1. Hormonal Contraceptives: The Good, The Bad, and The Controversial Mark A. Goedecker, MD York Hospital Department of Family Medicine July 5, 2007

2. Objectives Describe the pharmacologic differences in oral contraceptives Differentiate relative and absolute contraindications to contraceptives Review the wide range of contraceptive choices Identify patients who need emergency contraception and describe the methods of emergency contraception.

3. Outline Oral contraceptives Patch contraceptives Injectable contraceptives Ring contraceptives Implantable contraceptives Intrauterine devices Emergency contraception

4. Disclaimer I have nothing to disclose and have no financial relationships with any pharmaceutical or biotech company I have used brand names in this presentation to allow better understanding and application to practice

5. SORT Taxonomy A – Consistent, good-quality patient- oriented evidence B – Inconsistent or limited-quality patient oriented evidence C – Consensus, disease-oriented evidence, usual practice, expert opinion, or case series for studies of diagnosis, treatment, prevention, or screening

6. Important Dates Egyptian women use a pessary made of crocodile dung and lubricated with honey to prevent pregnancy 1700’s – condoms made of animal intestine used mainly for prevention of syphilis 1900 – The first modern IUD is marketed 1960 – FDA approves the first oral contraceptive containing 150 µg of mestranol 1974 – Dalkon Shield is withdrawn from the market 2002 – Norplant is removed from the U.S. market

7. Oral Contraceptive Trends Lower doses of estrogens Newer progestins Chewable tablets Fewer hormone free days Longer cycles (or no cycles)

8. Activity of OCP’s Contraceptive activity (efficacy) Estrogenic activity Progestational activity Androgenic activity Endometrial activity Effect on serum lipoproteins Managing Contraceptive Pill Patients, Twelfth Edition. Dickey R.

9. Combined vs. Progestin-Only Most oral contraception prescribed is combined (estrogen/progesterone) Progestin-only pills such as Nor-QD, Micronor, Camila, Errin, Jolivette, and Ovrette Effectiveness of the progestin-only pills is 99.5% (ideal use) versus 99.9% for the combined (actual use 97% for both)

10. Estrogens in OCP’s Most pills use ethinyl estradiol (EE) as their estrogen (50 µg mestranol = 35 µg EE) Doses range from 20 µg – 50 µg, but most are 20 µg – 35 µg Lower dose estrogens have the benefits of less bloating and breast tenderness but may increase the rate of breakthrough bleeding especially in obese patients

11. Estrogens in OCP’s 2004 Cochrane review Low-dose estrogen OCP’s resulted in higher rates of bleeding pattern disruptions Safety or effectiveness at preventing pregnancy could not be assessed Differences in progestin types not accounted for SORT A Gallo MF, Nanda K, Grimes DA, Schulz KF. 20 mcg versus > 20 mcg Estrogen Combined oral contraceptives for contraception. Cochrane Database

12. “Older” vs. “Newer” Progestins Newer: –Less androgenic (minimizes side effects such as acne, hirsutism, nausea, and lipid changes) –Increase progestational effects Levonorgestrel is the most androgenic available in US First, second, third, and fourth generation progestins Estranes and gonanes

13. “Newer” Progestins Minimal androgenic effects Norgestimate –Increases HDL and decreases LDL Desogestrel (etonogestrel) –Possible increase risk in venous thromboembolism (VTE) (Jick S et al. Contraception 2006:73:566-70. SORT B) Drospirenone –Antimineralocorticoid activity –Theoretically could cause hyperkalemia –Essentially no androgenic activity

14. Monophasics vs. Biphasics vs. Triphasics There is insufficient data that biphasic or triphasic combined oral contraceptive pills are better than monophasic pills (effectiveness, bleeding patterns, or discontinuation rates) SORT B Cochrane Database of Systematic Reviews 2007 Van Vliet HAAM, Grimes DA, Lopez LM, Schulz KF, Helmerhorst FM. Triphasic versus monophasic oral contraceptives for contraception Van Vliet HAAM, Grimes DA, Helmerhorst FM, Schulz KF. Biphasic versus monophasic oral contraceptives for contraception

15. Choosing the Right Pill Low androgenic activity is desirable in most if not all If patient weighs more than 160 pounds consider higher estrogen and progestin activity Low dose estrogen if: –History of nausea, edema or hypertension in pregnancy –Uterine fibroids –Fibrocystic breasts –Heavy menses –Migraines

