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Combination Oral Contraceptives Most popular method of reversible contraception in the U.S. Used by over 10 million women in the U.S. and 60 million women worldwide Mechanism of Action (COCs) Suppress ovulation contraceptive Reduce sperm transport in fallopian tubes contraceptive Change endometrium making implantation less likely interceptive Thicken cervical mucus (preventing sperm penetration) contraceptive Pharmacologic Actions of Progestin and Estrogen Progestin Estrogen Ovarian and pituitary inhibition Ovarian and pituitary inhibition Thickening of cervical mucus Thinning of/increase in cervical mucus Endometrial atrophy/transformation Endometrial proliferation Cycle control Cycle control Characteristics of COCs Individual product depend on three factors: 1. Estrogen dose  Ethinyl Estradiol - found in almost all COCs  Estradiol valerate -  Mestranol - Only found in high-dose COCs  Metabolized to ethinyl estradiol  50 mcg of mestranol = 35 mcg ethinyl estradiol  High vs Low Dose  High-dose COCs contain >30mcg of estrogen  Low-dose COCs contain <30 mcg of estrogen 2. Choice of progestin 3. Route of administration Progestins in Oral Contraceptives 19-Nortestosterone Estranes - 1st generation  Norethindrone  Norethindrone acetate  Ethynodiol diacetate  Norethynodrel Spironolactone Gonanes 2nd generation – most androgenic  Levonorgestrel  Norgestrel 3rd generation – least androgenic  Desogestrel  Norgestimate Adapted from Sulak PJ. OBG Management. 2004;Suppl:3-8. Antimineralocorticoid  Drospirenone  Dienogest Antimineralocorticoid progestins (drosperinone and dienogest) spironolactone analogs with antimineralcorticoid/ antiandrogenic activity reduces fluid retention, bloating, weight gain, irritability and anger Need to monitor potassium during first month of use Caution with other medications that can cause hyperkalemia (ACE inhibitors, NSAID) Component of Yasmin,Yaz, Beyaz, Safyral, Natazia, Angeliq (this product is for vasomotor symptoms) Beyaz contains levomefolate calcium, a metabolite of folic acid Not all progestins are created equal Risk of thromboembolism? Why? • Estrogen promotes clotting factors • Patch may increase overall exposure to estrogen – constant dose rather than peak and trough • Ring may significantly increase sex hormone binding globulin that can increase risk of thrombosis Progestin Risk of VT non-user 2-3 per 10,000 LNG-IUS may benefit etonorgestrel implant 1.7 per 10,000 older progestin 6 per 10,000 etonorgestrel (ring) 8 per 10,000 Product Label Lists related CIs drosperinone 10-15 per 10,000 Yes norelgestromin (patch) 10-15 per 10,000 Yes pregnancy 10 per 10,000 post-partum 50 per 10,000 • Rate of TE higher during 1st year of use with some products • Consider low-dose estrogen/older progestin products or LNG-IUS to ↓ risk of thrombosis • For women at ↑ risk of TE consider IUD or other estrogen-free product • >35 yrs, hx of VTE, severe HT, hypercoagulopathy Androgenic properties of COCs  Adverse effects include:  Hirsutism  Acne  Weight Gain  Two ways to decrease unwanted androgenic effects:  Choose progestin with lower androgenic properties  Increase estrogen, increases SHBG and decreases unbound testosterone Phasic Formulations of COCs  Purpose – ↓ dose-dependent ADRs of progestins  Monophasic - Fixed amt of progestin + estrogen X 21 days  Biphasic - Fixed estrogen X 21 days; ↑ed progestin:estrogen ratio in 2nd half  Triphasic - Estrogen the same, progestin changes; or dose of both changes  Four phasic - Estrogen ↑s, progestin ↓s  A Cochrane review found:  Choice of progestin is more important than phasic formulation Serious Adverse Effects of COCs Primarily due to estrogen content Serious ADRs Abdominal Pain – gallbladder disease, VTE Chest Pain - MI Headaches – stroke, hypertension, migraine Eye Problems – stroke, hypertension, vascular problems Severe Leg Pain –VTE in legs  VTE most common cardiovascular event among COC users (e.g. PE, DVT)  Risk is estimated at one case/10,000 women  Risk increases for