FDA Pregnancy Categories

FDA Pregnancy Risk Information: An Update

In 2015 the FDA replaced the former pregnancy risk letter categories (see below) on prescription and
biological drug labeling with new information to make them more meaningful to both patients and
healthcare providers. The FDA received comments that the old five-letter system left patients and
providers ill-informed and resulted in false assumptions about the actual meaning of the letters.

The new labeling system allows better patient-specific counseling and informed decision making for
pregnant women seeking medication therapies. While the new labeling improves the old format, it still
does not provide a definitive yes or no answer in most cases. Clinical interpretation is still required on
a case-by-case basis.

The Pregnancy and Lactation Labeling Final Rule (PLLR) went into effect on June 30, 2015; however,
the timelines for implementing this new information on drug labels (also known as the package insert) is
variable.

Prescription drugs submitted for FDA approval after June 30, 2015 will use the new format immediately,
while labeling for prescription drugs approved on or after June 30, 2001 will be phased in gradually.
Medications approved prior to June 29, 2001 are not subject to the PLLR rule; however, the pregnancy
letter category must be removed by June 29, 2018. For generic drugs, if the labeling of a reference listed
drug is updated as a result of the final rule, the abbreviated new drug application (ANDA) labeling must
also be revised. Labeling for over-the-counter (OTC) medicines will not change, as OTC drug products are
not affected by the new FDA pregnancy labeling.

The A, B, C, D and X risk categories, in use since 1979, are now replaced with narrative sections and
subsections to include:

Pregnancy (includes Labor and Delivery):

Pregnancy Exposure Registry

Risk Summary
Clinical Considerations
Data
Females and Males of Reproductive Potential

Pregnancy Testing
Contraception
Infertility
The Pregnancy subsection will provide information about dosing and potential risks to the developing
fetus and registry information that collects and maintains data on how pregnant women are affected when
they use the drug or biological product. Information in drug labeling about the existence of any pregnancy
registries has been previously recommended but not required until now. Contact information for the
 registries will also be included, and pregnant women are encouraged to enroll to help provide data on the
effects of drug use or biologics in pregnancy.

If information for the subsections of Pregnancy Exposure Registry, Clinical Considerations, and Data is
not available, these subsections will be excluded. The Risk Summary subheadings are always required,
even if no data is available.

The Lactation subsection will replace the Nursing Mothers subsection of the old label. Information will
include drugs that should not be used during breastfeeding, known human or animal data regarding active
metabolites in milk, as well as clinical effects on the infant. Other information may include
pharmacokinetic data like metabolism or excretion, a risk and benefit section, as well as timing of
breastfeeding to minimize infant exposure.

In the subsection entitled Females and Males of Reproductive Potential, relevant information on
pregnancy testing or birth control before, during or after drug therapy, and a medications effect on fertility
or pregnancy loss will be provided when available.

Why Did the FDA Make This Change?

Clinically, many women require drug treatment during pregnancy due to chronic conditions such as
epilepsy, diabetes, hypertension (high blood pressure), or asthma. To withhold drug treatment would be
dangerous for both mother and baby. In addition, women are having babies at a later age, which can boost
the number of women with chronic conditions. Accessible and understandable pregnancy and lactation
information is important for women and their health care providers to assess risk versus benefit.

The FDA has received requests to improve the decades-old content and format of pregnancy prescription
drug labeling since 1992. According to the Drug Information Division at the FDA, they obtained input
from many affected groups and held public hearings, advisory committee meetings, and focus groups to
assess the changes. In 2008, the FDA issued the proposed rule and then opened a docket for public
comments.

Clinicians and patients were often confused by the meaning of the pregnancy risk categories because,
according to the FDA, it was overly simplistic, led to misinformation, and did not adequately address the
available information.

Examples of drugs approved since June 30th, 2015 showing various new pregnancy and lactation
subsections in their labels:

Addyi (flibanserin) - indicated for generalized hypoactive sexual desire disorder (HSDD) in
premenopausal women.
Descovy (emtricitabine and tenofovir alafenamide fumarate) - indicated for HIV-1 infection.
Entresto (sacubitril and valsartan) - indicated for heart failure.
Harvoni (ledipasvir and sofosbuvir) - indicated for chronic viral hepatitis C infection (HCV).
Praluent (alirocumab) - indicated for heterozygous familial hypercholesterolemia, or patients with
atherosclerotic heart disease who require additional lowering of LDL-cholesterol.

FDA Pregnancy Risk Categories Prior to 2015

The former pregnancy categories, which still may be found in some package inserts, were as follows:

Category A
Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of
pregnancy (and there is no evidence of risk in later trimesters).
Example drugs or substances: levothyroxine, folic acid, liothyronine

Category B
Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and
well-controlled studies in pregnant women.
Example drugs: metformin, hydrochlorothiazide, cyclobenzaprine, amoxicillin, pantoprazole

Category C
Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-
controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite
potential risks.
Example drugs: tramadol, gabapentin, amlodipine, trazodone

Category D
There is positive evidence of human fetal risk based on adverse reaction data from investigational or
marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant
women despite potential risks.
Example drugs: lisinopril, alprazolam, losartan, clonazepam, lorazepam

Category X
Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of
human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks
involved in use of the drug in pregnant women clearly outweigh potential benefits.
Example drugs: atorvastatin, simvastatin, warfarin, methotrexate, finasteride