lynda jarrell f10pllr and implications for practice

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Pregnancy and Lactation Labeling Rule: Implications for

practiceLynda Jarrell, DNP, APRN, FNP-BC, CNE

Objectives• Upon completion of the presentation the NP will analyze the

information and:

1. Understand and explain the new PLLR.

2. Adequately counsel pregnant or lactating female patients about risk vs benefit of a medication, enabling them to make an informed decision about taking that medication.

3. Adequately counsel female and male patients of reproductive potential about medications that have drug associated fertility effects, enabling them to make an informed decision about taking that medication.

4. Understand and explain the effects of the PLLR on their practice.

Disclosure

• I attest that the CE content for which I am responsible is evidenced-based, fair and balanced, unbiased and free from commercial interest control.• I attest that I have no financial relationship or interest• Many Slides in the presentation are "Reprinted with permission from

the Food and Drug Administration (FDA)

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Importance

• 60 million females of reproductive age• 6.5 million pregnancies yearly in the United States• Many pregnant and lactating females have health issues that require

medication• 64% of women use at least 1 drug during pregnancy

History

• Thalidomide • Introduced early 60’s• Used to treat nausea and vomiting• Caused phocomelia

History of Labeling

1962 1979 1994 1997-2003 2008-2013 2014

Kefauver-Harris amendments

Pregnancy Categories established by regulation

Pregnancy Labeling initiativebegins

Proposed Rule written with new labeling format

Draft PLLR issued; revised after public comment

PLLR published December 4

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Problems with Letters

• Over simplistic• Misinterpreted as a grading system • A drug with adverse information in animals could be labeled as the

same category as a drug with no animal information• Two drugs in the same pregnancy risk category do not necessarily

have the same risk

Intent of PLLR

• Provide the prescriber with relevant information for critical decision-making when treating pregnant or lactating women

• More complete statement of the known risks based on the available data

• Considerations of medical/disease factors • Animal data put in context of human exposure • Human data added when available • Explicitly states when no data are available

PLLR

• Effective date June 30, 2015• Prescription drugs approved on or after June 30, 2001 have additional

content and formatting requirements• ALL prescription drugs to remove pregnancy letter categories by June

2020

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New Labeling

https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM5204

54.pdfREPrinted with permission

Pregnancy

8.1 Pregnancy

• Four Headings• Pregnancy Exposure Registry• Risk Summary• Clinical Considerations• Data

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8.1 Pregnancy Exposure REgistry• If there is a pregnancy exposure registry for the drug, the following

statement must appear:• There is a pregnancy exposure registry that monitors pregnancy

outcomes in women exposed to TRADENAME during pregnancy”• The statement must be followed by contact information needed to

enroll in or to obtain information about the registry• www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearc

h/ucm251314.htm• https://www.fda.gov/science-research/womens-health-research/list-

pregnancy-exposure-registries

8.1 Pregnancy Risk summary

• No drug systemic absorption• “[TRADENAME] is not absorbed systemically following (route of

administration) and maternal use is not expected to result in fetal exposure to the drug.”

8.1 Pregnancy Risk Summary

• Drugs with systemic absorption • When use of a drug is contraindicated during pregnancy, that information

must be stated first in the Risk Summary • Risk statement based on human data (required)• Risk statement based on animal data (required) • Risk statement based on pharmacology • Background risk information in general population (required)• Background risk information in disease population

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8.1 Pregnancy Clinical Considerations

• Clinical Considerations (five optional subheadings) • Disease-Associated Maternal and/or Embryo/Fetal Risk • Dose Adjustments During Pregnancy and the PostPartum Period • Maternal Adverse Reactions • Fetal/Neonatal Adverse Reactions • Labor or Delivery

