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93-1 EMERGENCY CONTRACEPTION Forget Me Not. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level II Emily C. Papineau, PharmD, BCPS A healthy, 19-year-old woman started her combined oral contraceptive (COC) pill pack 2 days late, extending her pill-free interval to 9 days. She had intercourse 2 days ago and wants to avoid pregnancy at this time. Her four options for emergency contraception include: (1) use of levonorgestrel (eg, Plan B OneStep [OTC]); (2) use of multiple COCs (Yuzpe method); (3) use of ulipristal; or (4) off-label use of the copper-intrauterine device (IUD). The patient should be counseled regarding the specific method selected, including how it works, what side effects may occur, and when to follow-up with her primary care provider if menses do not occur. She should also be educated on when and how to resume a routine form of birth control and the importance of remaining adherent to the regimen to avoid the need for emergency contraception. QUESTIONS Problem Identification 1.Identify the patient’s drug therapy problem. • The patient has extended her hormone-free interval to 9 days as she forgot to reinitiate her new COC pill pack on time. The patient had sexual intercourse 2 days ago and does not want to become pregnant at this time. When a sexually active patient misses two or more consecutive days of a COC (especially one that contains ≤20 mcg of ethinyl estradiol), emergency contraception is recommended.1 Extending the hormone-free interval beyond 7 days can increase the chances of ovulation and unintended pregnancy.1 Desired Outcome 2.What are the goals of pharmacotherapy in this case? • Prevention of pregnancy using an emergency contraceptive method that is acceptable to the patient. Therapeutic Alternatives 3.a. What pharmacotherapeutic options are available for emergency contraception for this patient, and what are the advantages or disadvantages of each? • Levonorgestrel-only method. This oral emergency contraception regimen is approximately 60–94% effective at preventing pregnancy when initiated within 72 hours of unprotected intercourse.2,3 On average, it is considered to reduce the pregnancy rate by about 89%.4 Ideally, it should be taken as soon as possible for greatest efficacy. This method is more efficacious than use of COC tablets and causes less nausea (18% incidence) and vomiting (4% incidence) than use of COCs for this purpose.2 ✓The primary mechanism of action is to prevent or delay ovulation.4 Conflicting evidence exists as to whether or not levonorgestrel can prevent implantation. It may impair sperm motility through the genital tract but appears unlikely to affect endometrial receptivity to a fertilized egg.2,3 If implantation has occurred, levonorgestrel has not been shown to cause any harm to the fetus. This emergency contraceptive option is not considered an abortifacient since it does not promote the shedding of the endometrial lining once implantation has occurred.2–4 • Multiple COC tablets. This method of emergency contraception was discovered prior to that of the progestin-only method and is called the Yuzpe method. It lowers the chance of pregnancy when initiated within 72 hours of unprotected sex by about 74% on average.1,4 Some evidence indicates that COCs used as emergency contraceptives may also work up to 120 hours after unprotected sex.1,2,4 This method of emergency contraception is associated with a much higher likelihood of nausea (43% incidence) and vomiting (16% incidence) when compared with the levonorgestrel-only products and is not as efficacious as levonorgestrel-only products or ulipristal acetate.1,2 One study demonstrated that levonorgestrel was 85% efficacious in preventing pregnancy as compared with 57% demonstrated by the Yuzpe method.2 ✓The primary mechanism of action is to prevent or delay ovulation4; however, other mechanisms may exist.2 • Ulipristal acetate (ella). This selective progesterone receptor modulator was FDA-approved in 2010 and is a third option for emergency contraception. Unlike the levonorgestrelonly and Yuzpe methods, this product is actually labeled for use up to 120 hours after inadequately protected intercourse and its efficacy does not appear to decrease during that time window. On average, it reduces the pregnancy rate by 90%.4 It is more efficacious than levonorgestrel, especially when used 4–5 days after inadequately protected intercourse.2 Ulipristal, like levonorgestrel, may also be less efficacious in obese women.2 As our patient is not obese, this product remains an option for her. ✓The primary mechanism of action is to prevent or delay ovulation; however, ulipristal has also been shown to alter the endometrial lining and may impair implantation.3–5 This potential contribution to its efficacy cannot be excluded. Animal models have demonstrated embryofetal loss in pregnant rats, rabbits, and monkeys.5 Because of this, ulipristal may be undesirable for individuals who may have ethical or religious concerns with a drug that could potentially prevent implantation. • Insertion of copper-releasing