Recent Change in Pregnancy and Lactation Labeling

Recent Changes in Pregnancy and Lactation Labeling:

Retirement of Risk Categories

Leda L. Ramoz, and Nima M. Patel-Shori*

Temple University School of Pharmacy, Philadelphia, Pennsylvania

The rapid development and increased availability of novel pharmacologic therapies and pharmaceuticalproducts has amplified the potential for drug exposure during pregnancy. Many drugs are beneficialfor disease state management during pregnancy and provide significant fetal and maternal health bene-fits. However, a paucity of safety data combined with the imprecision of the current risk category sys-tem renders risk versus benefit assessment difficult. In response to decades of criticism, the U.S. Foodand Drug Administration (FDA) is implementing a new pregnancy and lactation labeling rule designedto improve risk versus benefit assessment of drugs used in pregnant and nursing mothers. These rec-ommendations will provide clear and detailed information for both patients and health care providers,and they will include three main categories: risk summary, clinical considerations, and data. The newlabeling rules remove the previous letter risk categorization system (A, B, C, D, X). In this review, wesummarize the upcoming FDA labeling changes and discuss their potential consequences on clinicalpractice.KEY WORDS pregnancy, lactation, labeling, risk categories, U.S. Food and Drug Administration, FDA.(Pharmacotherapy 2014;34(4):389395) doi: 10.1002/phar.1385

There are an estimated 6.5 million pregnan-cies in the United States each year, and about 1in every 10 women of childbearing age is preg-nant each year.1 Inadequate management ofmaternal disease states during pregnancy canhave detrimental effects on fetal health. Maternalhealth issues during pregnancy and lactationmay require use of medication. Current evidencesuggests that 64% of women use at least oneprescription drug during pregnancy and an aver-age of three prescription drugs during preg-nancy.2 Despite uncertain safety, nearly half ofthe prescription drugs used during pregnancyare classified as risk category C, D, or X (poten-tial fetal risk or positive evidence of fetal risk),and 4.6% of these are from category X alone.2

This may be due in part to the high rate of unin-tended pregnancies (~50% of all pregnancies areunintended)3 or the fact that ~66% of all drugs

are categorized as category C.4 Recent changesto pregnancy and lactation drug labeling pro-posed by the U.S. Food and Drug Administra-tion (FDA) in 2008 will enable health carepractitioners to counsel women who are preg-nant, breastfeeding, or of childbearing potential.These changes will also enable practitioners andpatients to better evaluate the risks versus bene-fits of the use of medications in women who arepregnant or breastfeeding.

Historical Considerations

Drug-labeling regulations were introducedbetween 1962 and 1979 in response to the tha-lidomide disaster of the early 1960s. Thalido-mide was initially prescribed as a hypnotic agentand later used for treatment of nausea andvomiting in pregnancy. Thalidomide caused thetragic teratogenesis phocomelia, the congenitalabsence or underdevelopment of extremities.First submitted for approval to the FDA in 1960by William S. Merrell Co., the thalidomideapplication was expected to obtain approval in

*Address for correspondence: Nima M. Patel-Shori, Tem-ple University School of Pharmacy, 3307 N. Broad Street,Philadelphia, PA 19140; e-mail: [email protected]. 2014 Pharmacotherapy Publications, Inc.

as little as 2 months. However, thalidomide wasnever approved for use in the United States pri-marily due to concerns of FDA pharmacologistDr. Frances Kelsey with regard to a lack ofsafety data. Although thalidomide was never offi-cially approved for use, it was distributed tomore than 1000 U.S. physicians for investiga-tional use, resulting in at least 17 confirmedcases of phocomelia in the United States. Thiscan be compared with the more than 8000 chil-dren born with phocomelia worldwide. Despiteunrelenting pressure from William S. MerrellCo., Kelseys unwavering commitment to drugsafety helped safeguard U.S. public health andwellness.5

The thalidomide tragedy illuminated the needto assess all medications for teratogenic potentialprior to marketing or at least prior to use inwomen who are or may become pregnant. As adirect result, in 1962 Congress passed theKefauver-Harris amendments, allowing tighterregulation of drug approval by the FDA. Inaddition, the FDA developed the 1979 Labelingfor Prescription Drugs Used in Man thatincluded pregnancy labeling regulations andintroduction of the pregnancy letter risk catego-ries.5 This system was developed to help guidehealth care providers as they assess the risks ver-sus benefits of medications use during preg-nancy and lactation. This system consists of fiveletter risk categories A, B, C, D, and X (Table1).6 Although these regulations were pivotal inthe improvement of drug safety and efficacy,omission of pregnancy and lactation safety datais permitted for drugs that are not systemicallyabsorbed and those without adequate studies todemonstrate risk.6, 7