16. Choosing the Right Pill Low progesterone if: –History of preeclampsia, excessive weight gain, tiredness, or varicose veins during pregnancy, –Depression –Excessive premenstrual If history of polycystic ovaries, high progestational and low androgenic

17. Combined Contraceptives Effect on Weight Contraceptive pills and patches do not lead to major weight gain SORT A Gallo MF, Lopez LM, Grimes DA, Schulz KF, Helmerhorst FM. Combination Contraceptives:effects on weight. Cochrane Database of Systematic Reviews 2007 Issue 2

18. Newer OCP’s on the Market

19. Femcon Fe The new name for Ovcon Fe chewable Chewable spearmint flavored tablet EE 35 µg, norethindrone 0.4 mg (21 days) Placebo contains 75 mg ferrous fumarate ADVANTAGE: For those who cannot swallow pills (and need fresh breath)

20. Yaz 24/4 Same ingredients as Yasmin but… –EE 20 µg (instead of 30 µg) –3 mg of drospirenone –24 days of active medication and 4 days of placebo (as compared to the usual 21/7) ADVANTAGE: –Has an FDA indication for premenstrual dysphoric disorder (the only hormonal contraceptive with this) –Shorter periods

21. Loestrin 24 Fe 24 days of hormones (similar to Yaz 24/4) EE 20 µg, Norethindrone 1 mg Placebo pills contain iron ADVANTAGE: –Periods last less than 3 days –More pronounced suppression of follicular development

22. Extended Cycle Contraceptives Seasonale, Seasonique, Lybrel Oral contraceptives taken continuously for more than 28 days compare favorably to traditional cyclic oral contraceptives (bleeding, discontinuation rates, and reported satisfaction) SORT A Edelman AB, Gallo MF, Jense JT, Nichols MD, Schulz KF, Grimes DA. Continuous Or extended cycle versus cyclic use of combined oral contraceptives for contraception. The Cochrane Database of Systematic Reviews 2007 Issue 2

23. Seasonique Like Seasonale: –EE 30 µg, levonorgestrel 0.15 mg for 12 weeks But… –13 th week contains EE 10 µg (instead of placebo) ADVANTAGES: –Low dose EE may reduce hormone withdrawal symptoms (migraines and dysmenorrhea) –May cause less breakthrough bleeding then with Seasonale (main reason women stop Seasonale)

24. Lybrel Taken in a continuous 365-day regimen EE 20 µg and levonorgestrel 0.09 mg 28 pills in a pack FDA approved and will be released July 2007 ADVANTAGE: –No menstrual bleeding –During the 13 pill pack: 59% of women achieve amenorrhea 20% of women have spotting only 21% of women required sanitary protection due to breakthrough bleeding http://www.drugs.com/newdrugs/fda-approves-lybrel-first-low-combination-oral- contraceptive-offering-women-opportunity-period-free-491.html?printable=1http://www.drugs.com/newdrugs/fda-approves-lybrel-first-low-combination-oral- contraceptive-offering-women-opportunity-period-free-491.html?printable=1

25. Contraindications to Combined Oral Contraceptives Unexplained VTE or VTE associated with pregnancy or exogenous estrogen use (unless on anticoagulants) Women age 35 and older who smoke Poorly controlled diabetes or diabetes with complications such retinopathy, nephropathy, or other vascular complications Level A Use of hormonal contraception in women with coexisting medical conditions. ACOG Practice Bulletin No. 73. American College of Obstetricians and Gynecologists. Obstet Gynecol 2006: 107:1453-72.

26. Contraindications to Combined Oral Contraceptives OCP’s should be stopped one week prior to surgery or heparin prophylaxis should be considered Women with CAD, CHF, or cerebral vascular disease Use caution in obese women over the age of 35 Poorly controlled HTN (or complications) Patients with Factor V Leiden gene mutation or prothrombin gene mutations Level B Use of hormonal contraception in women with coexisting medical conditions. ACOG Practice Bulletin No. 73. American College of Obstetricians and Gynecologists. Obstet Gynecol 2006: 107:1453-72.

