FDA Pregnancy and Lactation Package Insert Labeling Changes

Julie L Cunningham, PharmD, BCPP

This session can be purchased in CPNP University.

Do the new changes in the FDA pregnancy categories have you confused? Or perhaps you might be missing the ease of the ABC rating scales? In December, 2014 the FDA published a final rule that sets standards for how information on the safety of medicines during pregnancy and lactation will be presented in the labeling of prescription drugs and biological products. The new content and formatting requirements will provide a more consistent way to include relevant information. This decision replaces the current product letter categories – A, B, C, D and X – used to classify the risks of using prescription drugs during pregnancy with three detailed subsections that describe risks within the real-world context of caring for pregnant and lactating women who may need to take medications.

The formal FDA Pregnancy and Lactation Labeling Rule (PLLR) went into effect on June 30, 2015. Pregnancy and lactation package insert information changes will be implemented in the labeling for all newly approved medications and all current medications will have the old pregnancy categories removed by June 30, 2018.¹ Many may be wondering how these changes will impact practice. At the CPNP 2016 session, Navigating the FDA Label Changes for Pregnancy and Lactation Risks Associated with Medications, Dr. Amy Crawford, PharmD, pediatric clinical specialist at the Eugenio Litta Children's Hospital at the Mayo Clinic, Rochester, MN provided an overview intended to help clarify these changes.

Dr. Crawford reviewed the history of FDA requirements related to pregnancy and lactation package labeling in the format of the ABCDX categories. When implemented in 1979, this information soon became highly relied upon but often misinterpreted or misused by allied health care providers and patients. The new labeling changes not only remove the familiar categories but also consolidate information and add a subsection in the prescription drug labeling. Section 8.1 includes pregnancy and labor and delivery information, section 8.2 provides lactation information, and the newly added section 8.3 provides information, when available, for females and males of reproductive potential.

In order to illustrate how to use the new section, Dr. Crawford walked through section 8 of a newly approved medication. Information is provided on the existence of a pregnancy exposure registry. Patients taking medications that have existing registries should be encouraged to enroll to provide outcome information. Next, a risk summary is provided that supplies information on any known adverse outcomes, including animal data. Following the summary section is the section on clinical considerations. This includes disease-associated maternal and or embryo/fetal risk, dose adjustment information, and any know maternal or fetal/neonatal adverse reactions.

Although the existence of a black and white letter category associated with risk no longer exists, the new format is intended to supply information in a manner that helps make prescribing decisions and to counsel women on the use during pregnancy. Much of the past criticism with the letter categorization included assumptions that medications in the same category carried equal risks.

When little information is available to guide decision making for pregnancy and lactation, we can consider medication pharmacokinetic factors when helping make informed decisions. Drugs that diffuse into the placenta and breast milk generally have the following characteristics: low molecular weight (<500-800 Da), high volume of distribution (>30 L/kg), lipid-soluble, low plasma protein binding, and high pH drugs may concentrate in breast milk.^2-4

When considering the risk versus benefit of psychiatric medication use in pregnancy with untreated maternal depression, drug effects need to be considered as well as the risk to the fetus. When medications are abruptly discontinued, 70% of women will have symptoms of depression and 33% will become suicidal.^5-6 Additional risks to the fetus include premature delivery, NICU admission, and decreased breastfeeding.

Take Home Points

• As of June 30, 2015 all new medication package insert labeling will no longer have the old, familiar pregnancy and lactation letter categorization.
• Medications approved prior to June 30, 2015 have until June 30, 2018 to completely remove the letter categorization from labeling.
• Consider pharmacokinetic information when evaluating medications for pregnancy and lactation risk when little clinical information is available.
• The risk of untreated disease state symptomatology should also be considered when counseling on medication pregnancy and lactation risk in addition to medication risk.

References

1. Content and Format of Labeling for Human Prescription Drug and Biological Products; 21 CFR Part 201
2. Syme MR, Paxton JW, Keelan JA. Drug transfer and metabolism by the human placenta. Clin Pharmacokinet. 2004;43(8):487-514. DOI: 10.2165/00003088-200443080-00001 . PubMed PMID: 15170365 .
3. Sachs HC. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics. 2013;132(3):e796-809. DOI: 10.1542/peds.2013-1985 . PubMed PMID: 23979084 .
4. Nice FJ, Luo AC. Medications and breast-feeding: Current concepts. J Am Pharm Assoc (2003). 2012;52(1):86-94. DOI: 10.1331/JAPhA.2012.10139 . PubMed PMID: 22257621 .
5. Einarson A, Selby P, Koren G. Abrupt discontinuation of psychotropic drugs during pregnancy: fear of teratogenic risk and impact of counselling. J Psychiatry Neurosci. 2001;26(1):44-8. PubMed PMID: 11212593 .
6. Engelstad HJ, Roghair RD, Calarge CA, Colaizy TT, Stuart S, Haskell SE. Perinatal outcomes of pregnancies complicated by maternal depression with or without selective serotonin reuptake inhibitor therapy. Neonatology. 2014;105(2):149-54. DOI: 10.1159/000356774 . PubMed PMID: 24356332 .