Public criticism of pregnancy risk categorieshas been extensive, including during the openhearing of the Public Affairs Committee of theTeratology Society in 1997. The committee sta-ted a unified opinion that the pregnancy riskcategories provide a confusing and inaccuratesource of information for patient counseling,which should be immediately revised by theFDA.7 Common critiques included the absenceof information for accidental exposures, and thenature, severity, timing, incidence rate, or treat-ability of potential fetal injury. For example,phenytoin exposure during pregnancy is thoughtto be most detrimental during the first trimesterdue to potential neural tube defects. Formationof the neural tube is only one important part oforganogenesis (the development of fetal organs),which occurs from 610 weeks of pregnancy

and when risk of teratogenic effects from drugexposure is highest.810 Such congenital malfor-mations produced during teratogenesis can becompared with the use of angiotensin-convertingenzyme inhibitors or angiotensin II receptorblockers during pregnancy, where prenatal expo-sure is associated with a specific fetotoxicity(fetal renin-angiotensin system blockade syn-drome).8, 11 Although teratogenesis results inphysical defects, fetotoxic substances causeinjury due to deleterious effects on fetal develop-ment and growth, potentially resulting indeath.11

In addition, these affects may be compared tothe risks of fetotoxicity throughout child devel-opment. Human clinical data suggest that theuse of selective serotonin reuptake inhibitors(SSRIs) during pregnancy, particularly the thirdtrimester, may increase risk of neurobehaviordisruptions, perinatal complications, and possi-

Table 1. Current Pregnancy Risk Categories and the Stan-dardized Language Delineated by the FDA

Riskcategory FDA statement

A Adequate and well-controlled (AWC) studiesin pregnant women have failed todemonstrate a risk to the fetus in the firsttrimester of pregnancy (and there is noevidence of a risk in later trimesters)

B Animal reproduction studies have failed todemonstrate a risk to the fetus, and there areno AWC studies in pregnant women oranimal studies that demonstrate an adverseeffect, but AWC studies in pregnant womenfail to demonstrate a risk to the fetus duringthe first trimester of pregnancy (and there isno evidence of risk in later trimesters)

C Animal reproduction studies have shown anadverse effect on the fetus, there are no AWCstudies in humans, and the benefits from theuse of the drug in pregnant women may beacceptable despite its potential risks; oranimal studies have not been conducted andthere are no AWC studies in humans

D There is positive evidence of human fetal riskbased on adverse reaction data frominvestigational or marketing experience orstudies in humans, but the potential benefitsfrom the use of the drug in pregnant womenmay be acceptable despite its potential risks

X Studies in animals or humans havedemonstrated fetal abnormalities or there ispositive evidence of fetal risk based onadverse reaction reports from investigationalor marketing experience, or both, and therisk of the use of the drug in a pregnantwoman clearly outweighs any possible benefit

Reprinted with permission from reference 6.

390 PHARMACOTHERAPY Volume 34, Number 4, 2014

bly result in withdrawal syndrome and abnormalneurobehavior beyond the neonatal period.8, 1214

Fluoxetine is excreted in breast milk, and themanufacturer does not recommend its use dur-ing breastfeeding.8, 13, 15, 16 Further investiga-tion is required to elucidate the full effects ofSSRIs on fetal development and neurobehaviorfrom prenatal exposure and exposure duringbreastfeeding.8, 15 The complexities of drug usein the pregnant patient are insufficientlyaddressed in such a minimalized system, result-ing in an overall inability to assess risks versusbenefits of therapy accurately during pregnancy.The pregnancy risk category system not only

provides a deficit of information, but it also gen-erates added confusion about the relative risk ofdrugs stratified within each category. Risk cate-gories are frequently misinterpreted as a gradedsystem, with drugs in the same category sharingthe same risk. For example, inclusion of drugswithin the A, B, and C risk categories are basedprimarily on risk of harm to the developing fetusdue to drug exposure. However, inclusion ofdrugs within the D and X categories is based notonly on the risk to the developing fetus but alsoany potential benefits of maternal (and subse-quent fetal) health in preventing a potentiallysevere or life-threatening disease state.7, 17

