Amy Crawford, PharmDMayo Clinic ‐ Eugenio Litta Children’s Hospital
31 May 2016
Disclosures No relevant financial or commercial conflicts of interest to disclose
Objectives Outline the FDA Pregnancy and Lactation Labeling Rule changes
Recognize available resources regarding medication use in pregnancy and lactation
Discuss risk versus benefit of pharmacological treatment during pregnancy with the patient using the new labeling
1962 1979
Kefauver‐Harris Amendments to Food, Drug, and Cosmetic (FD&C) Act. Requires manufacturers to prove both safetyand efficacy of medications.
FDA requires information for use during:Pregnancy: effects on child growth/development and teratogenicity – A, B, C, D, X implemented. Labor/delivery: effect on mother and fetus. Nursing mothers: excretion into breast milk and ADRs.
2008 2006
FDA investigates ways to improve pregnancy labeling
Moves pregnancy, L&D, and nursing sections from the Precaution to the Specific Population section. Content is unchanged.
6/30/2015Updated PLLR implemented!!
Implementation Approach Application Approval Date
When revised PLLR formatmust be submitted to FDA
Before 6/30/2001Does NOT need to conform,but change to new format is
recommended by FDA
After 6/30/2001 through implementation (6/30/15)
3 – 5 years6/30/2018 – 6/30/20
After implementation Time of submission
ALL prescription drugs for human useMust have Pregnancy Category REMOVED by 6/30/2018 (or when PLL renewed)
Content and Format of Labeling for Human Prescription Drug and Biological Products; 21 CFR Part 201
Ashley is a 34 yof, history of: Severe MDD diagnosed 2 yrs ago. Reportedly doing well on
sertraline 50mg daily (pregnancy category “C”). Just found out she is 10 weeks gestation (oops!)
Which statement is correct regarding the meaning of Pregnancy Category “C”? 1. Human studies have demonstrated adverse effect to fetus 2. Designation considers both structural malformation and long-
term cognitive adverse effects 3. A medication with Category “C” is safer than Category “D” 4. Potential benefits may warrant use despite potential risks
Creates a consistent format to provide information about risks and benefits of drug use during pregnancy/lactation
Goal of facilitating prescriber counseling for these populations
Content and Format of Labeling for Human Prescription Drug and Biological Products; 21 CFR Part 201
Pregnancy (Section 8.1)
Registry information & contact information
Statement about background risk of adverse pregnancy outcomes
PLLR requires the removalof pregnancy categories
(A,B, C, D, X) from all human prescription drug labeling
Rexulti Prescribing Information. Otsuka Pharmaceutical.
1. Disease‐associated maternal and/or embryo/fetal risk2. Dose adjustments during pregnancy/postpartum period3. Maternal adverse reactions4. Fetal/Neonatal adverse reactions5. Labor or delivery
Rexulti Prescribing Information. Otsuka Pharmaceutical.
Info for prescribing & counseling
Basis for information in Risk Summaryand Clinical Consideration sections:
Human data: both positive and negative experiences during pregnancy Animal data: findings in relation to anticipated human exposure
Rexulti Prescribing Information. Otsuka Pharmaceutical.
Drug presence in human milk& effects on child
If available: discuss ways to minimize drug exposure and list monitoring strategies.
Rexulti Prescribing Information. Otsuka Pharmaceutical.
8.3 Females & Males of Reproductive Potential This section not required if none of the subheadings are applicable
Describe if pregnancy testing or contraception is required before, during, or after drug therapy
Describe if drug‐associated fertility effects exist for those of reproductive potential
Content and Format of Labeling for Human Prescription Drug and Biological Products; 21 CFR Part 201
Pregnancy Categories Pros: ABC … it’s easy as 123!
