FDA Reproductive Health Drug Advisory Committee Meeting August 29, 2006 Gaithersburg, Maryland

1. FDA Reproductive Health Drug Advisory Committee MeetingAugust 29, 2006Gaithersburg, Maryland

2. New Drug Application for “Gestiva” 17 alpha-hydroxyprogesterone caproate (17 P) • Theresa Grossklaus, RN, BA, BSN • Current Master of Science of Nursing Student

3. Before approving NDA 21-945… • …consider lessons learned from 17 P’s prior use under the brand name • “Delalutin”

4. Prior use of “17 P” • 1980s 3 pregnancies • Treatment of different condition • Use during different gestation weeks of pregnancy

5. Delalutin

6. Treatment of Suspected Corpus Luteum Insufficiency

7. Supplement confirmed pregnancy with progesterone • Progesterone vaginal suppositories • Weekly injections of Delalutin (17 P ) 250 mg IM • Gestation weeks ~ 5-9 or 5-12 • Modified: gestation weeks 5-17, 5-18

8. Outcome: 3 children

9. Concerns – Delalutin (17 P)

10. Possible adverse interaction between alcohol and 17 P when used for treatment of corpus luteum insufficiency during gestation weeks 5-18

11. A most peculiar pregnancy characterized by 4 problems: • Congenital cardiac condition • Primary microcephaly • Intrauterine growth retardation • A maternal “drinking problem”

12. Our son, 1986 & 1991

13. 1991… • Conducted a review of literature on birth defects associated with progestins, and with alcohol, possible mechanisms of teratogenesis, congenital cardiac conditions, microcephaly, behavioral teratology, intrauterine growth retardation, alcohol metabolism, addiction, & more

14. Subjective experience • “addiction” to alcohol by 15-17 weeks • No intoxication • Sensation of fetal growth restriction within 1 week of “addiction” • Symptoms diminish between 18-21 weeks • Symptoms accelerate after 21 weeks • Intense compulsive drinking problem erupts ~ 26 weeks • “It’s all my fault for drinking in the 3rd trimester”

15. Oversimplified logical explanation • Alcohol is a 2 tiered psychotropic drug which requires transformation from ethanol to acetaldehyde • Ethanol is metabolized but the metabolism of acetaldehyde is restricted

16. Possible explanation • Acetaldehyde accumulates in mom’s brain, liver, and serum – • Acetaldehyde serves as a teratogen, a fetal growth inhibitor, a disruptor of steroid hormone biosynthesis, an addicting substance for mom, and an inhibitor of fetal brain growth

17. Treatment of corpus luteum insufficiency with 17 alpha-hydroxyprogesterone caproate (17 P) with probable complications due to prenatal alcohol consumption: a 1991 perspective

18. Request delay of approval of NDA 21-945 until a designated medical researcher can review this manuscript(>600 pages) and assess applicability to this newer use of 17 P

19. Birth defects are usually associated with first trimester exposure to teratogens… • Brain growth and migration of neurons can be inhibited by alcohol during pregnancy (including 2nd & 3rd trimesters) • Maternal “addiction” to alcohol might be possible at any time during pregnancy

20. …If either of our 2 daughters were pregnant and 17 P supplementation was recommended to them, I would want them to be very well informed about this possible outcome, and be given a very specific warning not to consume one bit of alcohol while on 17 P.

21. Consider protection for…FetusMotherPrescribing physicianPharmaceutical mfg.

22. Prospective means of capturing outcomes of pregnancies exposed to progesterone Uniform, specific warning could be communicated to pregnant patients to avoid alcohol while on 17 P while obtaining a signed consent Adverse effects could be closely monitored Longitudinal data could be tracked Pregnancy Exposure Registry

23. Before approving NDA-21-945… • …if a pregnant woman on 17 P became “addicted” and developed “a drinking problem” how could a professional identify this? • …how could this professional treat or intervene?

24. I am grateful for the opportunity to bear three children