update on the pregnancy and lactation labeling rule (pllr) melissa neglia, pharm.d. women’s health...

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

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Disclosure

This speaker has no potential or actual conflicts of interest to disclose in relation to this presentation.

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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.

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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

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Pregnancy Categories

Misused

MisinterpretedConfusing

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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


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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




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Staggered Implementation

Approved Applications Subject to the Physician Labeling Rule

Timeline



June 30, 2007, up to and including the effective date of the final rule



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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.

Selzer, Cindy C

Previous comments about font size - may need to split up

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Category Changes

AB

CD

X

Removed from product

labeling

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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


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Sample: New Package Insert

Daklina® (sofosbuvir) package insert.

Selzer, Cindy C

Can you blow this up so majority of slide is targting the "use in specific populations"?

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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

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8.1 Pregnancy

• Pregnancy Exposure Registry

• Risk summary

• Clinical considerations

• Data description


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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


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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

http://www.pregnancystudies.org/ongoing-pregnancy-studies/autoimmune-studies/autoimmune-disease-treatments-pregnancy/

http://www.pregnancystudies.org/ongoing-pregnancy-studies/autoimmune-studies/





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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


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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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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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• 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


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• Effect on labor and delivery• Effects on mother and fetus/neonate• Describe potential severity and reversibility


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Data

• Scientific basis for information found in Risk Summary

• Human data• Number of subjects• Study duration• Exposure duration• Limitations


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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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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.

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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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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


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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

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

http://acupuncture-pregnancy.com/wp-content/uploads/2012/06/blood-pressure1.jpg

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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 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.

Selzer, Cindy C

Consider shortening these to bullet points rather than sentences. Can discuss all this information but slide looks busy

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8.2 Lactation

• Risk summary• Clinical considerations• Data


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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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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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• 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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Data

• Descriptions of data from Risk Summary and Clinical considerations

• Updated as new information is available• If there is no data, omit this subheading


Selzer, Cindy C

Do you need a separate slide for this or can you just state it? Slide looks very lonely.

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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.

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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

Selzer, Cindy C

any way to blow this up or concentrate on website or search area?

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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


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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

http://www.otispregnancy.org/

http://www.cochrane.org/reviews/index.htm

http://www.motherisk.org/prof/drugs.jsp

http://www.perinatology.com/

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

update on the pregnancy and lactation labeling rule (pllr) melissa neglia, pharm.d. women’s health...

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