1. DRUG THERAPY DURING PREGNANCY AND LACTATION Azher Arafah, Pharm.D.,Ph.D., College of Pharmacy, KSU May. 2013

2. Objectives  Recognize the significance of the issue  Recognize the association between pregnancy/lactation & drugs  Describe FDA drug pregnancy categories and its limitations  Describe the FDA- proposed changes on labeling  Identify principles of therapy during pregnancy & lactation  Identify recommendations for common disease states  Identify vaccination recommendations during pregnancy  Utilize the main sources of drug information during pregnancy and lactation

3. Pregnancy/Lactation & Drug Use How Significant Is the Issue ?  50% of pregnant women will take a drug at some point in their pregnancy  About 2/3 of US women take one or more prescription medications during pregnancy  Unplanned pregnancies: 1/3 in the UK, 1/2 in the in US Postgrad Med J 2011;87:349-354 U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2010

4. Pregnancy/Lactation & Drug Use How Significant Is the Issue ?  Large percentage of pregnant women also use OTC medications or herbal and dietary products

5. Pregnancy/Lactation & Drug Use How Significant Is the Issue ?  A study from the Netherlands indicated that 65.9% of breast-feeding women took at least one medication over a 6-month period

6. How can we study the safety of medication in pregnancy and lactation?  Conducting randomized controlled trials (RCTs) in patients who are pregnant or breastfeeding is considered unethical

7. How can we study the safety of medication in pregnancy and lactation?  Drug data in these populations are first derived from animal studies which cannot guarantee safety in humans

8. How can we study the safety of medication in pregnancy and lactation?  In the absence of RCTs, epidemiology studies (cohort, case control, pregnancy exposure or birth defect registries) are the best way to identify associations between drug exposure & abnormalities in the newborn

9. How can we study the safety of medication in pregnancy and lactation? Among medications approved for use in the USA from 2000 to 2010, over 70% had no published human data which assess the teratogenicity risk and 98% had insufficient published data to characterize such risk Pharmacoepidemiol Drug Saf. 2013;22(3):324-8

10. True or False As long as the drug is not taken in early pregnancy, it will not pose adverse effects on the fetus

11. Teratogenesis  Teratogens are agents that act to irreversibly alter growth, structure, or function of the developing embryo or fetus  Examples: irradiation, mercury, alcohol, thalidomide, isotretinoin Obstet Gynecol 2009;113:166–88

12. Teratogenesis  Embryonic & fetal exposure depends on several factors:  Gestational age  Route of administration  Absorption of the drug  Dose of the drug medication  Maternal serum levels  Placental transfer (low molecular weight, ionization, high fat solubility)

13. Pregnancy & Drugs  Physiologic changes that can affect the pharmacokinetics /pharmacodynamics of drugs during pregnancy include: 1. Changes in total body weight and body fat composition 2. Delayed gastric emptying, prolonged gastrointestinal transit time which can affect the bioavailability of drugs 3. Expanded plasma volume, ↑ extracellular fluid space & total body water content which affect drugs’ volume of distribution Matern Child Health J (2006) 10:S129–S135

14. Pregnancy & Drugs  Physiologic changes that can affect the pharmacokinetics /pharmacodynamics of drugs during pregnancy include: 4. Decreased concentration of plasma albumin, which can reduce the protein binding of some drugs 5. Increased glomerular filtration rate early in pregnancy, with a continued rise throughout pregnancy 6. Changes in the activity of hepatic enzymes, including the cytochrome P450 enzymes (↑ or ↓) Matern Child Health J (2006) 10:S129–S135

15. Lactation & Drugs American Academy of Pediatrics (AAP) and the World Health Organization (WHO) recommend that children continue to breastfeed until at least one or two years of age, and thereafter as long as mutually desired www.uptodate.comwww.uptodate.com, Principles of medication use during lactation

16. Lactation & Drugs  Factors affecting transfer of drugs into human milk include:  Timing of the dose with respect to breastfeeding  Bioavailability  Maternal clearance www.uptodate.comwww.uptodate.com, Principles of medication use during lactation

17. Lactation & Drugs  Drugs most likely to be transferred from maternal plasma to milk have the following characteristics:  Nonionized  Nonprotein bound  Low molecular weight  High lipid solubility www.uptodate.comwww.uptodate.com, Principles of medication use during lactation

18. Is this the Answer ??

19. Principles of Therapy / Pregnancy  There are three reasons why a woman takes medication while pregnant: 1.Inadvertent exposure to medication 2.Intended continuation of treatment for a pre- existing medical condition Postgrad Med J 2011;87:349-354

20. Principles of Therapy / Pregnancy  There are three reasons why a woman takes medication while pregnant: 3.Initiation of treatment in pregnancy for example, for infection or a pregnancy-specific problem such as nausea Postgrad Med J 2011;87:349-354

21. Principles of Therapy / Pregnancy  The aim when prescribing in pregnancy (or in anticipation of pregnancy) is to balance risks of the potential adverse effects of the drug (usually to fetus) with the benefit (usually to mother) of treating disease  This balance may change during the pregnancy depending on the disease activity and the gestation Postgrad Med J 2011;87:349-354