It is important to note that two drugs withinthe same pregnancy risk category do not neces-sarily share the same risk. For example, bothisotretinoin and oral contraceptives are categoryX drugs. Whereas the teratogenic effects of iso-tretinoin in humans are well known throughoutthe pharmacologic community, oral contracep-tives are not as well known for having a harmfuleffect on fetal development, although they havedemonstrated some developmental abnormali-ties. Specifically, oral contraceptive exposure latein pregnancy has been associated with masculin-ization of the female infant in humans (~0.3%incidence).8, 18 Oral contraceptives are consid-ered category X drugs because they inducedevelopmental defects, but the primary reason isbecause there is no benefit in taking a medica-tion designed for preventing pregnancy in awoman who is already pregnant.8 Comparedwith other risk categories, the risk C classifica-tion is increasingly confusing due to the inclu-sion of drugs that either animal reproductionstudies have shown an adverse effect on thefetus, there are no adequate and well-controlledstudies in humans, and the benefits from the useof the drug in pregnant women may be accept-able despite its potential risks or animal stud-

ies have not been conducted and there are noadequate and well-controlled studies inhumans.6, 7

Upcoming Labeling Changes

To address these concerns, the FDA has pro-posed a new Pregnancy and Lactation LabelingRule (the Rule).6 Goals of the Rule includeproviding a format conducive to patient counsel-ing and facilitating the transfer of clinical infor-mation without providing a scripted protocol forthe health care provider that may become datedas new data are discovered. The new format ofthe Rule is designed to help provide patient-spe-cific therapy and improve the overall standard ofcare. The Rule was first proposed in 2008 andhas undergone extensive revision by the healthcare community including teratology experts.Currently, the final version of the Rule is in thewriting and clearance process. The FDA hasannounced that publication of the final versionof the Rule will be accompanied by informationfor industry and health care practitioners.19

A copy of the most recent version of the Rulecan be found at the FDA Web site (www.fda.-gov) and at www.regulations.gov. Once final-ized, the Rule will be published in the FederalRegister in the same manner as the 1979 preg-nancy and lactation labeling regulations. In thefuture, updated content requirements of the newrule will be found on each drugs respective pre-scription drug label (package insert). These canbe accessed through the National Library ofMedicine on a Web site called Daily Med (http://dailymed.nlm.nih.gov/).19 The Rule currentlystates that there will be a minimum of a 120-daylag period between publication of the final ruleand implementation of the Rule. The followingprescription drug applications submitted forapproval by the FDA on the following dates willbe required to follow the updated pregnancyand lactation labeling rule:

Applications submitted on or after June 30,2006

Applications for which approval was pendingon June 30, 2006

Applications approved between June 30,2001, and June 30, 2006

Drug applications approved after June 30,2001, but before publication of the Rule willhave a minimum of 3 years to submit labelingwith updated content. Drug applicationsapproved prior to June 29, 2001, are not subject

RECENT CHANGES IN PREGNANCY AND LACTATION LABELING Ramoz and Patel-Shori 391

to the updated pregnancy and lactation labelingrule and are not required to implement updatedcontent requirements. However, if any suchapplications carry a pregnancy risk category des-ignation, they will be required to remove thatdesignation within 3 years of the efficacy date ofthe Rule.6

Format of the new label incorporates a newstreamlined design led by a brief description ofany pregnancy registry contact information(Table 2). Although many medications have notbeen studied in pregnant women, it is importantto educate both the health care provider and thepatient on registries that collect and maintaindata on the effects of medication use by preg-nant and nursing women. The new label alsoincludes the following brief background riskstatement for all pregnancies: All pregnancieshave a background risk of birth defect, loss, orother adverse outcome regardless of drug expo-sure. The fetal statement risk summary belowdescribes (name of drug) potential to increasethe risk of developmental abnormalities abovethe background risk.6 Core elements of the

new labeling rule include three main subsections(in the following order): risk summary, clinicalconsiderations, and data for both pregnancy andlactation sections.6 The updated Rule proposesto combine the previous sections of pregnancyand labor and delivery into a single preg-nancy category; the breastfeeding section willbe converted into a lactation section.19

Pregnancy: Risk Summary, Clinical

Considerations, and Data

The risk summary section first describes theprobability of developmental abnormalities oradverse outcomes in humans and may containmore than one summary depending on other rel-evant risks. After the risk statement, a briefcharacterization of risk is described following aformat depending on the origin of the data. Ifthe risk is based on human data, there will be abrief description of data supporting the riskstatement. If the potential risk is inferred fromonly animal data (Table 3), a standardized state-ment will describe the risk using the following

Table 2. Overview of New Pregnancy and Lactation Labeling

General informationContact information if pregnancy registry available and general statement about background risk