Pregnancy Data

• Human Data must include the following elements: • Data source (e.g., controlled clinical trials, ongoing or completed pregnancy

exposure registries, other epidemiological or surveillance studies, case series) • Number of subjects • Study duration • Exposure information (timing, duration, and dose of exposure) • Limitations of the data, including potential confounders and biases, if known • If available, data from the comparator or control group, and data confidence

intervals and power calculations should also be included

Pregnancy data

• Animal Data must include:• Species studied• Describe doses in terms of human dose equivalents• Must provide basis for calculation

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Lactation

8.2 Lactation

• 3 Headings• Risk summary• Clinical considerations• Data

Risk summary

• 8.2 Lactation• No Drug Systemic Absorption• “[TRADENAME] is not absorbed systemically by the mother following

(route of administration) and breastfeeding is not expected to result in exposure of the infant to [drug name].”

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Risk summary

• 8.2 Lactation• Systemic drug absorption

• Presence of drug in milk* • Concentration in milk • Actual or estimated infant daily dose

• Effects of drug on the breastfed infant* • Effects of the drug on milk production* • Risk/Benefit Statement • *if unknown, must state so

Clinical consideration/Data

• 8.2 Lactation• Clinical Consideration/Data

• Clinical Considerations • Minimizing exposure to the breastfed infant • Monitoring the breastfed infant for Adverse Reactions

Example 1/Pregnancy and Lactation• Oral contraceptives: Letter Risk Category X• Pregnancy

• Use is contraindicated in pregnant women. Combination hormonal contraceptives are used to prevent pregnancy; treatment should be discontinued if pregnancy occurs. In general, the use of combination hormonal contraceptives, when inadvertently used early pregnancy, have not been associated with adverse fetal or maternal effects (Curtis 2016b).

• Combination hormonal contraceptives should not be started until > 4 weeks after delivery in women who choose not to breastfeed. Due to the increased risk of venous thromboembolism (VTE). The risk decreases to baseline by postpartum day 42. Individual risk factors for VTE also need to be taken into consideration.

• Lactation• Contraceptive steroids may be present in breast milk. Adverse health outcomes, or consistent

effects on infant growth or illness due to exogenous estrogens have not been reported following maternal use of combination hormonal contraceptives in breastfeeding (Curtis 2016b). Because estrogen containing contraceptives may reduce milk production, the manufacturer recommends use of other forms of contraception until the child is weaned.

Wolters Kluwer Clinical Drug Information, Inc. (Lexi-Drugs). Wolters Kluwer Clinical Drug Information, Inc.; July 2019,

August 2019, September 2019.

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Example 2/Pregnancy and lactation• Insulin Letter Risk Category B• Pregnancy

• Exogenous insulin bound to anti-insulin antibodies can be detected in cord blood (Menon 1990). • Poorly controlled diabetes during pregnancy be associated with an increased risk of adverse maternal and

fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia. To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA, 2019; Blumer 2013).

• Due to pregnancy-induced physiologic changes, insulin requirements tend to increase as pregnancy progresses requiring frequent monitoring and dosage adjustments. Following delivery, insulin requirements decrease rapidly (ACOC 2018; ADA 2019)

• Insulin is the preferred treatment of type 1 and type 2 diabetes mellitus in pregnancy, as well as gestational diabetes mellitus when pharmacologic therapy is needed (ACOG, 2018; ADA 2019). Rapid acting insulin analogs are preferred over short acting regular insulin when treatment is needed during pregnancy due to improved outcomes and increased compliance (ACOG, 2018; ADA 2019; Blumer, 2013). Regular insulin is used intravenously for glycemic control during labor.

• Females diagnosed with diabetes mellitus who wish to conceive should use adequate contraception until glycemic control is achieved (ADA 2019). Rapid acting insulin analogs are preferred over short acting regular insulin in females planning a pregnancy (Blumer, 2013).



Example 2 continued• Insulin• Lactation

• Both exogenous and endogenous insulin are present in breast milk (study not conducted with this preparation (Whitmore 2012).

• Adverse events have not been reported in breastfeeding infants following maternal use of regular insulin for injection. Adverse events have not been reported in breastfeeding infants. Adjustments of the mother’s insulin dose may be needed.

