Update on the Pregnancy and Lactation
Labeling Rule (PLLR)
Melissa Neglia, Pharm.D.
Women’s Health Clinical Pharmacist
St. Vincent Women’s Hospital
Indianapolis, IN
September 17, 2015
Disclosure
This speaker has no potential or actual conflicts of interest to
disclose in relation to this presentation.
2
Learning Objectives
• Discuss reasons as to why changes in pregnancy and
lactation labeling are being made.
• Identify the pertinent changes in the new pregnancy and
lactation labeling requirements and explain their use in
practice.
• Summarize the pregnancy and lactation labeling
requirements in each of the three subsections.
3
History
1979
Original
labeling
process in
place
1997-2003
Proposed rule
with new
labeling
format;
expert review
2006
2014
Physicians
Labeling
Rule (PLR)
final
PLLR
published;
revises 8.18.3 of PLR
Goal is to improve labeling as a communication tool.
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US Department of Health and Human Services. 2014: 1-149 accessed at
https://s3.amazonaws.com/public-inspection.federalregister.gov/2014-28241.pdf
Pregnancy Categories
Misused
Confusing
5
Misinterpreted
Affected Medications
Effective June 30th, 2015
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Applications
from June 30,
2015 and
beyond
• FDA requires new
content and format
changes immediately
Applications
June 30, 2001June 30, 2015
• Changes will be phased
in gradually; required
within 3 to 5 years
US Department of Health and Human Services. 2014: 1-149 accessed at
https://s3.amazonaws.com/public-inspection.federalregister.gov/2014-28241.pdf
Staggered Implementation
Approved Applications Subject
to the Physician Labeling Rule
Timeline
June 30, 2001, up to and
including June 29, 2002
3 years after the effective date
of the final rule
June 30, 2005, up to and
including June 29, 2007
3 years after the effective date
of the final rule
7
US Department of Health and Human Services. 2014: 1-149 accessed at
https://s3.amazonaws.com/public-inspection.federalregister.gov/2014-28241.pdf
Staggered Implementation
Approved Applications Subject
to the Physician Labeling Rule
Timeline
June 30, 2002, up to and
including June 29, 2005
5 years after the effective date
of the final rule
June 30, 2007, up to and
including the effective date of
the final rule
4 years after the effective date
of the final rule
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US Department of Health and Human Services. 2014: 1-149 accessed at
https://s3.amazonaws.com/public-inspection.federalregister.gov/2014-28241.pdf
Previous Definitions
• Controlled
A
studies show no risk or adequate, well-controlled
studies have failed to show risk.
B
• Animal findings show risk but human findings do not, or
animal findings are negative with no human studies done.
• Risk
C
cannot be ruled out. Human studies are lacking. Animal
studies show risk or are lacking as well.
• Evidence of
D
risk. Investigational or post-marketing data
shows risk to fetus. However, benefits may outweigh risk.
• Contraindicated in
X
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pregnancy. Studies have shown fetal risks
which clearly outweigh any possible benefit to the patient.
Category Changes
A
X
B
D
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C
Category Changes
Pregnancy
• 8.1 Pregnancy
Labor and delivery • 8.1 Pregnancy
Nursing mothers • 8.2 Lactation
New
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•8.3 Females and Males of
Reproductive Potential
US Department of Health and Human Services. 2014: 1-149 accessed at
https://s3.amazonaws.com/public-inspection.federalregister.gov/2014-28241.pdf
Sample: New Package Insert
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Daklina® (sofosbuvir) package insert.
Pregnancy Trimesters
13
First
Second
Third
•0-13
weeks
•14-26
weeks
•27-40
weeks
General Information
• Revising labeling-new information must be added to
labeling when available
• Formatting- consistent with PLR
• Cross referencing- PLLR subsections will have most
detailed information
• Example: Contraindications and warnings may
briefly discuss information and reference Use in
Specific Populations subsection for details
• May also see cross referencing with the PLLR
subsections (Data and Risk Summary)
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US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM425398.pdf
8.1 Pregnancy
• Pregnancy Exposure Registry
• Risk summary
• Clinical considerations
• Data description
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US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM425398.pdf
Pregnancy Registries
• Omitted if not available
• The FDA’s Office of Women’s Health keeps a list of
registries
• Registries for a number of drug products
• Examples: Drugs for cancer, epilepsy, arthritis, diabetes and
psychiatric conditions
• Information cross referenced in patient counseling section
of labeling
• www.fda.gov/pregnancyregistries
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US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM425398.pdf
Pregnancy Registries- Example
Medicine
Multiple Drugs
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Medical Condition
Registry
Autoimmune Diseases:
Crohn's disease,
OTIS
rheumatoid arthritis,
AutoImmune
psoriasis, psoriatic
Diseases Study
arthritis, multiple
sclerosis
How to contact
Status
MotherToBaby
Pregnancy Studies
conducted by the
Organization of
Teratology
Information
Specialists (OTIS)
Website:
Ongoing
http://www.pregna
ncystudies.org/ong
oing-pregnancystudies/autoimmun
e-studies/
Phone: 1-877-3118972
Pregnancy Registries- Example
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Risk Summary
• Includes background risk information on birth