smokers (especially >35 yo), hypertensive patients or those who take estrogen products >35mcg Cases per 100,000 Woman-Years Cardiovascular Mortality Risk with Smoking and Combination Oral Contraceptive Use Oral contraceptive nonuser Oral contraceptive user 30 25 20 15 10 5 0 Attributable Risk/100,000 User-Years Nonsmoker Smoker 0.06 1.73 < 35 years of age Nonsmoker Smoker 3.03 19.4 ≥ 35 years of age Oral Contraceptives and Breast Cancer Risk  large epidemiologic study suggests that OCs do not cause breast cancer  Breast cancer risk in women who have not taken OCs for ≥10 years is the same as those who have never used them  Tumors are more likely to be localized in oral contraceptive users than in nonusers  Recommendation:  Family history of breast cancer or history of benign breast disease: All forms of contraception are acceptable.  Current or past history of breast cancer: Copper IUD preferred. The theoretical and proven risks with all hormonal forms of contraception are unacceptable. Who should not take COCs?      High risk of VTEs > 35 yrs with obesity or smoker Newly breastfeeding Estrogen-related cancers hypertensive:  Systolic >160mm Hg or diastolic > 100mm Hg, or uncontrolled  Migraine with aura  Patient has ed risk of stroke  Without aura or menstrual migraine is okay  See handout “Contraception for Women with Chronic Medical Conditions” Factors that Increase Risk of Breakthrough Bleeding  beginning a new form of hormonal contraception  For adolescents, breakthrough bleeding may discourage continued use  inconsistent use or missed doses  chlamydial cervicitis and/or endometritis  likely cause when breakthrough bleeding appears several months after initiating an OC regimen  Smoking  possibly due to fluctuations in estrogen levels Controlling breakthrough bleeding  Usually occurs during first 3 months  More common with low dose pills  If problem continues after 3 months:   estrogen if current product has <30mcg  Change progestin to one with more estrogenic effect  If patient is taking a progestin only pill or a multi-phasic pill,  progestin dose  If patient has amenorrhea  Always rule out pregnancy  Often caused by insufficient estrogen to stimulate growth of endometrium Drug-Drug Interactions Which ones are significant?  Drugs that may decrease COC enterohepatic circulation  Ampicillin, tetracycline, sulfa  Drugs that induce COC metabolism  Carbamazepine  Phenytoin  Phenobarbital  Primidone  Ethosuximide  Rifampin Cause spotting or breakthrough bleeding Extended Cycle Products  Shortens or eliminates hormone-free days  consecutive days of hormone therapy extend to 84 or 365 days  Can use monophasic pills to achieve this regimen  Initially may cause intermenstrual bleeding and spotting  First three months Reasons for switching to extended cycle products  decrease menstrual-related symptoms experienced by women during the HFI  Dysmenorrhea, endometriosis, menorrhagia, PMS, PMDD  improve efficacy in women who forget to restart the pill  patient preference to decrease the frequency of menstruallike bleeding  Also perimenopausal women, athletes, military women, developmentally delayed women, adolescents Examples - Extended Cycle Products  84/7 regimens - Seasonale , Jolessa, Quasense  30µg EE + LNG 0.15mg  Seasonique - 84 tab 30µg EE/0.15mg LNG, 7 tabs of 10µg EE  24/4 regimens – Yaz, Beyaz  20µg EE+ 3 mg drospirenone  24/2/2 regimen - Lo Loestrin  24 tab containing 10µg EE+ 1mg norethindrone acetate followed by 2 tab containing 10µg EE followed by 2 placebo tab  42/21/21/7 – Quartette  LNG 0.15mg X 84 days with 20µg EE X 42 days, 25µg EE X 21 days, 30µg EE X 21 days; then 10µg EE X 7 days  Continuous regimen - Amethyst  20µg EE+ 90µg LNG – no days off EE = ethinyl estradiol; LNG = levonorgestrel Why is efficacy decreased in lower dose products?  