Cons: confusing and overly simplistic Reliance on categories is often misplaced and results in poorly informed decision making
Categories assumed that drugs in the same class carry equal risks
Focuses on structural abnormalities and not the full range of developmental toxicities
Content and Format of Labeling for Human Prescription Drug and Biological Products; 21 CFR Part 201
“Applauds the FDA for its final rule … the new labeling will make it easier for women who are pregnant, breastfeeding or trying to
conceive to understand how prescription medications affect their health and therefore the health of their baby”
‐American Academy of Pediatrics
“We understand the importance of keeping women healthy before, during, and after their pregnancies …medications can be vital to maintaining a mother's continued good health … we also want to ensure that medicines will help, and not harm, both
mother and child”
‐American College of Obstetrics and Gynecology
Ashley is a 34 yof, h/o severe MDD. Discontinued sertraline at 14 weeks gestation, now presents with depression symptoms at week 26.
MD would like to start vilazodone. Using the new labeling, how would you counsel on the use of this medication during pregnancy?
Vibriid Prescribing Information. Actavis, Inc. Updated 03/2015.
Using the new labeling, how would you counsel? 1. There is no pregnancy category listed – so she cannot use it2. There will be no fetal structural defects as long as her dose is less
than 50‐x the normal human dose 3. Her baby may be at risk for PPHN and drug discontinuation
syndrome – requiring monitoring/hospitalization after delivery
Section 8.1 (Pregnancy): “There are no adequate studies in pregnant women.”
“In animal studies, administration during organogenesis at doses up to 48 times the MRHD in rats resulted in decreased fetal body weight gain and delayed skeletal ossification, but no teratogenic effects.”“Exposure to SSRIs/SNRIs in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, persistent pulmonary hypertension of the newborn (PPHN), and drug discontinuation syndrome.”
Fundamentals of Medication use in Pregnancy and Lactation Additional Resources
Mother–Infant Interface Effect
Mother Fetus / Infant
Drug
Disease
Pregnancy
Risk vs Benefit
Exposure
Prenatal Care
Environ‐ment
Dose
Timing
Untreated Disease
Medication Risk
PK/PD changes
Measure [drug]?
Genetics
Placental Drug Transfer Drugs that can easily cross the placental membrane
Low MW: <500‐800 Da High Vd: >20 L/kg Lipid‐soluble Low plasma protein binding
Syme, et al. Clin Pharmacokinet 2004; 43(8): 487‐514
Active Placental Drug Transfer PGP: many antidepressants
OCT1/3: amphetamines, amitriptyline, citalopram
MCT: VPA
SERT: TCAs and SSRIs
NET: TCAs
SMVT: carbamazepine, primidone
Fetal
Materna
l Trans
fer
Maternal
Fetal Transfer
Staud, et al. J Drug Targeting 2012; 20(19): 736‐763O’Brien, et al. Br J Pharmacol. 2012 Jan; 165(2): 289–312.
Place
ntal CYP 450 + UDP Enz
ymes
Additive Resources Prescribing Information; Package Insert
Primary literature Guidance from national organizations and experts
Tertiary sources: reference books, online compilations
Timing & Teratogen Risk Stage of Development (after fertilization)
Effect on Embryo/Fetus
Implantation<20 days
Teratogenesis unlikelyExposure generally has an all‐or‐nothing effect
Organogenesis20‐56 days
Teratogenesis most likely. Exposure may cause spontaneous abortion (10% risk), sublethal anatomic defect, subtle metabolic/functional defect, or no measurable effect
Maturation and Growth 2nd and 3rd trimesters
Teratogenesis unlikely; Exposure may affect growth and function of organs/tissues. Risk of malformation leading to abortion is 1%
Shiota, et al. OrigArtic Ser 1993; 29(1): 189‐99
Teratogen DatabasesDatabase Features Mayo $$$ App
TERIShttp://depts.washington.edu/terisdb/
• 4100+ agents and exposures. • Source: PubMed,TOXLINE, Drugs in
Pregnancy & Lactation, etc. Does NOT include unpublished manufacturer data.
• Assesses quality of data and overall magnitude of teratogenic risk.
• Paid version: Shepard's Catalog of Teratogenic Agents.
√ ‐MM
$250/yr
ReproToxhttps://reprotox.org/
• 5000+ agents and exposures. • Source: their own research with
published data. • Indexes by CAS number, includes effect
on reproduction.• Paid version: can request research on
unlisted meds.