defects and miscarriage rates in United States for
comparison
• Presented in following order: human, animal,
pharmacologic
• Clinical trials, pregnancy exposure registries, large
scale epidemiologic studies
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US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM425398.pdf
Risk Summary
• Human data includes incidence, effects of dose, effect of
duration of exposure, and effect of gestational timing of
exposure
• Animal data includes number and types of species
affected, timing of exposure, doses expressed in terms of
human dose or exposure equivalents, and outcomes for
pregnant animals and offspring
• Pharmacologic data
• Example- cytotoxic drugs and drugs that inhibit normal sex
hormone production
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US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM425398.pdf
Clinical Considerations
• Disease associated maternal and/or embryo/fetal
risk
• Example- diabetes
• Increased risk for preeclampsia, fetal macrosomia,
ketoacidosis, neural tube defects, cardiovascular
malformations
• Dose adjustments (pregnancy and postpartum)
• Increased volume of distribution, increased renal
clearance
• P450 enzyme changes (ex. CYP1A2 decreases,
CYP2D6 increases)
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US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM425398.pdf
Clinical Considerations
• Maternal adverse reactions
• Reactions included that are unique to pregnancy or
increased in frequency or severity
• Interventions to help decrease this must be stated
here
• Fetal adverse reactions
• Describe severity and reversibility plus available
monitoring in order to avoid reaction
• Example- opiates during labor may cause reversible
respiratory depression in neonate
22
US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM425398.pdf
Clinical Considerations
• Effect on labor and delivery
• Effects on mother and fetus/neonate
• Describe potential severity and reversibility
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US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM425398.pdf
Data
• Scientific basis for information found in Risk
Summary
• Human data
•
•
•
•
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Number of subjects
Study duration
Exposure duration
Limitations
US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM425398.pdf
Data
• Animal data
• Animal species
• Dosing in human equivalents
• Presence or absence of maternal toxicity
• Data source (clinical trial vs. case series vs.
registry)
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US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM425398.pdf
Pregnancy Differences
•
•
•
•
•
•
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Volume of distribution increases
Increased insulin resistance
Cardiac output increases
Elevation of heart rate
Decrease in systemic vascular resistance
Decreased cardiac output in supine position in latter half
of pregnancy
Frederiksen MC. Seminars in Perinatology 2001;25:120-3.
Pregnancy Differences
• Decreased exercise tolerance with advanced gestational
age
• Decreased blood pressure in normal pregnancy
• Increased blood flow to uterus, kidneys, extremities,
breasts, and skin
• Increased renal excretion of certain medications
• Hepatic metabolism changes
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Frederiksen MC. Seminars in Perinatology 2001;25:120-3.
Pregnancy Metabolism Changes
Induction
CYP2A6
CYP2C9
CYP2D6
CYP3A4
Inhibition
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Nicotine (gum)
Phenytoin
Metoprolol, detromethorphan,
citalopram, fluoxetine
Nifedipine, methadone,
indinavir
UGT1A1
UGT1A4
UGT2B7
CYP1A2
Acetaminophen
Lamotrigine
Lorazepam
Caffeine, theophylline
CYP2C19
Proguanil, nelfinavir
Frederiksen MC. Seminars in Perinatology 2001;25:120-3.
Antibiotic use
A 23 year old, 25 week pregnant woman was admitted with
pyelonephritis. Urine culture revealed Citrobacter freundii.
The OB-GYN team asked for help to transition to an oral
antibiotic at home. It was sensitive to quinolones,
sulfamethoxazole/trimethoprim and was resistant to oral
penicillins and cephalosporins.
Is sulfamethoxazole/trimethoprim a reasonable option for
treatment in this patient?
• Yes
• No
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Antibiotic use
• Depends on timing!
• Second trimester use ok if needed
• First trimester use exhibits an increased risk of congenital
malformations
• Third trimester use close to delivery can cause kernicterus
in the newborn
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ACOG Committee Opinion No. 494: Obs & Gyn. 2011;117(6):1484-5.
Crider KS et.al. Arch Pediatr Adolesc Med 2009;163:978–85.
Hernandez-Diaz S et.al. NEJM 2000;343:1608–14.
Labetalol
At YR’s 20 week prenatal visit, her blood pressure is 155/100
(baseline 120/80.) She is started on labetalol 200mg bid.
How will pregnancy affect her labetalol serum concentration?
• A. Serum levels will be higher
• B. Serum levels will be lower
• C. Serum levels will be similar
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Labetalol
•Used for gestational hypertension or preeclampsia
•Metabolized by UGT 1A1
•Increased activity in pregnancy
•Oral clearance increased by 30%
•Shorter half-life
•Higher doses
•Shorter dosage intervals
•More frequent dosing
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Aspirin
A 29 year old with history of chronic hypertension and preeclampsia in previous pregnancy was admitted to the
hospital. Her weight was 197 kg, she was 33 weeks
gestation and her blood pressures at time of admission were
significantly elevated (>160/110). Her home medication list
included aspirin 81 mg orally daily.
