1. Medical Education Series © 2005 National Abortion Federation E A R L Y O P T I O N S A PROVIDER’S GUIDE TO MEDICAL ABORTION

2. E A R L Y O P T I O N S A PROVIDER’S GUIDE TO MEDICAL ABORTION MEDICAL ABORTION MEDICAL ABORTIONREGIMENS

3. Objectives Review the mechanism of action and pharmacology of medical abortion agents Describe and compare safety and efficacy data for mifepristone/misoprostol regimens Describe safety and efficacy data for alternative medical abortion regimens, including methotrexate/misoprostol and misoprostol alone Discuss clinical and practical issues relating to medical abortion

4. Overview Mifepristone/misoprostol: mechanism of action Mifepristone/misoprostol regimens Clinical issues Alternatives – methotrexate/misoprostol – misoprostol alone

5. Medical Abortion Agents Antiprogestin: mifepristone Antimetabolite: methotrexate Prostaglandin analogue: misoprostol

6. Mifepristone

7. Mechanism of Action: Mifepristone Derivative of norethindrone Side chains added at the 11-C and 17-C positions Binds to progesterone receptor with high affinity; does not activate receptor

8. Mechanism of Action: Misoprostol PGE 1 analogue Absorbed from oral, vaginal, buccal, sublingual, or rectal routes Inexpensive

9. Rhythmic Uterine Contractions Progesterone Blockade Decidual Necrosis Cervical Ripening DetachmentExpulsion Abortion Mechanism of Action: Mifepristone + Misoprostol Mifepristone-Induced Abortion © Lisa Penalver

10. Overview Mifepristone/misoprostol: mechanism of action Mifepristone/misoprostol regimens Clinical issues Alternatives – methotrexate/misoprostol – misoprostol alone

11. FDA-Approved & Evidence- Based Alternative Regimens 49 days LMPGestational limit Approximately Day 14Timing of initial follow- up examination 48 hrs later (Day 3)When misoprostol taken At homeAt office or clinicWhere misoprostol taken 800 µg PV400 µg POMisoprostol dosage 200 mg (one 200-mg tablet) 600 mg (three 200-mg tablets) Mifepristone dosage Evidence- Based Alternatives FDA-Approved Regimen 6-72 hrs later < 56 days 6-48 hrs later < 63 days From Day 4-14 Up to 63 days LMP ONLY in studies using 800µg VAGINAL miso

12. FDA-Approved Regimen* Day 1 –Mifepristone 600 mg PO (three 200-mg tablets) –Rh immune globulin, if indicated Day 3 –Misoprostol 400 µg orally –Provided in the office Day 14 (approximately) –Follow-up –Ultrasound, if necessary –Vacuum aspiration, if necessary *For pregnancies up to 49 days’ gestation

13. FDA-Approved Regimen: Efficacy *Data from first trial only **Additional 200 µg of misoprostol if abortion incomplete at 3 hours

14. Evidence-Based Alternative Regimens Mifepristone dose Vaginal misoprostol Home use of misoprostol Gestational age limits Timing of vaginal misoprostol administration Timing of follow-up evaluation

15. Mifepristone Pharmacology Peak serum levels in 2 hours Same pharmacokinetics for all doses 100 mg or greater Total serum concentration same during first 72 hours for 200-mg and 600-mg dosing Same peak concentration with 100-, 400-, 600-, and 800-mg doses

16. WHO Task Force. BMJ 1993 Mifepristone Dose Variations Mifepristone PO + Gemeprost 1 mg PV

17. Mifepristone Dose Variations Mifepristone PO + Misoprostol 400 µg PO* Complete Ongoing abortion (%)pregnancy (%) Mifepristone dose 200 mg (n = 792)893 600 mg (n = 797)882 Gestational age < 42 days921 43–49 days891 50–56 days873 57–63 days809 *For pregnancies up to 63 days by LMP WHO Task Force. Br J Obstet Gynaecol 2000

18. Zieman, et al. Obstet Gynecol 1997 Vaginal vs. Oral Misoprostol

19. El-Refaey, et al. N Engl J Med 1995 *P = 0.03 ** P < 0.001 *** P = 0.01 Vaginal vs. Oral Misoprostol  63 Days’ Gestation

20. Schaff, et al. Contraception 2001 *P = 0.001 ** P = 0.001 Vaginal vs. Oral Misoprostol  63 Days’ Gestation Success (%)* Complete abortion @ 1 week (%)** Continued pregnancy (%) Oral misoprostol 400µg + 400µg 2 hrs later (n = 548) 95 90 1.1 Vaginal misoprostol 800µg (n = 596) 99 97 0

