amy crawford, pharmd mayo clinic eugenio littachildren’s ... › sites › ce.mayo.edu › files...

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


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


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


Drug presence in human milk& effects on child

If available: discuss ways to minimize drug exposure and list monitoring strategies.


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


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


“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

amy crawford, pharmd mayo clinic eugenio littachildren’s ... › sites › ce.mayo.edu › files...

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