Less “forgiving” if doses are missed  Drug interactions are more likely  Body weight  Reduced efficacy  Recommendation  Consider OC with 30-35mcg estradiol in obese women  Due to risk of thrombosis, consider extended cycle instead of higher dose  Don’t use 50mcg due to risk of VTE Starting COCs Method First Day Start Sunday Start Today Start Description First active pill is taken on first day of menses First active pill taken Sunday after period STARTS First active pill taken day of doctor visit regardless of timing of menses if urine pregnancy test is negative BTB = Breakthrough bleeding Advantages • Immediate Protection  Less BTB • Most packs set up for Sunday start  Weekends free from period • Motivated pts can start pills right away Disadvantages • Pts with irregular cycles or amenorrhea may have to wait several weeks-months to start • Forgetting to start when Sunday comes several days after periods ends  Back up protection required for patch 7 days • More likely to have BTB  Must use back-up method for 2 weeks if begun midcycle  Confusion using packs Counseling Points for COCs  Remind patient COC ≠ protection against STDs  Discuss common side effects and warning signs for ACHES  Some side effects may decrease over time, recommend at least 3 month trial of new COCs  Missed pills:  1 missed/late pill = Take ASAP, even double up  2 missed pills = Take 2 pills on day remembered, then 2 pills the next day. Use back up method for 7 days  3+ missed pills = Use back up method and call physician Noncontraceptive Benefits of Oral Contraceptives  Improvement of cycle-related conditions:  Acne  Irregular menstrual cycles  Dysmenorrhea  Menorrhagia  Anemia  Functional ovarian cysts  Protective against cancer of certain organs:  Ovary  Endometrium  Colon and rectum Wallach M, et al., eds. Modern Oral Contraception: Updates from The Contraception Report. Emron, 2000. Indications for COC other than contraception  PCOS - regulate menstrual cycles in women who don't want to get pregnant. COCs also help decrease androgen levels  Endometriosis  Acne  Peri-menopause Use of COCs in perimenopausal women  Controls vasomotor symptoms and DUB while providing contraception  May increase BMD and decrease risk of ovarian and endometrial cancer  Extended cycle products may prevent hot flashes during HFI  Can be used in healthy nonsmokers >35 yo  Can continue use until age 55*  Remember that patch, vaginal ring, drosperinone-containing or desogestrel-containing products may have ↑ed risk of VTE than other estrogen-containing products  Consider implant or LNG-IUS rather than Depo Provera in women who are not candidates for estrogen-containing products *If no risk factors Why is failure rate for COCs so much higher than the ideal?  Noncompliance (~15%)  forgetfulness, didn’t refill, away from home  Women discontinue the pill because:  Side effects (46%) - Bleeding irregularities, nausea, weight gain, mood changes, breast tenderness, headaches  No further need (23%) - pregnant or relationship ended  Method-related (14%) - hard to use, concern over hormones, expense  61% of COC users who discontinue without use of another method or substitute a less effective method get pregnant  Most women who d/c COCs do so in the first 2 months  ~50% did not consult a healthcare provider Am J Obstet Gynecol, Vol. 179, Rosenberg MJ, Waugh MS, Oral contraceptive discontinuation: A prospective evaluation of frequency and reasons. 577-582, 1998. Vaginal Contraceptive Ring 4 mm 54 mm Why Vaginal Contraception?  Similar efficacy and ADRS to COCs  Higher compliance rates  Continuous release; constant hormone levels  Low ethinyl estradiol dose  Avoids GI interference with absorption  Avoids hepatic first-pass metabolism of the progestin  No GI interaction with antibiotics Veres S, Miller L , Burington B. Obstet Gynecol. 