Sunday, December 28, 2014

Changes to FDA Pregnancy and Lactation Labeling

On December 3, 2014, the FDA issued a new rule revising the current regulations pertaining to the pregnancy, labor and delivery, and nursing mother sections of the prescribing information for prescription drugs and biologic products. Initiation of this amendment was prompted by the FDA’s goal to provide women and their healthcare providers with sufficient information when deciding which medications to prescribe in pregnant and breastfeeding patients.

Why the change?

Recent data indicate that about 90% of pregnant women take at least one medication and 70% take one or more prescription drugs, potentially putting the fetus at high risk for drug-induced developmental abnormalities. Many pregnant women may also be on medications to control chronic disease states such as hypertension or to manage acute conditions developed during pregnancy such as gestational diabetes.  It is also necessary to consider that about half of all pregnancies are unexpected, leading to unintended drug exposure.

Pharmacokinetic and pharmacodynamic changes

During pregnancy, physiological changes to the cardiovascular, hepatic, and renal systems can alter the pharmacokinetics of medications. Therefore, appropriate dosage adjustments may be required to maintain therapeutic drug levels. Pregnant women have a 40% to 50% increase in blood volume, leading to larger volumes of distribution and potentially subtherapeutic levels of hydrophilic drugs at standard doses. Pregnancy is also associated with an increase in CYP3A4 activity, which contributes to the increased clearance of its substrates such as nifedipine and carbamazepine. Glomerular filtration rate increases 50% during pregnancy, increasing the elimination rate and decreasing the half-life for medications such as digoxin and piperacillin, which primarily undergo renal excretion. These changes in absorption, distribution, metabolism, and elimination must be considered to ensure therapeutic efficacy and safety when prescribing for pregnant women.

Original FDA pregnancy and lactation labeling

The original FDA regulations on pregnancy, labor and delivery, and lactation labeling for prescription drugs were formulated in 1979. Currently, this risk assessment is presented in the commonly known form of pregnancy categories consisting of A, B, C, D, and X designations as described in this table.  

Many limitations to this system were quickly identified and the FDA began public hearings in 1997 to evaluate the labeling regulations.  Some of these limitations include:
  • Purpose was only to present adequate information to assist when prescribing for patients already pregnant, not following drug exposure during an unplanned pregnancy
  • The meaning of these categories is commonly misunderstood and inappropriately applied in practice
  • Oversimplification leads to a misinterpretation
  • 65% to 70% of all prescription drugs are assigned to Pregnancy Category C yet have drastically different sets of supporting evidence and risks
  • Lack of differentiation between data from animal and human studies 

New pregnancy subsection

The new regulations will require elimination of the pregnancy letter categories and formation of a pregnancy subsection and a lactation subsection within the prescribing information.  Information will be presented in each subsection under the standardized headings “Fetal Risk Summary,” “Clinical Considerations,” and “Data.” Preceding these three headings, the drug’s pregnancy exposure registry and its contact information will be listed, if available.  The introduction will also include a concise statement on the background risk in all pregnancies as outlined in this table.

The pregnancy labeling subsection will contain a statement on elevated risk for developmental abnormalities due to the drug and identify whether the source of that data comes from animal or human studies under “Fetal Risk Summary.” Unlike current regulations, the new pregnancy subsection will be required for all prescription drugs including those that are not systemically absorbed and those with limited evidence of risk.  In the event that human data are available, the risk conclusion will also include an evaluation of the data such as changes in the risk with varying dosages, treatment duration, and gestational age.

The next section, “Clinical Considerations,” is aimed at providing information to aid healthcare providers during unexpected drug exposure, in prescribing decisions, and in use during labor and delivery. Finally, the “Data” section will include a comprehensive summary of the available data upon which the information in the “Fetal Risk Summary” and “Clinical Considerations” sections are based. Human data such as drug dosage, type of developmental abnormality, and other adverse events will be described first followed by animal data, including the animal species, available correlation of the drug’s effect in animals to that in humans, and the human dosage equivalent of the animal dosage

New lactation subsection

The lactation subsection is formatted similarly to the pregnancy subsection. For applicable medications, a sentence stating that the drug can be taken while breastfeeding will appear under “Risk Summary.” Drug effects on milk production, if any and/or how much of the drug enters maternal milk, and any adverse effects that have occurred to the infant are also included in this area. The “Clinical Considerations” section will include methods to decrease drug exposure to the infant such as taking the dose at a particular time or using a “pump and dump” strategy to dispose of potentially affected milk. Adverse effects and how to monitor for them along with required dosage adjustments during lactation are also present in this section. The “Data” section will consist of the findings that support the statements in the “Risk Summary” and “Clinical Considerations” sections


This new labeling will be mandatory for any drug approved after June 30, 2015.  For drugs that are approved before this, the deadline to implement the new labeling information ranges from 3-5 years depending on the original application date.

Federal Register. Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling.  21 CFR 201;72063 -72103  Available at: Accessed: January, 2015.
Ramoz LL, Patel-Shori NM. Recent changes in pregnancy and lactation labeling: retirement of risk categories. Pharmacotherapy. 2014;34(4):389-395.
Singh A, Hughes GJ, Mazzola N.  New changes in pregnancy and lactation labeling.  US Pharm  2014;39(10):40-43.

photo by mahalie

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