Course Authors

Susan C. Stewart, M.D.

Dr. Stewart reports no commercial conflict of interest.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 

Learning Objectives

Upon completion of this Cyberounds^®, you should be able to:

• Describe the hormonal effects considered responsible for emergency contraception

• List the currently used drugs or drug combinations that bring about emergency contraception

• Describe the timing and dosage of currently available emergency contraceptive drugs.

 

In 1997, when I reviewed on Cyberounds^® the status of emergency contraception (EC), "the Morning After Pill," the U.S. Federal Register had just published the doses of the Yuzpe (estrogen and progesterone combination) and the progestin-only effective regimens.(1) At that time, in the U.S., EC had to be prescribed via existing formulations of contraceptive pills. Now there are two specific products, Preven^® and Plan B^®. In this Cyberounds^®, I would like to bring you up-to-date on the available products and provide links for additional information.

Background

Although surveys conducted in 1994 and 1995 showed that EC was well-studied and safe, and had the potential to reduce unplanned pregnancy by at least 75% (and, derivatively, induced abortions), emergency contraception was not well known by patients in America nor was it frequently prescribed by physicians. Even among obstetrician-gynecologists, who had a high degree of knowledge (99%) and minimal reluctance to prescribe EC, the survey indicated that a majority (75%) prescribed EC fewer than five times a year.(2),(3)

Among women who might have need for EC, survey data showed that only 1% had used the technique, even though over one half of the women at risk indicated they would be willing to try such a method if they needed it. Fully two-thirds of the women surveyed did not know that anything could be done on an emergency basis to reduce the risk of an unplanned pregnancy.(3)

In the years since, however, some promising trends have emerged. The Kaiser Family Foundation's Third National Survey found a doubling of physicians prescribing more than six EC prescriptions per year (OBGyn 16% to 31%, FP 8% to 17% from 1995 to 2000). The Kaiser survey also documented a tripling of interest in EC on the part of patients (OBGyn 11% to 29%, FP 6% to 17% from 1997 to 2000.(4)

Emergency Contraception and Abortions

EC has tremendous potential for decreasing the number of induced abortions in the United States. From data collected in their 2000 - 2001 survey of women receiving abortions, Alan Guttmacher Institute researchers estimated that 51,000 fewer abortions were performed in the United States in 2000 because of the use of emergency contraception.(5) With more frequent use of EC, this number could be much higher. Half of the over 5 million pregnancies per year in the United States are unintended (>2,500,000), and half of these end in abortion (1,300,000 in 2000). With widespread EC, it is likely that we can reduce the number of abortions in the U.S., a goal shared by those who oppose abortion and those who are pro-choice.

Learn to Prescribe EC

My goal for this Cyberounds^® is to make every physician and clinician with prescribing privileges sufficiently knowledgeable about EC that they would be comfortable prescribing it for a woman who needs it. This means a friend, a wife, a daughter, as well as a patient. I also think that information about EC should be included in conversations about sexual history during medical examinations of both men and women and in routine gynecological care. Finally, every emergency facility or practitioner caring for rape victims should have prescribing knowledge and be able to provide easy access to this treatment for such patients.

In Washington State and California, pharmacists can directly screen and provide EC to patients. There is similar legislation being considered in New York State as well.

Emergency contraception is indicated in any situation in which a woman has had unprotected intercourse but does not wish to become pregnant. This can include failed contraception, intercourse with no contraception for any reason or forced intercourse.

The Methods

There are two currently well accepted methods of emergency contraception. The hormonal method consists of various formulations of estrogen and progestins or progestins alone; the other is the emergency insertion of the copper-containing IUD(intrauterine device). The latter can be used up to five days after unprotected coitus and is highly effective. It has the advantage of working as an ongoing contraceptive for up to ten years. Its use is limited by the requirement for special training for insertion, the initial expense and the fact that some women are not candidates for IUDs.

The Yuzpe Method

In the mid 1970s, Dr. Albert Yuzpe of Canada began publishing his research on a combination of an estrogen, ethinyl estradiol and a progestin, dl-norgestrel.(6) This medication is administered in two doses started within 72 hours after unprotected intercourse. A number of studies have shown that the use of EC reduces the risk of pregnancy by 75%.(7) This means that of the expected eight pregnancies that would occur in 100 women after a single act of unprotected intercourse in mid cycle (second or third week), six would be prevented. The Yuzpe regimen consisted of 100 mcg of ethinyl estradiol and 1 mg of norgestrel in each of the two doses. The Preven^® formulation is equivalent to the Yuzpe regimen but it contains levonorgestrel, which has twice the potency of norgestrel, so only half the milligrams, or 0.5 mg per dose, is needed.

The Progestin-only Method

A high dose of a progestin compound is also effective. Levonorgestrel (LNG), in a dose of 0.75 mg, given in two doses 12 hours apart, within 72 hours of unprotected intercourse, has been shown to be equivalent to the Yuzpe method. Note that this progestin dose is 1.5 times the amount of levonorgestrel than is in the Yuzpe regimen using levonorgestrel. Plan B^® is the progestin-only formulation.