27. Patients Who it is OK to Use OCP’s Benign breast disease or family history of breast cancer Mild lupus with no antiphospholipid antibodies Level A Use of hormonal contraception in women with coexisting medical conditions. ACOG Practice Bulletin No. 73. American College of Obstetricians and Gynecologists. Obstet Gynecol 2006: 107:1453-72.

28. Patients Who it is OK to Use OCP’s Healthy, non-smoking women can continue their OCP’s until age 50-55 Well-controlled HTN <35 who do not smoke and are healthy Well-controlled DM <35 who do not smoke and are healthy Women with migraines who are healthy, do not smoke, and have no focal neurologic signs Women with depressive disorders Level B Use of hormonal contraception in women with coexisting medical conditions. ACOG Practice Bulletin No. 73. American College of Obstetricians and Gynecologists. Obstet Gynecol 2006: 107:1453-72.

29. Patients Who it is OK to Use OCP’s Women with well-controlled dyslipidemia Remember progestin only contraceptives can be safely used in most women Level C Use of hormonal contraception in women with coexisting medical conditions. ACOG Practice Bulletin No. 73. American College of Obstetricians and Gynecologists. Obstet Gynecol 2006: 107:1453-72.

30. Other Subgroups BRCA1 and BRCA2 mutation carriers –No increased breast cancer risk before age 50 with at least one year of use –Possible increased risk in BRCA2 carriers who have been on OCP's for at least 5 years Lower risk of ovarian cancer is well documented (fewer ovulatory cycles) Possible lower risk of colon cancer

31. Ortho Evra Transdermal Contraceptive Patch EE 20 µg/d and norelgestromin 0.15 mg/d One patch weekly for three consecutive weeks followed by one patch-free week Mean serum concentrations are not affected by heat, humidity, exercise or cold-water immersion Contraceptive failure is higher in women with body weight >90 kg

32. Ortho Evra Transdermal Contraceptive Patch Possible increased risk of venous thromboembolism (VTE) –This is due to the increased serum concentration –Peak serum estrogen concentration is 25% less than the peak level with the pill (30 µg) –But women with the patch are exposed to 60% more estrogen than taking the pill –NuvaRing – 3.4 times less estrogen exposure than patch and 2.1 less than the pill Thacker H, Falcone T, Atreja A, Jain A, Harris CM. How should we advise patients about the contraceptive patch given the FDA warning? Cleveland Clinic Journal of Medicine 2006: 73(1): 45-47.

33. The Patch and VTE Two-fold increase in the risk of VTE versus norgestimate-containing oral contraceptives with 35 µg of EE Overall, the number needed to harm (NNH) was 4,444 (AMI, VTE, stroke) There is a five-fold increase in risk of VTE in pregnancy There is no increased risk for acute myocardial infarction or stroke Cole J, Norman H, Doherty M, Walker A. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol 2007: 109(2):339-46.

34. Injectable Contraceptives Only one currently available is Depo- Provera Lunelle was withdrawn from the US due to lack of demand and a recall (half-filled syringes)

35. Depo-Provera Medroxyprogesterone 150 mg given IM every 11-13 weeks New Depo-subQ Provera 104 –Given every 12-14 weeks –Can be administered by the patient in the thigh or abdomen Side effects are similar –Slow return to fertility (14 weeks to 9 months) –Irregular bleeding –Short-term loss of bone mineral density

36. Depo-Provera and Osteoporosis FDA has required a black-box warning since 2004 “only use as long-term birth control method(>2 years) if other methods inadequate” It has not been associated with postmenopausal osteoporosis or fractures Society for Adolescent Medicine, ACOG and WHO have recommended continuing Depo after appropriately counseling

37. Depo-Provera and Osteoporosis “Short- or long-term use of DMPA in healthy women should not be considered an indication for DXA or other tests that assess bone mineral density.” Level C Use of hormonal contraception in women with coexisting medical conditions. ACOG Practice Bulletin No. 73. American College of Obstetricians and Gynecologists. Obstet Gynecol 2006: 107:1453-72.