• Breastfeeding is encouraged for all females, including those with type I, type 2, or gestational diabetes mellitus (ACOG 2018; ADA 2019; Blumer 2013). A small snack before breastfeeding may help decrease the risk of hypoglycemia in females with pregestational diabetes (ACOG 2018; Reader 2004). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.



Example 3/Pregnancy and lactation• Levothyroxine: Letter risk Category A

• Levothyroxine has not been shown to increase the risk of congenital abnormalities or miscarriage. Maternal hypothyroidism, however, can be associated with adverse effects in the mother and fetus, including spontaneous abortion, stillbirth, premature birth, low birth weight, impaired neurocognitive development in the off-spring, abruptio placentae, gestational hypertension, and preeclampsia (ACOG 2015; Alexander 2017).

• Thyroid replacement therapy minimizes the risk of adverse pregnancy outcomes in females with overt hypothyroidism and treatment is recommended during pregnancy (ACOG 2015; Alexander 2017). Levothyroxine is the preferred treatment of maternal hypothyroidism; other agents should not be used in pregnant females (ACOG 2015; Alexander 2017; De Groot 2012).

• Due to alterations of endogenous maternal thyroid hormones, hypothyroid patients treated with levothyroxine prior to pregnancy require a dose increase as soon as pregnancy is confirmed. (Alexander 2017; De Groot 2012).

• Overt hypothyroidism increases the risk of infertility; treatment with levothyroxine is recommended to normalize thyroid function in infertile females with overt hypothyroidism who desire pregnancy. Levothyroxine may also be used in infertile females with subclinical hypothyroidism using assisted reproductive techniques (Alexander 2017).



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Example 3 continued

• Levothyroxine: Lactation• Levothyroxine is present in breast milk.• Levothyroxine was not found to cause adverse events to the infant or mother

during breastfeeding. Adequate thyroid hormone concentrations are required to maintain normal lactation.

• According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. The World Health Organization (WHO) considers levothyroxine to be compatible with breastfeeding.



Example 4/Pregnancy and lactation• Propylthiouracil (PTU): Letter Risk Category D

• Propylthiouracil crosses the placenta• Nonteratogenic adverse effects, including fetal and neonatal hypothyroidism, have been reported following

maternal propylthiouracil use.• Uncontrolled maternal hyperthyroidism may result in adverse neonatal outcomes (e.g. prematurity, low birth

weight) and adverse maternal outcomes (e.g. preeclampsia, congestive heart failure, stillbirth, and abortion).• The pharmacokinetic properties of propylthiouracil are not significantly changed by pregnancy; however the

severity of hyperthyroidism may fluctuate throughout pregnancy (De Groot 2013; Sitar 1979; Sitar 1982). Doses of propylthiouracil may be decreased as pregnancy progresses and discontinued weeks to months prior to delivery.

• Antithyroid drugs are the treatment of choice for the control of hyperthyroidism during pregnancy (ACOG 2015; Alexander 2017 ; De Groot 2012. Boxed Warning: Propylthiouracil may the treatment of choice when an antithyroid drug is indicated during or just prior to the first trimester of pregnancy. Due to adverse maternal events, other antithyroid medications should be considered after the first trimester. To prevent adverse outcomes, maternal TT4/FT4 should be at or just above the pregnancy specific upper limit of normal (Alexander 2017). Propylthiouracil may be used for the treatment of thyroid storm in pregnant females.

• Females taking propylthiouracil should notify their health care provider immediately once pregnancy is suspected (Alexander 2017).



Example 4 continued• Propylthiouracil: Lactation

• PTU is present in breast milk. The infant dose (RID) of propylthiouracil is < 2% when calculated using the highest mean breast milk concentration located and compared to a weight-adjusted maternal dose of 400 mg/day.

• In general, breastfeeding is considered acceptable when the RID of a medication is < 10% (Anderson 2016).