21. Misoprostol Routes of Administration Vaginal vs. oral misoprostol associated with: –Higher efficacy rates –Lower rate of GI side effects –More rapid expulsion –Lower rate of continuing pregnancy Sublingual misoprostol Buccal misoprostol Kahn, et al. Contraception 2000 Tang, et al. Hum Reprod 2003 Shannon, et al. 2003

22. Mifepristone (various doses) PO + Misoprostol 800 µg PV

23. Home Use of Misoprostol: Acceptability Survey Results

24. Gestational Age and Outcomes FDA approved regimen –Oral misoprostol –High efficacy through 49 days’ gestation –Efficacy decreases with increasing gestational age Evidence-based alternative regimens with vaginal misoprostol –Sustained high efficacy through 63 days’ gestation

25. Timing of Vaginal Misoprostol Administration In regimens of 200 mg mifepristone + 800 µg vaginal misoprostol Administer misoprostol: –6-72 hours after mifepristone < 56 days –6-48 hours after mifepristone < 63 days Sustained high efficacy

26. Timing of Vaginal Misoprostol Administration Randomized trial of 2,295 women through 56 days’ gestation –Mifepristone 200 mg –Misoprostol 800 µg PV 1, 2, or 3 days after mifepristone Efficacy by interval –1-day: 98% (95% CI 97%  99%) –2-day: 98% (95% CI 97%  99%) –3-day: 96% (95% CI 95%  97%) Acceptability of waiting time: significantly greater with 1-day vs. 2-day or 3-day interval Schaff, et al. JAMA 2000

27. Timing of Vaginal Misoprostol Administration Randomized trial of 1,080 women through 63 days’ gestation –Mifepristone 200 mg –Misoprostol 800 µg PV 6-8 hours or 23-25 hours after mifepristone Efficacy by interval –6-8 hours: 96%(95% CI 93.7%  97.3%) –23-25 hours: 98% (95% CI 96.6%  99.1%) Significantly higher rates of side effects after mifepristone and significantly higher rates of nausea & vomiting after misoprostol in 23-25 hour group. Creinin, et al. Obstet Gynecol 2004

28. Timing of Follow-up Evaluation FDA regimen: Follow-up about 14 days after mifepristone Data support acceptable earlier follow-up when: –Regimens involve vaginal misoprostol –Transvaginal ultrasonography is used for dating and evaluation after treatment Follow-up may be performed as early as 1 day after vaginal misoprostol Abortion complete at 1-week evaluation in > 95% of women Schaff, et al. Contraception 1999 Schaff, et al. Contraception 2000 Schaff, et al. JAMA 2000

29. Evidence-Based Alternative Regimens 200-mg dose of mifepristone Vaginal administration of misoprostol –Lower incidence of side effects compared to oral misoprostol –More rapid expulsion compared to oral misoprostol –Increases efficacy of medical abortion for gestations up to 63 days –Decreases continuing pregnancy rate Home use of misoprostol Flexibility in timing of vaginal misoprostol use Flexibility in initial follow-up evaluation

30. Overview Mifepristone/misoprostol: mechanism of action Mifepristone/misoprostol regimens Clinical issues Alternatives – methotrexate/misoprostol – misoprostol alone

31. Sample Protocol First visit* Counseling (including Medication Guide & Patient Agreement) Lab work Medical history & gestational dating (ultrasound if needed) Mifepristone (Serial number recorded in patient chart) Rh immune globulin, if indicated Misoprostol tablets or prescription dispensed for later use Medication and/or prescriptions given as needed for cramping Emergency contact information given Discuss post-abortion contraception, STDs, & EC as appropriate *In states with required waiting periods between a first visit and the abortion, these may be divided between two visits.

32. Sample Protocol (con’t) Misoprostol administration 6-72 hours after mifepristone Most often used at home First follow-up visit Approximately 4-14 days after mifepristone Ultrasound, if necessary Vacuum aspiration, if necessary

33. Contraindications Allergy to mifepristone, misoprostol, or other prostaglandin analogues Concurrent long-term systemic corticosteroid use Chronic adrenal failure Hemorrhagic disorder or concurrent anticoagulant therapy Intrauterine device in situ Possible ectopic pregnancy Inherited porphyria

34. Special Considerations Chronic medical conditions –Cardiovascular disease –Hypertension –Hepatic disease –Renal disease –Pulmonary disorders –IDDM –Severe anemia –Heavy smoking Breast-feeding Women over 35 years who smoke > 10 cigarettes daily

35. Teratogenicity Mifepristone: data do not indicate teratogenicity Methotrexate –High-dose therapy is teratogenic –Low-dose therapy with unknown risk Misoprostol: associated with birth defects

36. Ultrasound Standard in US medical abortion trials Usage varies in inter national studies Should be available for specific indications Useful, but not mandatory in the FDA labeling