2004;104:555– 63. Slide Source: ContraceptionOnline www.contraceptiononline.org Vaginal Contraceptive Ring: Administration  Vinyl, polymer ring  Continuous delivery of EE 15µg + etonorgestrel 120µg  Flexible, easy to insert/remove  Begin within 5days of onset of menses  Wear for 3 weeks, followed by a drug-free week What to Do if the Vaginal Ring…? …slips out or is left out  Expulsion occurs at least once in 1:4 users  Within 3 hours, rinse and re-insert  After 3 hours, rinse and re-insert AND use a back-up contraceptive for one week …is not replaced at day 8  Consider emergency contraception  Rule out pregnancy  Insert new ring  Use a back-up contraceptive for one week Slide Source: ContraceptionOnline www.contraceptiononline.org Transdermal Contraceptive Patch Slide Source: Contraception Online www.contraceptiononline.org Ortho Evra Patch  Matrix system with 3 layers  6mg norelgestromin (active metabolite of norgestimate) and 0.75mg EE  Apply to buttocks, upper outer arm, lower abdomen, or the upper torso (excluding the breast)  Don’t cut or flush down toilet Transdermal Contraceptive Patch Advantages Disadvantages  Weekly application encourages  Application site reactions compliance  Verification of presence reassures user of protection  No 1st pass effect  Contraceptive effects -rapidly reversible  Excellent cycle control after 3 months  Less effective >198 lbs  ADRs similar to COCs except: - ↑ breast pain X first 2 months - ↑ dysmenorrhea  ↑ total estrogen exposure (peak blood level 25% of COC)  May be difficult to conceal  No protection against STDs Ortho Evra – change to label (2008) Patch users at ↑risk for VTE than COC users  Women with risk factors for VTE should consider use of nonhormonal contraceptives  >35 years of age  smoking  obesity  < 4 weeks post-partum  4 weeks prior to surgery and 2 weeks after surgery  Bed rest  Personal or family history of heart attack, stroke or DVT http://www.fda.gov/medwatch/safety/2008/safety08.htm#orthoevrapatch Progestin-Only Oral Contraceptives Minipills, The Shot, Implant, IUS Progestin-Only Contraceptives Available in U.S.  Oral  Norethindrone (350 µg; Micronor, NorQD –     generics) Emergency contraception  Levonorgestrel (two doses of 750 µg or 1 dose of 1.5mg) DepoProvera – injectable Nexplanon - implant Mirena, Skyla, Liletta - IUS Pharmacologic Effects of Progestins as Contraceptives Inhibit ovulation by GnRH suppressing function of the hypothalamic-pituitaryovarian axis Modify midcycle surges of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) LH, FSH Diminish ovarian hormone production Produce endometrial changes unfavorable for ovum implantation Thicken cervical mucus to impede sperm transit Inhibit sperm action GnRH = gonadotropin-releasing hormone Candidates for Progestin-Only Oral Contraceptives  Women with contraindications for combination hormonal contraceptives, including a history of:  Venous thrombosis  Vascular disease  Hypertension  Smoking (>35 years)  Lactating women  Women preferring no estrogen or these dosage forms Progestin-Only Pills  Advantages  Decreased menstrual blood loss (amenorrhea 10%)  Avoids estrogen-related side effects  May be started immediately post-partum, after miscarriage or abortion  Disadvantages  Irregular bleeding  Must be taken same time every day; no missed days  Patient may still ovulate with typical use  Less effective than COCs with typical use (95-99%) Contraceptive Implant Nexplanon  Single-rod implant contains 68 mg etonogestrel  Also contains barium sulfate to make it radiopaque  Duration of use: 3 years  >99% effective  MOA  Suppresses ovulation within 1 day of insertion  Ovulation in <5% of users after 30 months of use  Increases viscosity of the cervical mucous  Rapid return of fertility - menstruation within 3 months  Appropriate for lactating women - 4th postpartum week  Requires clinician visit for insertion and removal  Does not protect against STDs Adverse Effects of Nexplanon  Most common – changes in menstrual bleeding  Longer or shorter bleeding, spotting, change in length of time between periods  Adverse events  Acne  Mood swings  Headache  Weight gain  Depression  Implant site - mild pain of short duration  $400-800 Injectable Contraceptive Depot-Medroxyprogesterone Acetate  Depo-Provera - 150 mg DMPA deep IM injection; gluteal or deltoid muscle  Depo-subQ Provera 104 - 104 mg DMPA SC injection; anterior thigh or abdomen  Duration of protection: 3 months (13 weeks)  MOA  Inhibits ovulation  Thickens cervical mucus  Endometrial