IUD. While not FDA-approved for this purpose, the copper IUD reduces the risk of pregnancy Copyright © 2017 by McGraw-Hill Education. All rights reserved. Emergency Contraception CASE SUMMARY CHAPTER 93 93 Some evidence suggests that levonorgestrel-only containing products may also work, albeit less effectively, up to 120 hours after unprotected sex.1,2,4 Levonorgestrel may be less efficacious in women whose BMI is 25–29.9 kg/m2 and especially in women whose BMI is ≥30 kg/m2.2 Product labeling in Europe has been changed to reflect a similar weight-related warning about decreased efficacy in overweight and obese women. Note that there are no restrictions or specific contraindications to using these products in women who are overweight and obese; however, efficacy may be reduced.2 Given this patient has a normal BMI, efficacy of emergency contraceptive products will not be affected by her current weight. 93-2 SECTION 9 Women’s Health (Gynecologic Disorders) by approximately 99% when inserted within 5 days of unprotected sex.2 It is also a more efficacious option compared with oral emergency contraceptive options on day 4 or 5 after unprotected sex and its efficacy is not affected by body weight, unlike ulipristal and levonorgestrel.1,2 One potential disadvantage to this method may be a slightly higher chance for expulsion of the IUD, particularly in a woman who is nulligravida. Since this patient has never been pregnant, it may be potentially more difficult for the uterus to accommodate the device although this is not likely to be a problem.5 Expulsion rates in adolescents range from 5 to 22%.6 The American College of Obstetricians and Gynecologists Committee on Adolescent Health Care recommends that long-acting reversible forms of contraception (LARC) such as copper- or progestin-releasing IUDs or Nexplanon (etonogestrel) be encouraged over the use of other forms of reversible contraception in adolescents and young adults.6 This is due to greater efficacy and patient satisfaction with LARC. Depending on how long our patient desires contraception, this may be an ideal choice and would eliminate the potential need for emergency contraception due to missed pills in the future.2,6 ✓Its proposed mechanism of action is preventing fertilization by the spermicidal activity of copper and by preventing implantation as it alters the endometrial receptivity.4,7 ✓Note: Levonorgestrel-releasing IUDs are not efficacious for emergency contraception.2,4 3.b. What contraindications exist to the use of emergency contraception, and do they apply to this patient? • The US Medical Eligibility Criteria for Contraceptive Use do not identify any contraindications to the use of the emergency contraceptive pills (ECPs) containing levonorgestrel or the Yuzpe method.8 Even the benefits of using the estrogen-containing Yuzpe method are thought to outweigh any potential estrogen-related risks. This holds true even for women who would otherwise have contraindications to the use of estrogen-containing products although the progestinonly method would be preferred for these individuals.2,4,8 Ulipristal is not included in the medical eligibility criteria document as it was FDA-approved after the publication of the criteria. • The patient is unlikely to have any contraindications to the use of an IUD such as an abnormally shaped uterus or recent exposure to sexually transmitted diseases (STDs) given her mutually monogamous relationship. • Pregnancy is identified as a contraindication to the use of the levonorgestrel-containing emergency contraceptive products and the Yuzpe method, not because any fetal harm has been identified, but because it is clearly too late to use these products. A pregnancy test does not have to be administered prior to initiating these types of emergency contraception regimens.2,4 Ulipristal is also contraindicated in pregnancy; however, its prescribing information specifically states that pregnancy should be ruled out prior to administering the product.5 If this cannot be accomplished by history and physical examination alone, then a pregnancy test is recommended.5 Patients in the ulipristal trials were given a pregnancy test prior to receiving the drug because the risks of ulipristal to a fetus are unknown.5 As expected, known hypersensitivity to any emergency contraception product component is a contraindication for its use as is undiagnosed abnormal genital tract bleeding prior to placing an IUD because this warrants investigation before any therapy is initiated.2,8 Copyright © 2017 by McGraw-Hill Education. All rights reserved. Optimal Plan 4.Recommend an appropriate emergency contraceptive method and dose for this patient. • Levonorgestrel-only products. This is the preferred method, given its efficacy, tolerability, ease of use, and cost. It is available in two dosing regimens: ✓Plan B was the first progestin-only emergency contraceptive available and was dosed as two 0.75 mg levonorgestrel tablets taken 12 hours apart. At the time this chapter was written, no brand or generic drug manufacturers were making this dosage. ✓Plan B One-Step (or equivalent product