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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