Fetal risk summaryBased on all available data, this section characterizes the likelihood that the drug increases the risk of developmentalabnormalities in humans and other relevant risks. More than one risk conclusion may be needed. For drugs that are notsystemically absorbed, there is a standard statement that states that maternal use is not expected to result in fetalexposureFor drugs that are systemically absorbed:

When there are human data, include a statement about the likelihood of increased risk based on these data. This state-ment is followed by a description of findings

Include a standard statement about likelihood of increased risk based on animal dataClinical considerationsThis section provides information on the following topics:

Inadvertent exposure: known or predicted risk to the fetus from inadvertent exposure to drug early in pregnancy Prescribing decisions for pregnant women:

Describe any known risk to the pregnant woman and fetus from the disease or condition that the drug is intendedto treat

Information about dosage 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

DataHuman and animal data are presented separately, with human data presented first

Describe study type, exposure information (dose, duration, timing), any identified fetal developmental abnormality, orother adverse effects

For human data, include positive and negative experiences, number of subjects, and duration of study For animal data, include species studied, and describe doses in terms of human dose equivalents (provide basis forcalculation)

Reprinted with permission from FDA.gov (http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/UCM093313.pdf).19


specific language delineating a scale: none, low,moderate, high, or unknown. The Rule willapply to all drugs, including those with no sys-

temic absorption and with limited data demon-strating risk. If a drug is not systematicallyabsorbed, it must contain the following state-

Table 3. Updated Pregnancy Labeling for a Fabricated Drug (Alphathon) for Which Only Animal Data Are Available forDevelopmental Toxicity Findings

General informationAll pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. Thefetal risk summary below describes Alphathons potential to increase the risk of developmental abnormalities above thebackground risk

Fetal risk summaryBased on animal data, the likelihood that Alphathon increases the risk of developmental abnormalities is predicted to behigh (see Data section)

Clinical considerationsAsthma complicates ~1% of all pregnancies, resulting in higher perinatal mortality, lowbirth weight infants, pretermbirths, and pregnancy-induced hypertension compared to outcomes for nonasthmatic women. Because of the risks of evenmild maternal hypoxia to the developing fetus, asthma should be clinically well controlled during pregnancy. There areno human studies evaluating Alphathon use in pregnant women. The time of gestation at which risk may be greatest isunknown; therefore, risks of inadvertent exposure in early gestation cannot be evaluated. Animal data suggest thatAlphathon exposure may result in early fetal loss and anomalies of major organ systems. There are no data regardingdosage adjustment needs in pregnancy. Given the lack of human data and the risks suggested by animal data, prescribersshould consider alternative treatments for asthma for pregnant women when possible (especially during the firsttrimester) and for women planning pregnancy

DataHuman data:

There are no data on human pregnancies exposed to Alphathon

Animal data:

Reproductive studies performed during early pregnancy in rats at oral doses 0.751.0 times the recommended humandose (adjusted for body surface area) showed implantation loss, fetal resorptions, and major congenital anomalies ofthe cardiac, skeletal, and renal systems without signs of maternal toxicity

Reproductive studies performed in early pregnancy in rabbits at doses ~0.331.0 times the recommended human dose(adjusted for body surface area) showed increased postimplantation loss. Studies at three times the human doseshowed significant fetal loss without signs of maternal toxicity

The effects of Alphathon on fetal growth, labor, or postnatal complications were not evaluated in the animal studiesReprinted with permission from FDA.gov (http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/UCM093313.pdf).19

Table 4. Updated Lactation Labeling for a Fabricated Drug (Gammatol) for Which Human Data are Available

Risk summaryGammatol is secreted in human milk. At a maternal dose of 400 mg daily, the average milk concentration, collected over24 hrs after dosing, was 10 mcg/ml, which is lower than maternal serum drug concentrations at steady state. Based on anaverage milk consumption of 150 ml/kg/day, a 2-mo-old infant would consume ~6 mg/day of Gammatol through breastmilk, which is ~1.3% of the maternal dose. No studies have been performed to assess infant absorption and exposure toGammatol from breast milk. No studies have been performed to assess the impact of Gammatol on milk production or itseffects on the breastfed child

Clinical considerationsBecause Gammatol is taken once daily, mothers can reduce infant exposure by taking their Gammatol dose immediatelyafter breastfeeding at the time of day when feedings are less frequent