such as Opcicon One-Step or My Way) has combined the dose to be 1.5 mg of levonorgestrel taken once. This larger dose does not increase side effects but may increase adherence to the regimen as a single dose.2 ✓For many years, these products were available without a prescription to any individual 17 years of age and older and were available only by prescription to those younger than 17 years. Now, Plan B One-Step was ultimately granted OTC status without age restriction in 2013. Other 1.5 mg levonorgestrel products are now also available over the counter. This 19-year-old patient should be able to obtain Plan B One-Step or an equivalent product without difficulty.2 • Multiple COC tablets (Yuzpe method). This involves taking one dose of 100 mcg of ethinyl estradiol with 0.5 mg of levonorgestrel followed by a second dose 12 hours later. This method is not preferred due to lesser efficacy and greater gastrointestinal side effects. ✓There are no FDA-approved products solely marketed for this purpose. The FDA has identified certain COCs containing ethinyl estradiol and levonorgestrel to be considered safe and efficacious for emergency contraception use when used at specified doses higher than those used as daily contraception. ✓An example of such use is taking five orange Aviane pills (her current birth control medication containing ethinyl estradiol 20 mcg/levonorgestrel 0.1 mg per tablet) now and five pills 12 hours later. ✓Meclizine taken 1 hour prior to the first COC dose can lessen nausea and vomiting.1,2 • Ulipristal acetate (ella) is available by prescription only and is dosed as a single 30 mg tablet taken with or without food.5 • Regardless of which version of oral emergency contraception is selected, some professional organizations (including the Women’s Health Practice and Research Network of the American College of Clinical Pharmacy, the American College of Obstetricians and Gynecologists, and the American Academy of Pediatrics) recommend that patients should obtain these products in advance of their actual need.2,4,9,10 While having emergency contraception available before it is needed may encourage its use, studies have not shown a decrease of unintended pregnancies even with advance provision of the medication.1–3 • Use of emergency contraception may be repeated during the same menstrual cycle. Patients should be educated that emergency contraception, while thought to be safe to use repeatedly, is not as efficacious at preventing pregnancy as are other forms of hormonal contraception or IUDs. 93-3 • Copper-releasing IUD: 5.What clinical and laboratory parameters are necessary to evaluate the efficacy of the therapy? • Absence of pregnancy. When emergency contraception is used, the menstrual cycle usually occurs 1 week before or after when it is expected to occur.2 This is typically earlier than expected for levonorgestrel products and later than expected for ulipristal. If she does not have menses after 3 weeks or a week after she would normally have menses, a urine pregnancy test should be performed to rule out pregnancy.1,5 The patient may also experience some unscheduled bleeding with use of these products.1,2 Patient Education 6.a. Counsel the patient regarding how the emergency contraceptive regimen works, how to take it, and what side effects may occur. How emergency contraception works: • Depending on the patient’s social or religious beliefs, it may be important to her to know how the various emergency contraception products work. ✓Emergency contraceptive pills or ECPs like levonorgestrel or the Yuzpe method (which involves taking multiple traditional birth control pills in 12 hours) are anywhere from about 60% to 94% effective at preventing pregnancy, but you could still become pregnant even after taking this medication. ECPs are thought to help prevent pregnancy mainly by preventing or delaying ovulation. It is still unclear whether or not they can decrease the ability of a fertilized egg to implant into the lining of the uterus. These pills are not considered to be “abortion pills.” Pregnancy is defined as occurring once a fertilized egg has implanted into the lining of the uterus. Once this has happened, ECPs containing levonorgestrel or traditional birth control pills will not work, and they have not been shown to harm a fetus if you are already pregnant.2,4,7 ✓The emergency contraceptive pill, ulipristal, is very effective at preventing pregnancy, even more effective than the other oral emergency contraceptive options, especially 4–5 days after inadequately protected sex.4 It prevents or delays ovulation and can change the lining of the uterus to make it harder for a fertilized egg to implant.4 This could be partly why it is so effective. Unlike the levonorgestrel or Yuzpe methods which have not shown harm to the fetus if you are already pregnant, it is unknown whether or not ulipristal could cause harm if you are already pregnant.5 For this reason, your primary care provider may have you take a pregnancy test before using this pill if he or she is not reasonably sure that you are not pregnant. ✓The copper IUD is a contraceptive