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Contraceptive TechnologyUpdateSatellite Conference and Live WebcastWednesday, October 25, 20062:00 - 4:00 p.m. (Central Time)FacultyLeigh Beasley, MD, FAAFPEmory University Regional Training CenterAtlanta, GeorgiaProduced by the Alabama Department of Public HealthVideo Communications and Distance Learning DivisionProgram Objectives Describe current thinking oncontraceptive efficacy and the statusof experimental contraceptives. Describe the interrelationships ofmedical contraception methods withspecific drugs, reproductivedisorders and other health problems.Contraceptive Use in theUS: 2002 Report Percentage of men and women whoused contraception ranged from 67%(Guam) to 88% (Idaho). Women reported OC’s as thepredominant method in 49 areasfollowed by tubals, condoms andvasectomy. Men reported tubal, vasectomy, OC’s,and condoms. Note lack of “new methods” in the topfour.Program Objectives Describe the new World HealthOrganization's (WHO) medicaleligibility criteria; Intrauterine Device(IUD) and teens, IUD and PlevicInflammatory Disease (PID);spermicides; and knownthrombogenic mutations and oralcontraceptives. Discuss management of commoncontraceptive problems.Half of All Pregnancies in theUnited States Each Year riage9%Pregnancies(6.3 Million)1

The Oral Contraceptive Cycle Progestin prevents luteinizinghormone (LH) surge. Estrogen suppresses folliclestimulating hormone (FSH)and follicular development. Together, the hormones incombination OCs inhibitproliferative changes inuterus, leading to endometrialatrophy. When placebo pills are taken,a “pill period” results.OC Developments New Estrogen doses: 25mcg;Cyclessa, Ortho-Tricyclen Lo. Extended Cycle Use: Seasonale,Seasonique. Widening EC use. “Natural” estrogen pills andnonsteroidal progesterone agonist(tanaproget).Depo-Provera andBMD in Teens NIH-funded study (J. Adoles Health 2004)– 370 girls (mean age, 15).– 53 chose Depo, 165 chose OC’s (20 ugof estrogen) and 152 chose nohormonal contraception.– BMD values after 12 months. At lumber spine: -1.4%, 2.3% and 3.8%. At the hip: -2.2%, 0.3% and 2.3%.– Clinical relevance ?OC Developments New Progestin: Drospirenone;Yasmin. Berlex has obtained FDA approvalfor Yaz (20 mcg EE/3 mgdrospirenone) for BC and PMDD(unique dosing 24 days active pillsand 4 placebo pills).Depo-Provera November 17, 2004: the FDA issued a“black box” warning recommendingthat Depo-Provera be used long-term(i.e. more than two years) only if allother pharmacologic contraceptivesare not appropriate or tolerated dueto bone loss data in adult women.Effect of Contraception onBone Mineral Density Studied women ages 18-33 seekingcontraception. Injectable Depomedroxypgogesterone acetate150mg vs. 0.030 mg EE plus 0.15 mgdesogestrel vs. 0.035 mg EE plus 1.0mg norethindrone vs. controls (nohormonal contraception). Followed for 2 years.2

Effects of Contraception onBone Mineral Density Depo users-average loss from baselineof 5.7 % (in spinal BMD). Desogestrel OC-average loss formbaseline of 2.0 % (not statisticallysignificant). Norethindrone- no significant changein BMD. Controls-average gain of 2.6 % in BMD. Clinical relevance?Effect of Pregnancyand Lactation on BoneMineral Density Bone turnover is reduced in earlypregnancy, returned to normal duringthe third trimester and increased inpostpartum lactating women(Cole et al. 1987) No evidence that high parity isassociated with an increased incidenceof osteoporotic fractures in later life(Alffram, 1964; Walker et al. 1972).DMPA and Bone Health Complete recovery of BMD was notfound at all skeletal sites assessed(but would it have if followed for 2DMPA and Bone Health Three studies that indicate BMD iscomparable in former and neverusers following discontinuation ofDMPA.– Petitti DB et al (Obstet Gynecol2000;95:736-744).– Scholes D et al (Epidemiology2002; 13:581-587).– Scholes D et al (Arch PediatrAdolesc Med 2005; 159: 139-144).DMPA and Bone Health Data presented at the May 2005ACOG meeting (co-author AndrewKaunitz, MD). Loss of BMD of approximately 1%2% annually, with slower loss afterthat and substantial recoveryfollowing discontinuation (followedpatients for 2 years after DMPA wasdiscontinued).World Health OrganizationDMPA Statement July 2005: There should be norestriction on the use of DMPA,including no restriction on durationof use, among women ages 18-45years post DMPA?).who are otherwise eligible to use themethod.3