Should aspirin be continued in this patient?
• Yes
• No
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Aspirin
• Use in women with a history of early-onset preeclampsia
and preterm delivery (<34 0/7 weeks), or preeclampsia in
≥1 prior pregnancy
• Fetal adverse effects: premature closure of the ductus
arteriosus
• Maternal adverse effects: anemia, hemorrhage, prolonged
gestation, and prolonged labor
• Indomethacin for prevention of preterm labor?
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Abou-Ghannam et al. Am J Perinatol. 2012;29(3):175-86.
Executive Summary: Hypertension in Pregnancy. Obstet Gynecol. 2013;122:1122-31.
8.2 Lactation
• Risk summary
• Clinical considerations
• Data
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US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM425398.pdf
Risk Summary
• Presence of drug in human milk
•
•
•
•
Concentrations in human milk
Actual or estimated infant daily dose
Compared to labeled infant/pediatric or maternal dose
Animal data must specify species with cross reference to
data portion of lactation
• Effects of drug on breastfed child
• Likelihood and seriousness of effects on child
• Include systemic and/or local adverse reactions
• Age related differences in absorption, distributions,
metabolism, and elimination
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US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
Risk Summary
• Effects in milk production/excretion
• Pharmacologic actions or clinically relevant data
• Effect is temporary or permanent
• Example: hydrochlorothiazide for post partum
hypertension can decrease milk volume and suppress
lactation
• Risk and benefit statement
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US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM425398.pdf
Clinical Considerations
• Minimizing exposure
• Drug/metabolite present in clinically relevant
concentrations
• No established safety profile in infants
• Used intermittently, single dose, or short course
• “Pump and dump” discard instructions included
• Monitoring for adverse reactions
• Used for counseling women on relative risks and benefits
• How to monitor for adverse drug reactions in breastfed
child
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US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
Data
• Descriptions of data from Risk Summary and
Clinical considerations
• Updated as new information is available
• If there is no data, omit this subheading
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US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM425398.pdf
New Package Insert- Daklinza®
8.2 Lactation
Risk Summary
No information regarding the presence of daclatasvir in human
milk, the effects on the breastfed infant, or the effects on milk
production is available. Daclatasvir is present in the milk of
lactating rats [see Use in Specific Populations (8.1)]. The
development and health benefits of breastfeeding should be
considered along with the mother’s clinical need for DAKLINZA
and any potential adverse effects on the breastfed infant from
DAKLINZA or from the underlying maternal condition.
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Daklina® (sofosbuvir) package insert.
Older Drugs
• Example- hydrochlorothiazide
• Found in breast milk
• Risk-benefit not discussed in labeling
• Detected in milk but not infant blood
• May have potential for serious adverse reactions in
the nursing infant
• May be needed for post partum hypertension
control especially if not nursing
• May also decrease milk volume and suppress
lactation
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Briggs GG et al. Drugs in Pregnancy and Lactation. 9th ed.; 2011.
Miller ME et al. J Pediatr. 1982;101:789-91.
Sachs, H et al. Pediatrics. 2013;132:e796 -e809.
LactMed Database
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8.3 Females and Males of Reproductive
Potential
Provides a dedicated subsection
• Pregnancy testing
• Contraception information
• Infertility information
Available
• Recommendations or requirements for pregnancy testing
and/or contraception before/during/after drug therapy
• Human and/or animal data is available suggesting drugassociated effects on fertility and/or preimplantation loss
effects
• May be omitted if none of the subheadings are applicable
43
US Department of Health and Human Services. December 2014: 1-21 accessed at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM425398.pdf
Example- Thalidomide (Thalomid®)
• Seen in warning section of older package inserts
and cross referenced in special populations
section
• Provides contact information about program
enrollments
• Information about THALOMID and the THALOMID
REMSTM program
• www.celgeneriskmanagement.com or by calling the
manufacturer’s toll-free number 1-888-423-5436
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Example- Thalidomide (Thalomid®)
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Additional Information
•Briggs’ “Drugs in Pregnancy and Lactation”
•Hale’s “Medications and Mothers’ Milk”
•IN Teratogen Information Service- (317) 274-1071
•Ovid, Medline
•Lexicomp or Micromedex
•OTIS: www.otispregnancy.org
•Cochrane reviews: http://www.cochrane.org/reviews/index.htm
•Motherisk: www.motherisk.org/prof/drugs.jsp
•Perinatology.com: www.perinatology.com
•LactMed: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
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Conclusion
Why modifications to the current package labeling?
• Improved communication allowing for safe and effective
use of medications by prescribers
• Up to date recommendations as change to the label is
required per the new rule
• Less confusion with removal of letter categories
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Update on the PLLR
Melissa Neglia, Pharm.D.
Women’s Health Clinical Pharmacist
St. Vincent Women’s Hospital
Indianapolis, IN
September 17, 2015