atrophy DMPA = depot-medroxyprogesterone acetate Slide Source: Contraception Online www.contraceptiononline.org Depo Provera Advantages  Continuous protection X 3 mo  No estrogen  No adverse effects seen among lactating women  ↓ risk VTE compared to estrogen  Minimal drug-drug interactions  Reduction of menstrual bleeding and lower risk of anemia Disadvantages  Bleeding irregularity and amenorrhea  Weight gain (>2 kg) common  Depression  ↓bone density  ADRs continue approximately 6 - 8 mos after last injection  Return to fertility up to 6-12 mos  MD visit every 11-13 weeks  Changes in lipid profile  No protection against HIV, other STDs Injectable Depot-Medroxyprogesterone Acetate: Food and Drug Administration Black Box Warning November 17, 2004: Women who use Depo-Provera Contraceptive Injection may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of Depo-Provera Contraceptive Injection during adolescence or early adulthood, a critical period of bone accretion, will reduce bone mass and increase the risk of osteoporotic fracture in later life. Depo-Provera Contraceptive Injection should be used as a long-term birth control method (e.g., longer than 2 years) only if other birth control methods are inadequate. Depo Provera: Management of Prolonged Spotting or Moderate Bleeding  Reassure patient - irregular and prolonged bleeding episodes are common during first 3 - 6 months  Consider short-term management:  Combined oral contraceptive for one cycle  Ibuprofen (up to 600 mg 3 times/day for 5 days)  Other forms of exogenous estrogen for 5 days  Explain that irregular bleeding may recur  Assess for nonhormonal causes (cervicitis, sexually transmitted infections, uterine pathology) Depo Provera : Noncontraceptive Benefits  Amenorrhea in 25 - 50% of women at one year  ↓ menstrual cramps, pain, mood changes, headaches, breast tenderness, and nausea  ↓ risk of ovarian cancer  ↓ risk of pelvic inflammatory disease  ↓ pain associated with ovulation and endometriosis Timing of Depo Provera Injection  Initial injection:  On day 1 to 5 of menstrual cycle  Within first 5 days of the postpartum period if not breastfeeding  After the 6th postpartum week if breastfeeding  Immediately or within first 7 days after abortion  Reinjection (week 11 to 13):  If injection is missed or late (+14 weeks), back-up contraception should be used and absence of pregnancy should be confirmed Emergency Contraception widespread use of emergency contraception could prevent 1 million abortions and 2 million unintended pregnancies each year in the United States What is Emergency Contraception? “Therapy used to prevent pregnancy after an unprotected or inadequately protected act of sexual intercourse.” ACOG  Not just “morning-after pill” – hormonal EC can be given up to 72 hours (or 120 hrs) after unprotected intercourse  Oral contraceptive formulations ®  Plan B and Ella  Mifepristone (off label, <120 hrs after unprotected sex)  Copper IUD (up to 5 days after ovulation) Emergency Contraception: Indications  Intercourse within past 72 hours (or 5 days) without contraceptive protection (independent of time in the menstrual cycle)  Contraceptive mishap  Barrier method dislodgment/breakage  Expulsion of IUD  Missed oral contraceptive pills  Error in practicing coitus interruptus  Sexual assault  Exposure to teratogens (e.g., cytotoxic drugs) Yuzpe Regimen: Oral Contraceptive Formulations Brand Name Pills/Dose EE µg/Dose Levonorgestrel mg/Dose Ovral Alesse 2 white 5 pink 100 100 0.50 0.50 Levlite 5 pink 100 0.50 Nordette Levlen Levora Lo/Ovral Triphasil Tri-Levlen Trivora 4 light orange 4 light orange 4 white 4 white 4 yellow 4 yellow 4 pink 120 120 120 120 120 120 120 0.60 0.60 0.60 0.60 0.50 0.50 0.50 EE = ethinyl estradiol Yuzpe regimen = ethinyl estradiol + levonorgestrel Yuzpe Regimen  In a meta-analysis of 8 studies,Yuzpe resulted in an estimated 75% ↓ in number of pregnancies  Side effects  Nausea (50%)  Vomiting (20%)  Heavy menses/breast tenderness  Antiemetic 1 hr before first dose ↓s nausea and vomiting  Menses occurs within 3 weeks in up to 98% of women  No evidence of teratogenicity (based on COC data) Progestin-Only Emergency Contraception  Single dose of 1.5 mg levonorgestrel appears as effective and causes similar ADRs as traditional two-dose levonorgestrel.  