World Health OrganizationDMPA Statement Among adolescents (menarche toWorld Health OrganizationDMPA Statement Since the data are insufficient toless than 18) and women over 45, thedetermine if this is the case with longadvantages of using DMPA generallyterm use among this age group, theoutweigh the theoretical safetyoverall risks and benefits forconcerns regarding fracture risk.continuing use of the method shouldbe reconsidered over time with theindividual user.Lower Dose, SubcutaneousDepo-Provera Study compared LDSQ Depo(104mg/0.65ml) with IM Depo(150 mg/ml). Confirmed study participants wereovulatory. Received single injection andfollowed up until they ovulated(up to 12 months). 19 women who received IM and 39received SQ were evaluated.NuvaRing Non-biodegradable, flexible,transparent vaginal ring. Contains two active components:ethinyl estradiol and etonogestrel(an estrogen and a progestin). Releases 0.015 mg/day ofethinylestradiol and 0.120 mg/ day ofetonogestrel over a three weekperiod.Lower Dose, SubcutaneousDepo-Provera Ovulation was suppressed in allparticipants for at least 3 months. Median time to return to ovulationwas similar in the two groups (183days in the IM group and 212 days inthe SQ group). Dose and maximum serumconcentration are substantially lowerwith the SQ formulation so ? Lessside effects?NuvaRing : Metabolic andSafety Conclusions Minimal effect on lipid parameters. No clinically relevant effect oncarbohydrate metabolism. Minimal effect on hemostaticvariables, comparable with 30 EE/150LNG COC.4

NuvaRing : Metabolic andSafety Conclusions Low androgenic effects. No adverse effect on blood pressure. No unfavorable effects on the cervixand vagina.Nuva Ring Update Effectiveness not lower in very heavywomen (Westhoff-ACOG 2005). Continuous use can be based on a“calendar approach” since the NuvaRing is active for 35 days, not 21(Timmer et al Clin Pharmokin2000;39:233). Clinicians can obtain free fittingrings by going to www.nuvaring.comEmergency Contraception:The Nations Best-KeptSecretCalifornia Women’s HealthSurvey 6198 women (age 18-44) were asked“If a woman has unprotected sex, isthere anything she can do in the 3days after intercourse that willprevent pregnancy?”– Slightly more than said yes, 1/3rdsaid no and around 10% said theydidn’t know.California Women’s HealthSurvey– 19% of those who answered yeslisted incorrect responses to “whatcan she do?” (included RU 486 anddouche) and 7% gave ambiguousanswers (“seek medical help”).Why Everyone Should KnowAbout EC 43% of the decrease in abortions inthe US in the last 5 years has beenattributed to the use of EC. Up to 51,000 pregnancies areprevented annually by the use of EC. (Finer et al. Perspec on Sexualand Reprod health 2003) Works like LAM.5