device that is inserted into the uterus and is very effective at preventing pregnancy for How to take it and side effects: • Levonorgestrel only products. Plan B One-Step, Opcicon OneStep, and My Way are examples of a one-dose 1.5 mg levonorgestrel tablet that should be taken with 72 hours of unprotected intercourse, available OTC. Ideally, it should be taken right away, as the sooner it is taken after inadequately protected intercourse, the more effective it is. ✓ Most women do not experience side effects with these medications. There is a small chance that it could cause nausea or vomiting. Repeat the dose if vomiting occurs within 2 hours after taking a dose.2 You may also experience a small amount of bleeding in the week after taking this medication. ✓If you experience persistent abdominal pain or irregular bleeding, contact your healthcare provider. ✓If you do not restart your Aviane, your period may start a week sooner or later than the expected 3 weeks.2 • Multiple COCs. Take five of the orange Aviane pills now and five pills 12 hours later. ✓ Because taking five pills at once can cause nausea and vomiting, take meclizine 25 mg, an antinausea medication, 1 hour prior to the first dose to lessen these side effects. Repeat the dose if vomiting occurs within 2 hours after taking a dose.2 These birth control tablets may be administered vaginally if you cannot keep them down.2 ✓If you experience persistent abdominal pain or irregular bleeding, contact your healthcare provider. • Ulipristal. Take one 30 mg tablet now with or without food. ✓Most women do not experience side effects with this medication. You may experience a headache, nausea, or abdominal pain. If you vomit within 3 hours of taking the medication, ask your primary care provider if you should take it again.5 ✓Contact your healthcare provider if you experience persistent abdominal pain or if your period is delayed by more than 1 week.5 • Copper-IUD. This may cause some abdominal discomfort, vaginal bleeding, or a small amount of vaginal bleeding known as spotting, for a couple of days after the IUD is inserted.4 ✓During the first few months after IUD placement, spotting is common. A copper-releasing IUD can also cause more menstrual bleeding and cramping with your periods; however, this tends to diminish after the first 2–3 months. Taking a medication like ibuprofen or naproxen at the start of your period can lessen this.4 ✓Most women do not have unusual side effects from having an IUD. Talk to your primary care provider if you experience anything in the acronym PAINS. “P” stands for a period that is late. “A” stands for severe abdominal pain. “I” stands for infection. Tell your primary care provider if you have any abnormal or foul-smelling vaginal discharge. “N” stands for not feeling well such as getting a fever or chills. “S” stands for Copyright © 2017 by McGraw-Hill Education. All rights reserved. Emergency Contraception Outcome Evaluation CHAPTER 93 ✓If only used for emergency contraception, it is an expensive option for the healthcare system with prices for Paragard estimated to be around $500. Due to the Affordable Care Act, insurance companies typically cover this product for free. If the patient does not have insurance, a patient assistance program may provide an eligible patient the IUD at little to no cost. If continued contraception is desired, this product can remain in place for 10 years. 10 years. When used for emergency contraception purposes, it is thought to help prevent fertilization by affecting the sperm movement in the female reproductive tract, and it could also make it harder for a fertilized egg to implant into the lining of the uterus, should a fertilized egg be present.4,7 While the copper IUD is 99% effective at preventing pregnancy, you could still become pregnant even after receiving the IUD. 93-4 SECTION 9 string. Monitor the IUD string length to make sure that the IUD has not moved.4 6.e. Counsel the patient regarding how she can minimize the need for emergency contraception in the future. 6.b. Explain to the patient how she will know if the emergency contraception regimen was effective. • You may continue to use your oral birth control pill if you desire. If you choose not to take the seven pills in the last week of your pill pack, consider discarding them one day at a time to help keep you in the habit of using your pill pack and so you do not start your next pack too late. Women’s Health (Gynecologic Disorders) • Your period may come 1 week earlier or 1 week later than expected, especially if you do not restart your Aviane right away. You should expect a period within the next 3 weeks. If this does not occur, you should take a pregnancy test or contact your primary care provider.1,2 You may also experience some bleeding during the first week after using emergency contraception.4 6.c. Instruct the patient on when emergency contraception may be warranted, should she need to use it in the future. • Contact your primary care provider or pharmacist if you forget to take any of your birth control pills in the future. Depending on the strength of your birth