37. Assessing When Ultrasound is Needed: Study Results 1 Gestational age & abortion outcome assessed based on history & physical exam, and compared with TVU results Gestational age –TVU rated as “not indicated” for 60% of women at 50 days. –1.4% clinically assessed 63 days by TVU –9.1% clinically assessed >63 days but <63 days by TVU Abortion outcome –Confident in clinical assessment for 59.5% of women –1.3% (7/522) were assessed with clinical confidence to have a complete abortion, but did not by TVU –Clinicians assessed ultrasound was desired or indicated in 71% (17/24) of women who did not have a complete abortion 1 Fielding et al, Contraception 2002

38. Medical Abortion: Acceptability Generally well-accepted by providers and patients Patient attitudes towards mifepristone/misoprostol –“Satisfactory” or “very satisfactory”: 88%–97% –% of eligible women choosing mifepristone varies –More than half of eligible women choose mifepristone in France, Scotland & Sweden –Patients dislike multiple-visit requirements Winikoff, et al. Int Fam Plann Perspect 1997 Winikoff, et al. Arch Fam Med 1998 Ngoc, et al. Int Fam Plann Perspect 1999 Jones, et al. Perspect Sexual Reprod Health 2002

39. Overview Mifepristone/misoprostol: mechanism of action Mifepristone/misoprostol regimens Clinical issues Alternatives – methotrexate/misoprostol – misoprostol alone

40. Alternatives: Methotrexate Mechanism of Action Over 40 years of use in cancer chemotherapy Antimetabolite –Blocks dihydrofolate reductase –Primary effect is to impede DNA synthesis Affects cytotrophoblast cells—impairs implantation

41. Medical Abortion with Methotrexate/ Misoprostol: Contraindications Anemia (Hgb < 10 g/dL) Known coagulopathy Active renal or liver disease Uncontrolled seizure disorder Acute inflammatory bowel disease Intrauterine device in situ Intolerance of methotrexate or misoprostol

42. Methotrexate/Misoprostol Regimens* Methotrexate: 50 mg/m 2 IM or 50 mg PO Misoprostol: 800 µg PV 3–7 days later Efficacy decreases after 49 days’ gestation Rh immune globulin to Rh negative patients before misoprostol Initial follow-up ~1 week after methotrexate Subsequent care based on results of physical exam, ultrasonography *For pregnancies up to 49 days’ gestation

43. Methotrexate/Misoprostol vs. Mifepristone/Misoprostol Schaff, et al. Fam Med 1996 Schaff, et al. Contraception 1999

44. Clinical Trial Results: Mifepristone vs. Methotrexate 83.2% **88%Acceptability 0.4%0%Ongoing pregnancy 96.0% 74.5% * 20.3% * 96.1% 90.5% 3.9% Overall Success By day 8 After day 8 Methotrexate/ misoprostol Mifepristone/ misoprostol * p<.001 ** p=.031 Wiebe, et al. Obstet Gynecol 2002

45. Misoprostol as a Single Agent *Moistened **Plus additional 400–1,200 µg after expulsion was confirmed

46. Misoprostol-Alone Regimen* 2 doses 800 µg vaginal misoprostol 24 hours apart Up to 9 weeks LMP Moistening tablets may increase success *Consensus Statement, 2003

47. Conclusion Various mifepristone/misoprostol regimens have 95- 99% efficacy rates Evidence-based regimens –200 mg mifepristone –Vaginal misoprostol 800 µg –Gestations < 63 days with vaginal misoprostol –Home use of misoprostol –Flexibility in timing of vaginal misoprostol use –Flexibility in initial follow-up evaluation Methotrexate/misoprostol and misoprostol-alone regimens are safe & effective alternatives

48. E A R L Y O P T I O N S A PROVIDER’S GUIDE TO MEDICAL ABORTION This educational program does not define a standard of care, nor does it dictate an exclusive course of management. It contains recognized methods and techniques of medical care that represent currently appropriate clinical practice. Variations in patient needs and available resources may justify alternative approaches. Laws governing abortion, informed consent, and medical malpractice vary among states. These materials are strictly for informational purposes, and do not constitute legal advice or representation. These materials are not intended as a substitute for the advice of a health care provider. Neither NAF nor its agents are responsible for adverse clinical outcomes that might occur where they are not expressly and directly involved in the role of primary caregiver. This educational program is protected by copyright. Any unauthorized duplication, reproduction, or alteration of the presentations or any part of the presentations contained therein is strictly prohibited. This educational program is intended for the use of the original recipient and his/her agents and cannot be sold, distributed, transmitted or transferred in any form without prior written authorization by the National Abortion Federation. © 2005 National Abortion Federation