DataA lactation study was performed in 30 women who were 2 mo postpartum and exclusively breastfeeding their infants. Allwomen enrolled in the study were taking a single dose of Gammatol 400 mg daily. Breast milk samples were collectedfrom each breast at the beginning and end of each feeding for 24 hrs after a Gammatol dose. An average maximum milkconcentration of 20 mcg/mL occurred 3 hrs after dosing, and drug concentrations in milk rapidly declined over the next12 hrs. The average milk concentration was 10 mcg/ml. No drug was detectable in milk samples obtained 36 hrs or laterafter dosing. No data are available to assess the impact of Gammatol on milk production or its effects on the breastfedchild

Reprinted with permission from FDA.gov (http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/UCM093316.pdf).19


ments within the risk summary: (Name ofdrug) is not absorbed systemically from (part ofbody) and cannot be detected in the blood.Maternal use is not expected to result in fetalexposure to the drug.6, 7

The second section of the labeling formation,clinical considerations, will include relevantinformation for prescribing decisions and patientcare along with information about unintendedexposures. This section also addresses the risksof untreated conditions, dosage adjustmentinformation during pregnancy, unique orincreased adverse reactions present during preg-nancy, and potential fetal complications andpossible interventions. Information detailing useduring labor and delivery will be containedunder the clinical considerations subsection.The final segment of the new pregnancy label,

the data section, will include a detailed discus-sion on the clinical trial or study. Drug informa-tion such as dosage, duration, timing, type offetal abnormality, or other adverse outcomesobserved will be declared in this section. Humandata will be discussed before animal data, andanimal data must include species informationand compare to human dose equivalent (mustprovide a basis for comparison such as body sur-face area).6, 19

Lactation: Risk Summary, ClinicalConsiderations, and Data

The previous Nursing Mothers section willbe relabeled Lactation. The core of theupdated lactation label will follow the sameformat as the updated pregnancy label withsections including a risk summary, clinical con-siderations, and data segment (Table 4). Anyadverse effects on the breastfed infant and milkproduction must be described. A drug undetect-able in breast milk that is also not shown toaffect quantity and quality of breast milk or doesnot adversely affect the breastfed child will con-tain the following label: The use of (name ofdrug) is compatible with breastfeeding.6

Drugs present in breast milk must include adescription of the concentration and sensitivityof assay used to measure the quantity of drugfound in breast milk and the estimated dailyinfant dose during breastfeeding. Clinical con-siderations include adverse effects to the infant,monitoring recommendations, and associatedinterventions as well as a description of anyfeeding techniques or dosage adjustments tominimize infant drug exposure.6, 7, 19

Elimination of the Letter Risk Categories

The Rule also proposes the retirement of thehighly criticized letter risk categories (A, B, C, D,X). This should help eliminate some of the confu-sion regarding drug use and fetal health risk. TheRule delineates removal of all pregnancy risk cat-egories from any drug application within 3 yearsof its effective date. Undoubtedly, there will benew drug applications approved within this 3-year time frame that will adhere to the updatedpregnancy and lactation labeling requirements.6

This creates an interim where there will exist notonly a new, but also a dual, pregnancy risk strati-fication system. This raises additional potentiallyserious concerns for health care practitionersattempting to optimize the clinical care of preg-nant and lactating patients. Prudent health carepractitioners should keep a close watch on theupcoming debut of these changes.In a categorical fashion similar to the risk cat-

egories, the Rule proposes the use of standard-ized language (none, low, moderate, high, orunknown [Table 3]) to describe the risk fordrugs in which only animal studies are avail-able.6 Although the Rule provides an added ben-efit of including much more information thanwhat was provided for the risk categories, it isimportant to note that most of the prescriptionmedications only provide animal data to supportsafety and efficacy use. This underscores theimportance of enrolling patients who are takingmedications during pregnancy in pregnancy reg-istries. It is also important to emphasize theimportance of making educated health care deci-sions using a patient-specific versus a standard-ized one-size-fits-all approach.

Conclusion

The rapid evolution of modern pharmacypractice necessitates constant revision of policyand procedure to maintain the safety and welfareof patients. Implementation of the new Preg-nancy and Lactation Labeling Rule will improvethe ability of health care practitioners andpatients to better understand the risks associatedwith medications (or lack thereof) during preg-nancy and lactation. The new labeling designshould provide additional information necessaryfor providing the best standard of care for boththe mother and child during pregnancy andbreastfeeding that was not present in the originalpregnancy labeling rule. This streamlined formatwill enable practitioners to identify critical infor-


mation quickly during a busy workday and navi-gate the complexity of medication use and thera-pies within this specific subgroup of patients toprovide optimal recommendations. Overall, theRule will improve the standard level of care andrisk management of pregnancy and of childbear-ing or breastfeeding patients.

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Recent Change in Pregnancy and Lactation Labeling