• The RID of propylthiouracil was calculated using a mean milk concentration of 0.7 mcg/mL providing an estimated daily infant dose via breast milk of 0.11 mg/kg/day. This milk concentration was obtained following maternal administration of a single dose of propylthiouracil 400 mg/day to nine breastfeeding women, 1-8 month’ postpartum. The amount of propylthiouracil collected in breast milk over 4 hours was equivalent to 0.025% of the ingested dose (Kampmann 1980).

• Maternal use of propylthiouracil is considered acceptable while breastfeeding (Alexander 2017; WHO 2002). The American thyroid Association recommends using the lowest effective dose and doses ≤ 450 mg/day. Infants exposed to antithyroid medications via breast milk should be monitored for adequate growth and development/ routine tests of thyroid function are not recommended (Alexander 2017).



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Example 5 pregnancy and Lactation• Lisinopril: Letter Risk Category C• Boxed Warning: Drugs that act on the renin-angiotensin system can cause injury and death to the

developing fetus. Discontinue as soon as possible once pregnancy is detected. Lisinopril crosses the placenta (Bhatt-Mehta 1993; Filler 2003).

• Drugs that act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. The use of these drugs in pregnancy is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. Teratogenic effects may occur following maternal use of an ACE inhibitor during the first trimester although this finding may confounded by maternal disease. Because adverse fetal events are well documented with exposure later in pregnancy, ACE inhibitor use in pregnant women is not recommended (Seely 2014; Weber 2014). Infants exposed to an ACE inhibitor in utero should be monitored for hyperkalemia, hypotension, and oliguria. Oligohydramnios may not appear until after irreversible fetal injury has occurred. Exchange transfusions or dialysis may be required to reverse hypotension or improve renal function, although data related to the effectiveness in neonates is limited.

• Chronic maternal hypertension itself is also associated with adverse events in the fetus/infant and mother. ACE inhibitors are not recommended for the treatment of uncomplicated hypertension in pregnancy (ACOG 2013) and they are specifically contraindicated for the treatment of hypertension and chronic heart failure during pregnancy by some guidelines (Regitz-Zagrosek 2011). In addition, ACE inhibitors should generally be avoided in women of reproductive age (ACOG 2013). If treatment for hypertension or chronic heart failure in pregnancy is needed other agents should be used (ACOG 2013; Regitz-Zogrosek 2011).



Example 5 Continued

• Lisinopril/Lactation• It is not known if lisinopril is present breast milk. Due to the potential for

serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer.

• Peripartum cardiomyopathy (PPCM) that is diagnosed postpartum may be treated with ACE inhibitors; however, lisinopril is not the preferred ACE inhibitor (Regitz-Zagrosek 2011). In addition, breastfeeding is not recommended for women with PPCM due to the high metabolic demands of lactation and breastfeeding (Regitz-Zogrosek 2011; Sliwa 2010).



Example 6 pregnancy/lactation • Sertraline: Letter Risk Category B

• Sertraline crosses the human placenta. Available studies evaluating teratogenic effects following maternal use of sertraline in the first trimester have not shown an overall increased risk of major birth defects. Studies evaluating specific birth defects have provided inconsistent results. Nonteratogenic effects I the newborn following SSRI/SNRI exposure late in the third trimester include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypo or hypertonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor. Symptoms may be due to the toxicity of the SSRIs/SNRIs or a discontinuation syndrome and may be consistent with serotonin syndrome associated with SSRI treatment. Persistent pulmonary HTN of the newborn has also been reported with SSRI exposure. The long-term effects of in utero SSRI exposure on infant development and behavior are not known.

• Due to pregnancy-induced physiologic changes, women who are pregnant may require adjusted doses of sertraline to achieve euthymia. The ACOG recommends that therapy with SSRIs or SNRIs during pregnancy be individualized; treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. According to the American Psychiatric Association (APA), the risks of medication treatment should be weighed against other treatment options and untreated depression. For women who discontinue antidepressant medications during pregnancy and who may be at high risk for postpartum depression, the medications can be restarted following delivery. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy (ACOG 2008; APA 2010; Yonkers 2009).

• Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 18-45 years of age or their health care providers may contact the registry by calling 833-405-6185. Enrollment should be done as early in pregnancy as possible.



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Example 6 continued• Sertraline: Lactation

• Sertraline and the active metabolite desmethylsertraline are present in breast milk. Using pooled data, the relative infant dose (RID) of sertraline was calculated to be 0.5% to 3.0% of the weight-adjusted maternal dose (Berle 2011); a RID of 3.7% was noted in one review (Orsolini 2015). In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000), however, some sources note breastfeeding should only be considered if the RID is < 5% for psychotropic agents (Larsen 2015). When an RID is >35%, breastfeeding should generally be avoided (Anderson 2016; Ito 2000). When evaluated, desmethylsertraline milk concentrations were higher than sertraline (Stowe 1997; Stowe2003). Peak milk concentrations occurred 7-8 hours after (sertraline) and 5 to 11 hours (desmethylsertraline) after the maternal dose (Stowe 1997). However, avoiding breastfeeding during the expected peak concentrations will not generally decrease infant exposure significantly for antidepressants with long half-lives (Berle 2011). Most available studies evaluated serum serumconcentrations of sertraline in the breastfeeding infant as opposed to those in breast milk. Using data from 53 mother-infant pairs, the manufacturer notes sertraline concentrations in exclusively breastfed infants is 2% (range: 0 to 15%) of the mother’s serum concentration.

• Adverse events have been reported in breastfeeding infants following maternal use of sertraline in some studies (Hale2010; Muller 2013; Uguz 2016). Infants of mothers using psychotropic medications should be monitored daily for changes in sleep, feeding patterns, and behavior (Bauer2013) as well as infant growth and neurodevelopment (Sachs 2013; Sriraman 2015. Maternal use of an SSRI during pregnancy may cause delayed lactogenesis.

• When first initiating an antidepressant in a breastfeeding woman, sertraline is one of the preferred agents. Women successfully treated with sertraline during pregnancy may continue to use while breastfeeding if there are no other contraindications (Berle 2011). According to the manufacturer, the decision to breastfeed during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of the treatment to the mother.



Females and males of reproductive potential

8.3 Females and males of Reproductive Potential• Include when there are requirements or recommendations for

pregnancy testing and/or contraception and/or when human and/or animal data suggest drug effects on fertility

• Three headings • Pregnancy Testing • Contraception • Infertility

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8.3 Females and males of Reproductive Potential• Example of pregnancy Testing Specialty Populations• When there is embryofetotoxicity:

• Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating drug treatment.

Example 1 pregnancy testing• Isotretinoin• Isotretinoin and its metabolites can be detected in fetal tissue following maternal use during pregnancy.

Boxed Warning: Use of isotretinoin is contraindicated in patients who are or may become pregnant. Birth defects (facial, eye, ear, skull, central nervous system, cardiovascular, thymus, and parathyroid gland abnormalities have been noted following isotretinoin exposure during pregnancy and the risk for severe birth defects is high, with any dose or even with short treatment duration. Low IQ scores have also been reported. The risk for spontaneous abortion and premature births is increased. Because of the high likelihood or teratogenic effects, all patients (male and female), prescribers, wholesalers, and dispensing pharmacists must register and be active in the iPLEDGE™ risk evaluation and mitigation strategy (REMS) program; do not prescribe isotretinoin for patients who are or who are likely to become pregnant while using the drug. If pregnancy occurs during therapy, isotretinoin should be discontinued immediately and the patient referred to and OBGYN specializing in reproductive toxicity. This medication is contraindicated in patients of childbearing potential unless they are able to comply with the guidelines of the iPLEDGE™ pregnancy prevention program. Patients of childbearing potential must have two negative pregnancy tests with a sensitivity of at least 25 milliunits/mL prior to beginning therapy and testing should continue monthly during therapy. Patients of childbearing potential should not become pregnant during therapy or for1 month following discontinuation of isotretinoin. Upon discontinuation of treatment, patients of childbearing potential should have a pregnancy test after their last dose and again one month after their last dose. Two forms of contraception should be continued during this time. Any pregnancies should be reported to the iPLEDGE™ program (www.ipledgeprogramcom or 866-495-0654) and the FDA through MedWatch (800-FDA-1088).