38. NuvaRing EE 15 µg/day and etonogestrel 0.12mg/day Inserted into vagina and left in for three weeks Removed for one week Can be re-inserted if it has been out for less than three hours (rinse with cold or warm water, not hot) 8/10 partners do not feel the ring during intercourse (can removed prior to intercourse) http://www.nuvaring.com/HCP/PrescribingNuvaRing/StartingYourPatients/index.asp

39. Implantable Contraceptives Norplant was on the US market from 1991-2002 Six rods containing levonorgestrel Several class action law suits over: –Failure to disclose side effects (irregular bleeding) –Difficulty removing rods

40. Implantable Contraceptives IMPLANON™ released August 2006 One rod containing etonogestrel Can be left in for up to three years Only providers who have completed a “comprehensive practical training session” can insert IMPLANON™ (sponsored by Organon) www.implanon-usa.com

41. IMPLANON™ Mean insertion time 1.3 minutes (range 1- 15 minutes) Mean removal time 3.8 minutes (range 1- 60 minutes) 4 cm long and 2 mm in diameter

42. IUD’s Fell out of favor in the 70’s and 80’s There are two on the market today –Paragard Lasts 10 years Copper (non-hormonal) Increase bleeding with menses –Mirena Lasts 5 years Contains levonorgestrel Bleeding will decrease or even become absent!

43. IUD’s - Contraindications ACTIVE pelvic inflammatory disease Pregnancy Current sexual behavior suggesting a high risk for PID Post-pregnancy or post-abortion uterine infection in the past three months Cancer of the uterus or cervix Infection of the cervix Vaginal bleeding of unknown cause http://www.paragard.com/hcp/custom_images/ParaGard_HCP_Safety_Info.pdf

44. IUD’s - Complications PID/endometritis –Very rare – use of prophylactic antibiotics confer little benefit prior to insertion (Grimes DA, Schulz FK. The Cochrane Database of Systematic Reviews SORT A) Uterine perforation Expulsion of IUD

45. Emergency Contraception

46. Levonorgestrel (LNG) emergency contraception (EC): –Has little or no effect on post-ovulation events (i.e. fertilization, implantation) –In rare circumstances EC may prevent implantation but by a similar mechanism as OCP's –Does not increase risk to an established pregnancy or developing embryo Novikova N et al. Effectiveness of levonorgestrel emergency contraception given before or after ovulation – a pilot study. Contraception 2007:75:112-18.

47. Emergency Contraception Treatment with EC should be initiated as soon as possible after unprotected intercourse EC should be made available to patients who request it up to 120 hours after intercourse No clinician examination or pregnancy testing is necessary before EC is given

48. Emergency Contraception FDA approved over the counter sales of LNG-EC (Plan B) August 2006 Patient must be 18 or older and present an ID to the pharmacist Insurance may not pay without a prescription Average cost is $42 per pack

49. Emergency Contraception LNG-EC is more effective and is associated with less nausea and vomiting than estrogen-progestin regimens (1.1% vs 3.2%) LNG-EC can be taken as a single dose The two doses of LNG-EC are equally effective if taken 12-24 hours apart Level A Emergency contraception. ACOG Practice Bulletin No. 69. American College of Obstetricians and Gynecologists. Obstet Gynecol 2005: 106:1443-52.

50. Emergency Contraception Preven (combined EC) no longer available in the US OCP's can be used –Regimens can be complicated –Combined OCP’s associated with nausea and vomiting Insertion of an IUD within 120 hours of intercourse can be used

51. Summary Newer progestins and lower dose estrogens have greatly improved combined oral contraceptive choices Venous thromboembolism remains the greatest risk to all combined oral contraceptive users (especially those who smoke and are over age 35) Extended cycle contraceptives are excellent choices but have increased risk of breakthrough bleeding

52. Summary Ortho Evra and Depo-Provera remain good options in the right patients Don’t forget about IUD’s and NuvaRing for those patients who cannot remember to take pills Emergency contraception is contraception

53. A Must-Have Book for the Office Managing Contraceptive Pill Patients, 12 th edition. Dickey R.

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55. References Gallo MF, Nanda K, Grimes DA, Schulz KF. 20 mcg versus > 20 mcg Estrogen combined oral contraceptives for contraception. Cochrane Database of Systematic Reviews 2007 Issue 2 Van Vilet HAAM, Grimes DA, Helmerhorst FM, Schulz KF. Biphasic versus monophasic oral contraceptives for contraception. Cochrane Database of Systematic Reviews 2007 Issue 2. Van Vliet HAAM, Grimes DA, Lopez LM, Schulz KF, Helmerhorst FM. Triphasic versus monophasic oral contraceptives for contraception. Cochrane Database for Systematic Reviews 2007 Issue 2. Gallo MF, Lopez LM, Grimes DA, Schulz KF, Helmerhorst FM. Combination Contraceptives: effects on weight. Cochrane Database of Systematic Reviews 2007 Issue 2.