Unlabeled equivalent  20 pills/dose of Ovrette taken 12 hours apart  More effective/fewer side effects than Yuzpe  MOA: primarily prevents ovulation and fertilization; does not disrupt events that occur after implantation.  Recent evidence suggests that there is no interceptive action*  Only contraindication – known pregnancy * Noe G, Croxatto HB, Salvaiterra AM, et al. Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation. Contraception 2010;81:414–20. Durand M, del Carmen Cravioto M, Raymond EG, et al. On the mechanisms of action of short term levonorgestrel administration in emergency contraception. Contraception 2001;64:227–34. Plan B One-Step and Next Choice  Plan B One-Step, Next Choice One Dose  Single dose version – one 1.5mg levonorgestrel (LNG) tablet  Next Choice  Two 0.75mg LNG tablets  Can take both tablets in one dose  Available over the counter to female or males of any age Patient Counseling for EC  How to take medication (provide written instructions )  Take ASAP  Expected side effects (nausea/vomiting/cramping)  Use antiemetic one hr before the 1st dose if Yuzpe regimen  If patient vomits tablet in 3 hrs, repeat dose  Enzyme inducers – rifampin, phenytoin may ↓ effectiveness  Expected menses >98% bleed within 21 days of EC  If period does not occur after 3 weeks, rule out pregnancy  Remind patient that EC does not prevent STDs  Do not use EC as a regular means of contraception; seek another more efficacious method Ella (ulipristal) - Rx only EC  Can be used up to 5 days post-coitus - One 30mg tablet  Progesterone receptor modulator  May delay ovulation or inhibit follicular development  Phase III study data  If vomiting occurs within 3 hrs, repeat dose  Comparative study with LNG halved pregnancy risk of LNG products if taken <72hrs risk reduced by almost 2/3 if taken within 24 hrs H/A (19%), dysmenorrhea (13 /14%), nausea (13 / 11%), abdominal pain (5 /7%), dizziness (5%), fatigue (6/ 4%)  Disruption of menstrual bleeding common – ~2 days Ella (ulipristal)  Safety appears similar to LNG  Estimated cost = $50  Recommended for EC between 72 -120 hrs after unprotected sex  Investigational for treatment of symptomatic uterine fibroids, endometriosis , breast cancer  Somewhat controversial  MOA similar to mifepristone (Mifiprex)  Could interfere with hormonal contraceptives in same cycle  Effectiveness may be  by drugs that induce CYP 3A4 (anticonvulsants, rifampin, St John’s wort, etc) Emergency Contraception in Obese women  For women who weigh >154 pounds, levonorgestrel may not work as well  Ulipristal seems to be less effective in women who weigh over 187 pounds  However, this doesn't mean that overweight women shouldn't use these products, especially if they are the only options available Copper IUD for EC  Estimated failure rate  0.1% (n=8,400) – most effective  Mechanism(s) of action  Impairs fertilization  Alters sperm motility and integrity  Impairs implantation  Indications:  Unprotected intercourse  Need/desire for long-term contraception  May insert <5 days after earliest estimated ovulation  Contraindications - Pregnancy or sexual assault with high risk of STD  May be difficult to have it placed within 5 days Approval of OTC use of oral contraceptives  Oregon law went into effect 1/1/16  California law soon to be in effect  http://www.oregon.gov/pharmacy/Pages/ContraceptivePr escribing.aspx#Tool-Kit_Resources Resources: Emergency Contraception  Hotlines  1-888-NOT-2-Late or 1-800-584-9911  Web Sites  The Emergency Contraception Website—http://www.NOT-2- Late.com  Consortium for Emergency Contraception— http://www.cecinfo.org/  American College of Obstetricians and Gynecologists— http://www.acog.org  National Women's Health Information Center Emergency Contraception Information— http://www.4woman.gov/faq/econtracep.htm