How Does Hormonal Emergency Contraception Work?

Hormonal EC is thought to work through a number of mechanisms: interference with ovulation, fertilization, fallopian tube motility and endometrial receptiveness to implantation. It is not just a morning after pill. There is a well-documented 72-hour window for effectiveness of this regimen, although it becomes less effective the later it is taken.

EC is emphatically not a substitute for regular contraception. Reducing the risk of pregnancy by 75% for one cycle does not compare with an effectiveness rate of over 99% for a year, as is seen with oral contraceptives when they are used perfectly.(7) Furthermore, if there were multiple acts of intercourse during the cycle, a pregnancy could result from the coitus not followed by the EC regimen. Finally, there are significant side effects to hormonal EC, most prominently nausea and vomiting, particularly with the Yuzpe method, which makes it sufficiently unpleasant that women who get these side effects would not want to use it frequently.

How Do You Prescribe Emergency Contraception?

With the introduction of Preven^® and Plan B^®, EC became much easier. Before, a clinician needed to cobble together pills from oral contraceptive packages. You still can, and you should know how to do it. [See Table 1, Yuzpe Regimen, and Table 2, Progestin-only Regimen below.]

Preven^®, Emergency Contraceptive, Yuzpe Regimen

Preven^® was the first EC to be released in the U.S. after the FDA's article in the Federal Register requesting that drug companies prepare and market such products in February of 1997. No major oral contraceptive manufacturer did so and, currently, none of them includes the indication and dosing requirements in their package insert. Preven^® is made and marketed by Gynetics, a small private company. It was released in September 1998. It got a big boost in publicity and sales in May of 1999 when Walmart refused to stock Preven^®.(8)

Preven^® was initially released as a kit, containing the medication and a pregnancy test. Subsequently, an additional product with the pills only has become available. If you want to read the package insert on Preven^®, don't go to the PDR. It is not there. It is available at Preven or Gynetics. The packet contains four blue pills, each containing 50 mcg of ethinyl estradiol and 0.25 mg of levonorgestrel. A dose is two tablets. So for Preven^®, the patient takes two tablets as soon as possible after the act of unprotected intercourse and two tablets 12 hours later. The shelf life of Preven^® is 48 months (4 years).

There are many currently available oral contraceptives that will yield a dosage equivalent to the Yuzpe regimen. You have to remember that norgestrel has half the potency of levonorgestrel. So one dose of the Yuzpe must contain either 0.50 mg of levonorgestrel or 1.00 mg of norgestrel, combined with the 100 mcg of ethinyl estradiol. (See Table 1.)

Plan B^®, Emergency Contraceptive, Progestin-only Regimen

Retail distribution of Plan B^® began in September 2000. As with Preven^®, it is made and distributed by a small private company, Women's Capital Corporation. There is brief mention of it in the 2003 PDR, but not the detailed insert. The Plan B^® insert is available on the website. The preparation consists of two tablets of levonorgestrel 0.75 mg. The woman takes one tablet immediately and one twelve hours later. The shelf life is 36 months (3 years).

The currently available oral contraceptive that will yield an equivalent dose to Plan B^® is Ovrette^®. Ovrette^® contains 0.075 mg of norgestrel. Keep in mind that norgestrel has half the potency of levonorgestrel, so each tablet contains 0.0375 mg of active drug. Therefore, the patient needs to take 20 Ovrette^® pills (1.5 mg norgestrel) to get the equivalent of a 0.75 mg dose of levonorgestrel. There are 28 pills in a package, so she must have two packs for a full course.

One interesting new finding about levonorgestrel regimen is that taking both pills at once was as effective as taking them 12 hours apart.(9)

Timing: It is very important to start EC as early as possible in the 72-hour window after intercourse. But it is also very important that the second dose be 12 hours later. However you have to be practical. If a woman takes her first dose at 3 PM, she would have to wake up at 3 AM to take the second dose. It might be better for her to take the first dose at 6 PM and the second at 6 AM. As mentioned above, one study has shown that the progestin-only regimen works when the doses are taken at the same time. That would be an off-label application of Plan B^®.

Protocol Questions for Prescribing EC

There are only three questions you have to ask before prescribing EC.

1. Have you had sexual intercourse in the last 72 hours?
2. What was the first day of your last menstrual period?
   Date

   ---

   Was it less than 4 weeks ago?
3. Was it normal in timing and length?

If the answer to these three questions is yes, you can go ahead and prescribe emergency contraception. (For more information, go to Plan B and the Association of Reproductive Health Professionals' Emergency Contraception Protocol). Click on Appendix, at end of this Cyberounds^®, for a printable copy of Tables 1 and 2, and helpful notes.