control pill and when you have missed it in your cycle, you may be at risk for pregnancy. Using ECPs at that time may decrease your chance of pregnancy. Some women choose to keep a supply of ECPs at home in case they are needed.1,4 If you find it difficult to remember to take your Aviane pills every day, you may want to discuss other contraception options with your healthcare provider such as long-acting reversible forms of contraception like an IUD or Nexplanon. • Keep in mind that ECPs are not as effective as taking oral contraceptive pills on a regular basis and should only be used as a “back-up” plan, not as the only method to prevent unintended pregnancy.2,4 6.d.Instruct the patient when she should reinitiate her combined oral contraceptive regimen. • ECPs will not prevent you from getting pregnant if you have unprotected sex in the days following therapy. You should resume a regular method of birth control the day after your ECP regimen is completed.1,2 If you used the levonorgestrel or the Yuzpe method, use a back-up method of birth control, such as a condom, until you have taken your new birth control pill pack for seven consecutive days. This is because it will take 7 days for your Aviane to begin working again. If you used ulipristal, it is recommended you wait 5 days before restarting your Aviane.2 You will need to use an additional back-up method of birth control, such as a condom, until you have had your next period or until you have taken your contraceptive pill for 14 days, whichever is less.1 This is because Aviane may make ulipristal less effective and ulipristal may make your birth control pills less effective within that same menstrual cycle.2,5 It would probably be best to wait until after your next period to begin your next pack of Aviane to avoid this.4 If you choose to wait to start your pack until after your period has begun, remember to use a barrier method of contraception during that entire time and until you have taken the Aviane for seven consecutive days. If the copper-IUD is used, it will work immediately to help prevent pregnancy and continue to do so for 10 years.2 • As you may know, birth control pills or an IUD can help prevent pregnancy but do not protect against STDs. Use a condom if you, or your husband, have an additional sexual partner. Copyright © 2017 by McGraw-Hill Education. All rights reserved. • There are also extended-cycle birth control options that would allow you to only have a period once every 3 months or potentially not at all. This could be taken in the form of a daily birth control pill or a birth control injection administered every 3 months typically by a healthcare professional. Longer birth control options include a small hormone rod called Nexplanon which sits under the skin of your upper arm for 3 years, or an IUD which can remain in your uterus for 3, 5, or 10 years, depending on the device. Both the hormone rod and the IUDs are more effective at preventing pregnancy than birth control pills and can be removed at any time should you want to become pregnant.6 If these options interest you, discuss them with your healthcare provider who can describe the risks and benefits to using these methods. The nonoral forms of birth control could be started after your next menstrual cycle.2 REFERENCES 1. Centers for Disease Control and Prevention. U.S. Selected Practice Recommendations for Contraceptive Use, 2013: adapted from the World Health Organization selected practice recommendations for contraceptive use, 2nd edition. MMWR Recomm Rep 2013;62:1–60. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6205a1.htm. Accessed April 29, 2016. 2. American College of Obstetricians and Gynecologists (ACOG). Practice Bulletin No. 152: emergency contraception. Obstet Gynecol 2015;126(3):e1–11. 3. Shrader SP, Hall LN, Ragucci KR, Rafie S. Updates in hormonal emergency contraception. Pharmacotherapy 2011;31:887–895. 4. Zieman M, Hatcher RA, Allen AZ. Managing Contraception for your Pocket, 13th ed. Tiger, Georgia: Bridging the Gap Foundation, 2015. 5. Ulipristal prescribing information. Morristown, NJ: Watson Pharma, Inc, 2010. Revised March 2015. 6.American College of Obstetricians and Gynecologists. Committee Opinion No. 539: adolescents and long-acting reversible contraception: implants and intrauterine devices. Obestet Gynecol 2012;120:983–988. 7.Baird DT. Emergency contraception: how does it work? Reprod Biomed Online 2009;18(1):32–36. 8. Centers for Disease Control and Prevention. U.S. Medical Eligibility Criteria for Contraceptive Use, 2010: Adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th ed. MMWR Recomm Rep 2010;59:1–86. Available at: http://www.cdc.gov /mmwr/preview/mmwrhtml/rr5904a1.htm?s_cid=rr5904a1_e. Accessed April 29, 2016. 9. Rafie S, McIntosh J, Gardner DK, et al. Over-the-counter access to emergency contraception without age restriction: an opinion of the Women’s Health Practice and Research Network of the American College of Clinical Pharmacy. Pharmacotherapy 2013;33:549–557. 10. American Academy of Pediatrics. Policy statement: emergency contraception. Pediatrics 2012;130:1174–1182.