Emergency ContraceptionMechanism of Action Inhibition of ovulation. Decreases the probability offertilization after ovulation. Changes in the endometrium(decreasing the likelihood ofimplantation). Does NOT interfere with anestablished, post implantationpregnancy.EC’s Effects on OvulationEC’s Effects on Ovulation Studied 58 women with regularmenstrual cycles (either had tubalsor IUD). Treatment regimens: two 0.75 mgdoses of levonorgestrel (12 hoursapart), single 0.75 mg dose oflevonorgestrel plus placebo ordouble dose of placebo. Randomized to take meds whenleading follicle reached a diameter of12-14 mm (Group I), 15-17 mm(Group II) and 18 mm (Group III).EC’s Effects on Ovulation Within 5 days of treatment, there was Percentage of cycle either ovualtoryno ultrasound evidence of follicularrupture (i.e., no ovulation) in 44%,dysfunction or no follicular rupture50% and 36% of cycles with 2 levo.doses, 1 dose and placebo. Ovulatory dysfunction (disorderedsurges in LH and FSH) in 35%, 36%and 5%.EC’s Effects on Ovulation Caution in interpreting results: usedhormonal parameters and ultrasoundand did not test EC’s efficacy. 13% of women with dominant follicle(i.e. 18 mm) did not ovulate whentreated with placebo. Single dose used in this study wasnot the “single dose” used intreatment studies.– (Contraception 2004 Dec.)was similar in with 3 regimens inGroup 1, significantly higher withlevo than placebo in Group II andsignificantly higher with one doselevo than placebo in Group III.Emergency Contraception Most effective if taken within 72hours of unprotected intercourse(the sooner the better). New data suggests equaleffectiveness if both doses are takentogether and may be used up to 120hours after unprotected intercourse. EC treatment is indicated regardlessof the cycle day on whichunprotected intercourse occurred.6

Emergency Contraception No absolute contraindications. Initiate long term contraceptionimmediately following EC(emergency contraception does NOTcontinue to prevent pregnancyduring the rest of the cycle).Mirena – A LevonorgestrelReleasing System T-shaped frame, 32 mm in length,that holds a cylinder that containslevonorgestrel. Resumption of next menstrual cycle. Releases levonorgestrel into theuterine cavity at a rate of 20 mcg aday. Over the counter status. Approved for five years of use.Plasma concentrationsconcentrations (pg/mL)PlasmaPlasma Concentrations ofLevonorgestrelMirena – A LevonorgestrelReleasing System Safety:90008000– Ectopic pregnancy7000 One of 5 contraceptive failuresassociated with the Mirena is anectopic pregnancy, resulting inan annual ectopic pregnancyrate of 0.02%.6000500040003000200010000LNG IUSImplantMini-pillCombined OCsMirena – A LevonorgestrelReleasing SystemPercent Changes in bleeding pattern:– Initially there is an increase inbleeding days (menstrual days andintermenstrual spotting dayscombined).– Irregular spotting during the first 3-6months.– Bleeding may remain irregular insome women.– 20% will become amenorrheic withinthe first year of use.LNG IUS as Alternative ctomyLNG IUSMedical Therapies7

Paraguard Lasts 10 years. Highly effective. Has no systemic effects (e.g.headaches, acne). Most women have regular menses. Women may experience increasedduration of menses and increasedamount of bleeding.Perhaps the Copper IUD isPermanent, ReversibleContraception? WHO reported the copper IUD waseffective for 12 years (contraception1997;56:341). Brazilian study followed women upto 16 years of use.this study needscorroboration. Explusion (? causedby fibroids?) may be a concern(contraception 2005 Nov; 72:337-41).Ortho EvraContraceptive Patch Once-a-week combination hormonalpatch. Changed on the same day of the week,three times a month, with the fourthweek patch-free. Carrier for ethinyl estradiol andnorelgestromin.– EE – 20 µg released daily.– Norelgestromin - 150 µg released daily.Perhaps the Copper IUD isPermanent, ReversibleContraception? In 1984, the FDA approved thecopper IUD for 4 years of use. Eventually the FDA said it was “goodfor up to 10 years.”Paraguard Package Insert The new insert does not recommendthat this IUD be avoided by womenwho are:– Nulliparous.– Have a history of PID.“Seventeen Deaths in Usersof Ortho Evra Patches” In October 2004, AP found 17 deathsamong users of the Ortho Evra patch. We know NOTHING about thedenominator data and very little aboutthe numerator number. Two epidemiological studies mayreveal more about this rare butserious complication. Biologic plausibility.8