019

  Category: Good Industry Practices

The professional prescription drug labeling, such as the prescribing information (PI) or package inserts found in the PDR or at FDA websites, is intended to be the main drug information communication tool directed to prescribers.  The labeling must describe the proper and approved uses of a drug.  In addition, safety information detailing potential and observed adverse events, including strategies to mitigate their occurrence, must be provided to ensure safe drug administration and proper care of patients, including patients in special populations.  One of the most important concepts that must be considered when prescribing pharmaceutical products is the potential impact on the fetus in a pregnant woman.  Therefore, these risks must be thoroughly and clearly relayed to prescribers in the professional labeling.

The Pregnancy Categories for the labeling of U.S. prescription pharmaceutical products were finalized in 1979 and codified in 1980 by FDA (44 FR 37434, 1979; 21 CFR §201.57(f)(6)).  Thecategory designations were directed to be placed in the Precautions[i] section of the professional labeling under the subsection titled “Pregnancy.”  Under this subsection, all systemically absorbed drugs were required to have the heading “Teratogenic effects” in which the drug was classified into one of five FDA-specified pregnancy categories: A, B, C, D, or X. 

The Pregnancy Category A (e.g. folic acid,levothyroxine) designation was given to products for which a risk to the fetus was not demonstrated in the first trimester in adequate and well-controlled clinical trials and there were no reports at other times of exposure.  Category B (e.g. amoxicillin, ranitidine, buspirone, metformin) described drugs for which fetal risk was not demonstrated in animal reproduction studies and no adequate and well-controlled studies in pregnant women existed.  Additionally, Category B was also used if animal studies had shown fetal effects, however human fetal risks were not demonstrated in adequate and well-controlled studies during the first trimester of pregnancy (and no evidence of risk in later trimesters). Category C (e.g. fluconazole, albuterol, sertraline, fluoxetine) described products for which animal studies showed a risk to the fetus, yet no adequate and well-controlled trials in humans existed. Category D (e.g. valproate/valproic acid for epilepsy and mania, clonazepam, paroxetine)was required if evidence showed human fetal risk based on adverse reaction data from investigational or marketing experience, or human studies. However,with Category D, the potential benefits from the use of the drug in pregnant women were acceptable despite its potential risks (e.g. drug necessary in a life-threatening situation or serious disease for which safer drugs could not be used or were ineffective).  Additionally, both human and animal data were to be described in the Warnings section of the professional label.Finally, the designation Category X (isotretinoin, valproate/valproic acid for migraine, atorvastatin and other statins, warfarin, temazepam, thalidomide) was reserved for drugs in which human or animal studies revealed fetal abnormalities or evidence existed of fetal risk based on adverse reaction reports from investigational or marketing experience.  Additionally, the risk to the pregnant woman and fetus with a Category X drug clearly outweighed any possible benefit (for example, safer drugs or other forms of therapy were available). The Category X drugs were required to describe pertinent human and animal data in the Contraindications section of the labeling. If a pregnant woman happened to be exposed to a Category X drug, it was imperative that she be apprised of the potential hazard to the fetus. 

In 2006, FDA revised the content and format of prescription drug labeling (FDA Guidance for Industry: Labeling for Human Prescription Drug and Biological Products – Implementing the New Content and Format Requirements, January 2006; 21 CFR §201.56; 21 CFR §201.57).[ii]A result of these changes was the creation of a new ‘Use in Specific Populations’ section.  This section included the Pregnancy Category information.  The general pregnancy regulations remained unchanged. 

Over the decades that the pregnancy category requirements were in place, concerns arose related to the use of these categories to sufficiently warn of congenital malformations (Proposed Rule 73 FR 30831, May 29, 2008; Summary of Proposed Rule on Pregnancy and Lactation Labeling, November 12, 2009).  For example, the categories did not necessarily connote escalation of teratogenic risks across categories (A, B, C, D, X) and did not take into consideration relevant predictive factors.  Additionally, multiple drugs within the same category (e.g. Category D) did not necessarily present equivalent risks for congenital abnormalities.  These issues could lead to misleading/confusing information provided to potential prescribers and patients, not allowing for an informed risk-benefit analysis.  This wasa concern even though the human and animal data used to determine the pregnancy categories were required to be described in the labeling.

Under the current Pregnancy and Lactation Labeling Rule (PLLR), products marketed pursuant to 21 CFR 201.80 (many older drugs) are now required to remove the pregnancy category letter, but not the standard language that describes the category.  However, along with no longer having a pregnancy category, drugs marketed according to 21 CFR 201.57 (more recent approvals) are required to present narrative summaries of the risks of exposure during pregnancy in Section 8.1 of the label.  These summaries are to include discussions of both the human and animal data that describe the risks to the fetus across all trimesters, any information regarding pregnancy exposure registries, important clinical considerations, and overall risk summary statements (even if no data or information is available).  Additionally, any impact on lactation or female and male reproductive potential is required to be discussed in Sections 8.2 and 8.3, respectively.  These changes are intended to present less confusion and eliminate any artificial hierarchies of risk that previously existed, especially when making clinical prescribing determinations with comparisons among various drugs.

Many companies are now required to change the pregnancy information and presentation in the professional labeling of their products.  Additionally, new products must conform to this entirely new pregnancy information format.  These FDA label regulations apply to products approved by both New Drug Applications (NDA) and Abbreviated New Drug Applications (ANDA) pathways.  The scientists, regulatory affairs consultants, and FDA experts at Biotech Research Group (BRG) have an abundance of experience with writing the professional labeling across various drug classes to ensure FDA compliance.  This includes the pregnancy labeling sections and the information required to be included so that prescribers and patients are fully informed of potential risks and the necessary steps to mitigate these risks.  Feel free to contact us with any questions related to your product labeling or any other regulatory affairs services and consulting needs you may have.

Author Information:

Darren Scheer, MPH, RAC is Vice President of Epidemiology and Pharmacovigilance for BRG.  He has more than 20 years of experience with FDA regulated products, including drugs, biologicals, devices, combination products, and tissue.  He has directed and developed various pharmacovigilance and epidemiological assessments.  These include a wide variety of regulatory and development projectsrequiring FAERS/MAUDE analyses, health claims database assessments, adverse event/safety summaries, and product labeling adequacy determinations.

Dr.Catherine E. Patterson is Chief Scientific Officer for BRG and offers regulatory expertise utilizing her background in Molecular Biology with academic experience in life science research, grant writing and publishing. She actively directs and participates in regulatory submissions, clinical trials and safety surveillance activities on behalf of BRG clients.

Mikel Alberdi, MPH, RAC is Vice President of Regulatory Affairs for BRG. He has over a decade of regulatory affairs experience, with expertise in facilitating FDA meetings and the pivotal submissions (e.g. pre-IND, IND, NDA,505(b)(2), ANDA, and post marketing supplements). He oversees all BRG development activities and ensures regulatory appropriateness of the information provided by BRG.

BRG is a global scientific & regulatory consulting firm with extensive experience in the strategic development of drug products, biologics, medical devices, combination products and in FDA regulatory affairs. As such, BRG is an integral part of client decision-making processes.

The opinions and statements in this blog are those of the authors and do not necessarily reflect those of BRG. This blog is based on personal experience and reviews of information publicly available or identified in other database searches.

[1] The Warnings and Precautions, as one unified section, was not implemented until 2006 with the ‘Physician Labeling Rule’ (PLR) and the final regulations governing the package insert [1] Ibid