8.3 Females and males of Reproductive Potential• Example Specialty population• When there are drug-contraceptive interactions

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Example 2

• Carbamazepine• Carbamazepine may decrease plasma concentrations of hormonal

contraceptives; alternate or back-up methods of contraception should be considered.



8.3 Females and males of Reproductive Potential• Example Specialty Population• Infertility

• Infertility Females Based on findings from animal studies, female fertility may be compromised with a particular drug

• Drug can lead to inhibition of spermatogenesis and may impair fertility in males of reproductive potential.

Example 3

• Testosterone• Large doses of testosterone may suppress spermatogenesis; the

impact of fertility may be irreversible. Treatment of hypogonadotropic hypogonadism is not recommended for men desiring fertility (Endocrine Society [Bhasin 2018]).



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Implications for Practice• All medications carry some risk so patients should not take any medication

if possible• Medications should be individualized for each patient• Prescribing for pregnant and lactating females and males and females of

reproductive potential should be a multidisciplinary approach• The narrative format of new labeling does not facilitate a consistent

decision-making process for prescribers• The process will be very time consuming• Practitioners should use caution and sound clinical judgment when

assessing the safety data provided to support the use of medications when weighing potential benefits to the risks they propose

• Continued education of clinicians of the new PLLR changes is essential

Future Challenges

• Most human data related to drug use during pregnancy and lactation do not come from adequate and well-controlled trials.

• Ongoing discussions about what to do when: • Data are limited • Lack of a specific or consistent safety findings • Whether to include case reports

Questions

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References• Dinatale, Miriam. (2016) .“The Pregnancy and Lactation Labeling Rule (PLLR).” Food and

Drug Administration. https://www.fda.gov/media/100406/download• Dinatale, Miriam. (2017). “Two Years In: Lessons Learned With Pregnancy and Lactation

Labeling Rule-Approaches to Human data. Food and Drug Administration. https://www.fda.gov/media/111774/download

• FDA Briefing Document. (March 5-6, 2018). Risk Communication Advisory Committee. https://www.fda.gov/media/111821/download

• Johnson, Tamara. (2017). “ Two Years of PLLR Implementation”. Food and Drug Administration. https://www.fda.gov/media/111782/download

• Mosley, J, Smith L, & Dezan M. (2015). An overview of upcoming changes in pregnancy and lactation labeling information. Pharmacy Practice, April-June, 12(2): 1-4.

• Leidtka, J. (2017). “PLLR Labeling and Process considerations.” Food and Drug Administration”. https://www.fda.gov/media/111790/download

References• Pernia, S. & Demaagd, G. The new pregnancy and lactation labeling rule.

(2016). P&T, 41(11): 713-716.• Ramoz, L. & Patel-Shori, N. (2014). Recent changes in pregnancy and

lactation labeling: Retirement of risk categories. Pharmacotherapy, 34(4): 389-395.• Sahin, L. (2018). “Fulfilling the Intent of PLLR: Current Approaches and

Challenges”. Food and Drug Administration. https://www.fda.gov/media/111588/download• Watkins, E. & Archambault, M. (2016). Understanding the new pregnancy

and lactation drug labeling. JAPPA, 29(2): 50-52.• Wolters Kluwer Clinical Drug Information, Inc. (Lexi-Drugs). Wolters Kluwer

Clinical Drug Information, Inc.; July 2019, August 2019, September 2019.

lynda jarrell f10pllr and implications for practice

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