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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
2
Disclosure
This speaker has no potential or actual conflicts of interest to disclose in relation to this presentation.
3
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.
4
History
1979 Original labeling
process in place
1997-2003Proposed rule
with new labeling format;
expert review
2006Physicians Labeling
Rule (PLR) final
2014PLLR
published; revises 8.1-8.3 of PLR
Goal is to improve labeling as a communication tool.
US Department of Health and Human Services. 2014: 1-149 accessed at https://s3.amazonaws.com/public-inspection.federalregister.gov/2014-28241.pdf
5
Pregnancy Categories
Misused
MisinterpretedConfusing
6
Affected Medications
Applications from June 30,
2015 and beyond
•FDA requires new content and format changes immediately
Applications June 30, 2001- June 30, 2015
•Changes will be phased in gradually; required within 3 to 5 years
Effective June 30th, 2015
US Department of Health and Human Services. 2014: 1-149 accessed at https://s3.amazonaws.com/public-inspection.federalregister.gov/2014-28241.pdf
7
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
US Department of Health and Human Services. 2014: 1-149 accessed at https://s3.amazonaws.com/public-inspection.federalregister.gov/2014-28241.pdf
8
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
US Department of Health and Human Services. 2014: 1-149 accessed at https://s3.amazonaws.com/public-inspection.federalregister.gov/2014-28241.pdf
9
Previous Definitions
A• Controlled 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.
C• Risk cannot be ruled out. Human studies are lacking. Animal studies show risk or are lacking as well.
D• Evidence of risk. Investigational or post-marketing data shows risk to fetus. However, benefits may outweigh risk.
X
• Contraindicated in pregnancy. Studies have shown fetal risks which clearly outweigh any possible benefit to the patient.
10
Category Changes
AB
CD
X
Removed from product
labeling
11
Category Changes
Pregnancy • 8.1 Pregnancy
Nursing mothers• 8.1 Pregnancy
Labor and delivery • 8.2 Lactation
New •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
12
Sample: New Package Insert
Daklina® (sofosbuvir) package insert.
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Pregnancy Trimesters
First• 0-13 weeks
Second• 14-26 weeks
Third• 27-40 weeks
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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)
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
15
8.1 Pregnancy
• Pregnancy Exposure Registry
• Risk summary
• Clinical considerations
• Data description
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
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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
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
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Pregnancy Registries- Example
Medicine Medical Condition Registry How to contact Status
Multiple Drugs
Autoimmune Diseases: Crohn's disease, rheumatoid arthritis, psoriasis, psoriatic arthritis, multiple sclerosis
OTIS AutoImmune Diseases Study
MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS)Website: http://www.pregnancystudies.org/ongoing-pregnancy-studies/autoimmune-studies/ Phone: 1-877-311-8972
Ongoing
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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
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
20
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
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
21
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)
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
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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
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
23
Clinical Considerations
• Effect on labor and delivery• Effects on mother and fetus/neonate• Describe potential severity and reversibility
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
24
Data
• Scientific basis for information found in Risk Summary
• Human data• 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/Guidances/UCM425398.pdf
25
Data
• Animal data• Animal species• Dosing in human equivalents• Presence or absence of maternal toxicity
• Data source (clinical trial vs. case series vs. registry)
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
26
Pregnancy Differences
• 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.
27
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
Frederiksen MC. Seminars in Perinatology 2001;25:120-3.
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Pregnancy Metabolism Changes
Induction CYP2A6 Nicotine (gum)
CYP2C9 Phenytoin
CYP2D6 Metoprolol, detromethorphan, citalopram, fluoxetine
CYP3A4 Nifedipine, methadone, indinavir
UGT1A1 Acetaminophen
UGT1A4 Lamotrigine
UGT2B7 Lorazepam
Inhibition CYP1A2 Caffeine, theophylline
CYP2C19 Proguanil, nelfinavir
Frederiksen MC. Seminars in Perinatology 2001;25:120-3.
29
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
30
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
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.
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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
32
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 pre-eclampsia 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?
Abou-Ghannam et al. Am J Perinatol. 2012;29(3):175-86.Executive Summary: Hypertension in Pregnancy. Obstet Gynecol. 2013;122:1122-31.
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8.2 Lactation
• Risk summary• Clinical considerations• Data
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
36
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
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
37
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
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
38
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
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
39
Data
• Descriptions of data from Risk Summary and Clinical considerations
• Updated as new information is available• If there is no data, omit this subheading
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
40
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.
Daklina® (sofosbuvir) package insert.
41
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
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.
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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 drug-
associated effects on fertility and/or preimplantation loss effects
• May be omitted if none of the subheadings are applicable
US Department of Health and Human Services. December 2014: 1-21 accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425398.pdf
44
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
45
Example- Thalidomide (Thalomid®)
46
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
Update on the PLLR
Melissa Neglia, Pharm.D.
Women’s Health Clinical Pharmacist
St. Vincent Women’s Hospital
Indianapolis, IN
September 17, 2015