56. References Edelman AB, Gallo MF, Jense JT, Nichols MD, Schulz KF, Grimes DA. Continuous or extended cycle versus cyclic use of combined oral contraceptives for contraception. The Cochrane Database of Systematic Reviews 2007 Issue 2. FDA approves Lybrel, first low dose combination oral contraceptive offering women the opportunity to be period-free over time. http://www.drugs.com/newdrugs/fda-approves-lybrel- first-low-combination-oral-contraceptive-offering-women- opportunity-period-free-491.html?printable=1 http://www.drugs.com/newdrugs/fda-approves-lybrel- first-low-combination-oral-contraceptive-offering-women- opportunity-period-free-491.html?printable=1 http://www.drugs.com/newdrugs/fda-approves-lybrel- first-low-combination-oral-contraceptive-offering-women- opportunity-period-free-491.html?printable=1 Archer D et al. Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol: phase 3 study results. Contraception 2006:74:439-45

57. References Use of hormonal contraception in women with coexisting medical conditions. ACOG Practice Bulletin No. 73. American College of Obstetricians and Gynecologists. Obstet Gynecol 2006: 107:1453-72. Cole J, Norman H, Doherty M, Walker A. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol 2007: 109(2):339-46. Thacker H, Falcone T, Atreja A, Jain A, Harris CM. How should we advise patients about the contraceptive patch given the FDA warning? Cleveland Clinic Journal of Medicine 2006: 73(1): 45-47. Courtney K. The contraceptive patch: latest developments. AWHONN 2006:10(3):250-54

58. References Rager K. No bones about it – depot medroxyprogesterone acetate remains an excellent contraceptive option for adolescents. Journal of Pediatric and Adolescent Gynecology 2005:4(5):187-88. Depot medroxyprogesterone acetate and bone mineral density in adolescents – the black box warning: a position paper of the Society for Adolescent Medicine 2006:39:296-301. Sidney S et al. Venous thromboembolic disease in users of low-estrogen combined estrogen-progestin oral contraceptives. Contraception 2004:70:3-10.

59. References Jick S, Kaye JA, Russman S, Jick H. Risk of nonfatal venous thromboembolism with oral contraceptives containing norgestimate or desogestrel compared with oral contraceptives containing levonorgestrel. Contraception 2006:73:566-70. Jick S, Jick H. The contraceptive patch in relation to ischemic stroke and acute myocardial infarction. Pharmacotherapy 2007:27(2):218-20. Haile R et al. BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50. Cancer Epidemiol Biomarkers Prev 2006:15(10):1863- 70.

60. References Lin J, Zhang S, Cook N, Manson J, Buring J, Lee I. Oral contraceptives, reproductive factors, and risk of colorectal cancer among women in a prospective cohort study. American Journal of Epidemiology 2007:advanced publication. Grimes DA, Schulz FK. Antibiotic prophylaxis for intrauterine contraceptive device insertion. The Cochrane Database of Systematic Reviews 2007 Issue 2. Emergency contraception. ACOG Practice Bulletin No. 69. American College of Obstetricians and Gynecologists. Obstet Gynecol 2005: 106:1443-52. Raymond EG, Trussell J, Polis C. Population effect of increased access to emergency contraceptive pills. Obstetrics & Gynecology 2007:109(1):181-88

61. References Glasier A. Emergency postcoital contraception. NEJM 1997:337(15):1058-64. ‘Morning After Pill is Cleared for Wider Sales’. Harris G. The New York Times August 24, 2006. Novikova N et al. Effectiveness of levonorgestrel emergency contraception given before or after ovulation – a pilot study. Contraception 2007:75:112-18. Raine T et al. Direct Access to emergency contraception through pharmacies and effect on unintended pregnancy and STIs. JAMA 2005:293(1):54-62. Gainer E et al. Menstrual bleeding patterns following levonorgestrel emergency contraception. Contraception 2006:74:118-24.