√ ‐MM
$200/yr
√
AAP Guidelines for Breastfeeding
Goal is to breastfeed exclusively x6 months then for 1 year or longer
AAP policy statement. Pediatrics 2012; 129(3) KJ Meador et al. JAMA Pediatr. 2014;168(8):729‐736.
Maternal
Benefits
Higher intelligence outcomes and IQ
72% lower RTI/AOM
58% NEC, 36% SIDS
Breastfeeding Risk Profiles Safe ‐moderately safe
Highly protein bound Low protein binding and low MW with minor adult adverse effects
Possibly hazardous Long‐half life Low protein binding and low MW with severe known adult adverse effects
Infant cannot metabolize
VeibyG, et al. Seizure. 2015; 28: 57‐65.
Sertraline
Pregnancy & Lactation Databases
Database Features Mayo $$$ App
Drugs in Pregnancy & Lactation
• 1200+ medications. • Linked in Facts & Comparisons
monographs. • Available as desktop reference.
√$140 book
F&C
Medications & Mother’s Milk
• 1300+ medications. • Uses a L1‐L5 rating system, contains
most succinct PK data and infant monitoring.
• Available as desktop reference.
$40/yr
Database $$$ App
LactMedhttp://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm
FREE! √
Which of the following resources would NOT be appropriate in this situation? 1. LactMed2. TERIS3. Drugs in Pregnancy & Lactation 4. Medications & Mothers’ Milk
You are working on the overnight shift. • The operator patches through a call from a lactating woman,
exclusively breastfeeding a 1 month old infant. • She is asking about the risks of using OTC guaifenesin for the
sniffles.
Goals of Therapy 1. Maximize maternal and infant well‐being 2. Minimize exposure to medications, mental illness,
environmental toxins during pregnancy and lactation
Counseling Shared clinical decision making!
Assess what they have already learned ‐ address remaining questions and concerns
Discuss both positive and negative outcomes: relative risk vs absolute risk
Discuss methods to maximize benefit for mother while minimizing exposure to fetus/infant
Mother to Baby: http://mothertobaby.org/
ACOG Guidelines. ObstetGynecol 2008;111:1001–20Cipriana, et al. Lancet. 2011; 378:1306–1315
Minimizing Exposure in Pregnancy
Be proactive!
Contraception Pre‐
pregnancy counseling
Medication
Lowest effective dose –consider TDM
Monotherapy, Lowest
teratogen potential
in Breast Milk
Breastfeed first in am, then take meds
Avoid BF at Tmax
Agents with short
T1/2
Pump & dump
Ashley is now the proud mother of a baby boy! She did not start vilazodone, but restarted sertraline 50mg daily.
She has been exclusively breastfeeding x4 months, and now her infant presents to the PICU after an ALTE requiring cardiac resuscitation.
She is distraught – wondering if her medication could have caused this incident. How would you counsel her?
Zoloft Prescribing Information. Pfizer. Lactmed: Sertraline. CASRN: 79617‐96‐2.
Which of the following is the most correct statement?
1. Sertraline use is associated with significant neonatal adverse effects and probably caused her sons ALTE
2. Sertraline, especially when used low-dose, is unlikely to cause significant neonatal serum levels
3. We don’t have any information on sertraline use during lactation
Sertraline Prescribing Information - Nursing Mothers• It is not known whether, and if so in what amount, sertraline or its metabolites
are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ZOLOFT is administered to a nursing woman
LactMed (ToxNet) Information • From data in 6 postpartum mothers and taking sertraline in an average 64mg
daily dose, the authors estimated that an exclusively breastfed infant would receive 0.9% of the maternal weight-adjusted dosage.
• Adverse neonatal effects that possibly relate to sertraline include benign neonatal sleep myoclonus and agitation that spontaneously resolved
Summary PLLR changes include the removal of pregnancy categories in lieu for known data of drug use during pregnancy/lactation
Determining risk during pregnancy/lactation is complex –be aware of resources other than package inserts
Medication decisions should be made along with the mother – utilize strategies to minimize fetal drug exposure
Amy Crawford, PharmDMayo Clinic ‐ Eugenio Litta Children’s Hospital
31 May 2016