22. FDA Pregnancy Labeling  Current pregnancy labeling uses five categories: A B C D X

23. FDA Pregnancy Labeling What is wrong the current pregnancy labeling?  May mislead providers to believe that risk increases from category B to C to D. In fact, categories C, D.  Do not distinguish between differences in frequency, severity, and type of fetal developmental toxicities

24. FDA Pregnancy/Lactation Labeling Changes  In 2008, the FDA published a proposed regulation on format and content for pregnancy and lactation labeling for prescription medications

25. FDA Pregnancy/Lactation Labeling Changes  The FDA proposal:  Pregnancy categories will be eliminated from the labeling and prescribing information  Information for both pregnant and lactating women will be presented in 2 consecutive label subsections: “Pregnancy” and “Lactation”

26. FDA Pregnancy/Lactation Labeling Changes  The “Pregnancy” section will consist of three major subsections: 1.Fetal Risk Summary 2.Clinical Considerations 3.Data For drugs with an enrolling pregnancy exposure registry, the labeling will include contact information for the registry

27. FDA Pregnancy/Lactation Labeling Changes  The “Lactation” section will also have three sections entitled 1.Fetal Risk Summary 2.Clinical Considerations 3.Data

28. How Are We Doing ?  A survey of three countries, Canada, the Netherlands, Iceland with 120 pharmacists included  When asked drug related queries in pregnancy, 90% of pharmacists directly referred patients to physician  Only 14% referred to the literature to dispense evidence-based information Int J Clin Pharm (2011) 33:882–885

29. How Are We Doing ?  Another study of 163 randomly selected community pharmacists  Pharmacists provided pharmacologically unscientific advice and recommended drugs for which there is no evidence for use in pregnancy Int J Clin Pharm (2011) 33:882–885

30. Principles of Therapy / Pregnancy Postgrad Med J 2011;87:349-354

31. Principles of Therapy / Pregnancy Postgrad Med J 2011;87:349-354

32. Practical Points  Consider whether each drug is necessary in pregnancy  If decided that a drug is needed:  Choose the safest one that will also be effective  Use older drugs  Prescribe at the lowest effective dose  Prescribe for the shortest duration possible  If possible, the dose should be reduced as term approaches to reduce the risk of withdrawal in the neonate Postgrad Med J 2011;87:349-354

33. Practical Points  Address misconceptions regarding teratogenic potential  Encourage pregnant women who are taking medications to enroll in pregnancy registries  Utilize risk management programs  iPLEDGE is a mandatory program for all marketed isotretinoin products that requires wholesalers, pharmacies, doctors, and patients to register with the program in order to obtain the drug Postgrad Med J 2011;87:349-354 Matern Child Health J (2006) 10:S129–S135

34. Practical Points What about Preconception Period?  Establish effective treatment for chronic conditions before conception occurs  Counsel women to avoid the use of nonessential medications (including prescription, OTC, dietary or herbal supplements)  Avoid the use of medications with high teratogenic risk when equally effective treatments with lower risks are available Matern Child Health J (2006) 10:S129–S135

35. Practical Points What about Preconception Period?  Limit use of essential medications to the smallest number of drugs possible  Limit each essential medication to the smallest dose Matern Child Health J (2006) 10:S129–S135

36. Principles of Therapy/ Lactation  Use medications with a short half-life, high protein binding, low oral bioavailability,high molecular weight  Use medications for which data are available regarding safety in infants and/or pharmacodynamics in breastfeeding  If a drug has short half-life, give it after nursing or before a prolonged period of infant sleep www.uptodate.comwww.uptodate.com, Principles of medication use during lactation

37. Principles of Therapy/ Lactation  Use caution with low-birth weight or preterm infants (potentially immature organ systems)  Collaborate with infant's pediatrician to monitor infant  Discuss risks and benefits with the patient www.uptodate.comwww.uptodate.com, Principles of medication use during lactation

38. Conclusion  Prescribing decisions are complex and highly individualized, especially for women who are pregnant, lactating, or of childbearing potential  Medication labeling should be a clearly written communication tool for health care professionals to support informed prescribing for and counseling with patients  The FDA proposed labeling requirements will improve the safe and effective use of medications during pregnancy and breastfeeding

39. Principles of Therapy Recommendations for Common Chronic Medical Conditions Postgrad Med J 2011;87:349-354

40. Pregnancy & Vaccines

41. Sources of Information  UK Teratology Information Service (http://www.uktis.org)http://www.uktis.org  Organisation of Teratology Information Specialists (OTIS) (http://www.otispregnancy.org)http://www.otispregnancy.org

42. Sources of Information  Thomas Hale’s website (http://neonatal.ama.ttuhsc.edu/lact/)http://neonatal.ama.ttuhsc.edu/lact/  Teratogen Information System (TERIS) (http://depts.washington.edu/terisweb/teris)http://depts.washington.edu/terisweb/teris  Centers for Disease Control and Prevention’s TRxeating for Two: Safe Medication Use in Pregnancy Initiative (http://www.cdc.gov/pregnancymedication)http://www.cdc.gov/pregnancymedication

43. Sources of Information  REPROTOX (http://www.reprotox.org)http://www.reprotox.org  LactMed ( http://www.toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT ) http://www.toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT  American Academy of Pediatrics  Books  Briggs' Drugs in Pregnancy and Lactation  Hale’s Medications and Mothers' Milk

44.  List of Pregnancy Exposure Registries by the FDA http://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm134848.htm