Comparison of Yuzpe and Progestin-only Regimens

Efficacy: A large multicenter trial published in 1998 definitively showed that the progestin-only regimen was more effective than the Yuzpe. When used correctly the progestin prevented 89% and Yuzpe prevented 76% expected pregnancies.(10) Both showed proportional decreasing effectiveness the longer the delay from unprotected coitus.(11)

Side effects and contraindications: The package inserts mention all warnings that apply to oral contraceptives, but the incidence of any serious effect is so very low that the World Health Organization (WHO) only lists current pregnancy as a contraindication.(12) The presence of ethinyl estradiol in the Yuzpe regimen is responsible for an increased incidence of nausea and vomiting; and the two relative contraindications, history of thromboembolic disease and migraine with focal aura. Undiagnosed genital bleeding is considered a contraindication for the progestin-only regimen. For both regimens, hypersensitivity to any component or current pregnancy are absolute contraindications, though there is no documented harmful effect on a fetus from either regimen. Although frequently confused with the "abortion pill," mifepristone, these emergency contraceptives, as with the standard oral contraceptives, will not interrupt (or harm) a current pregnancy.

What to do about nausea and vomiting: These symptoms have been noted with both regimens but are more common with the Yuzpe. The 1998 trial reported nausea 50.5% and vomiting 23% with Yuzpe and nausea 18.8% and vomiting 5.6% with progestin. The main concern is whether the vomiting will interfere with the absorption of the medication. It stands to reason that women who have experienced these symptoms with oral contraceptives will be most susceptible. The current opinion is that if the patient vomits within one hour of ingestion or notes the pill(s) in the vomitus, a second dose can be given, preceded 1 hour by an antiemetic like meclizine (Bonine^®) 25-50 mg.(13) Highly susceptible patients may be prescribed the antiemetic as a precaution. As you can see from the statistics, 75% of Yuzpe patients and over 90% of progestin patients will not vomit. Of those that do, most will probably not vomit the medication or a sufficient amount to interfere with its effectiveness. Patients should be warned about the side effect of drowsiness from anti-emetics and cautioned about driving or operating hazardous machinery.

Resumption of menses, other side effects: Patients should also be informed that other temporary side effects like headache, breast tenderness, dizziness, fatigue and fluid retention may occur. Bleeding or spotting in the 5-7 days after the EC regimen, which is not the patient's menstrual period, can occur in 10 - 20% of patients. In the 1998 study, 72% of patients resumed menses early or within three days of their expected date. Fifteen percent experienced a 3-7 day delay and 13% resumed menstruation more than seven days after expected. If menses have not resumed 21 days after the administration of emergency contraception, a pregnancy test should be done. If the woman is found to be pregnant, there should be no adverse effect on the pregnancy from taking EC. Birth control pills have frequently been taken in early pregnancy without adverse effects on the fetus, and the FDA required manufacturers to remove warnings about increased risk to the fetus several years ago.(1)

Ectopic pregnancy: There is no evidence that ectopic pregnancy is more frequent in patients receiving EC, but you must always keep the diagnosis in mind. The rate of ectopic pregnancy is about 2% of reported pregnancies in the U.S. This possibility should be considered in patients with a positive pregnancy test and/or abdominal pain.

What Else to Tell the Patient

Women should be cautioned to avoid unprotected coitus until their menses occur, because if EC delayed ovulation, ovulation may yet occur for that cycle. They should abstain from intercourse or use reliable back-up contraception until their next menstrual period. Oral contraception can be started immediately after EC. (See Reference 13 for instructions.) Women should also be told that, if they had unprotected coitus earlier in the cycle, there is a risk that they might already be pregnant.

When to Get a Pregnancy Test

As mentioned previously, some cycle disruption can occur after EC, making the subsequent menstrual period either a few days early or a few days late. If menses have not started within three weeks after EC, a woman should see her clinician for an exam and a pregnancy test. Keep the possibility of ectopic pregnancy in mind and be sure to rule that out if there are any suspicious symptoms or signs.

Following up EC

A follow up visit after successful EC is always advisable. It presents an opportunity to review contraceptive needs and insure maintenance or initiation of effective contraception for women who wish it. It is also a chance to educate and institute protection against STIs (sexually transmitted infectons). As discussed above, although EC is not a good method of contraception, it can be repeated without risk. Providing a prescription to be filled and kept at home is a wise precaution and will result in more immediate use and a higher success rate. Remember, both products have a long shelf life: Preven^®, four years, and Plan B^®, three years.

Resources for Direct Patient Care

For an excellent detailed discussion of the EC protocol, see the Emergency Contraceptive Protocol, Boston Family Planning on the Association of Reproductive Health Professionals website.

Practical Considerations

EC is not used nearly as frequently as it could be if it were easily available. The best possible scenario is for women to have the medication on hand and use it if needed. The current products have a shelf life of 3-4 years. The next best scenario is that the products are available at the local pharmacy. Not all pharmacies stock EC pills. To locate pharmacies stocking the medications, consult Target B, which has a database of pharmacies.

Those of you reading this Cyberounds now know how to prescribe EC. But patients can be "caught out" in circumstances where they cannot reach a knowledgeable physician. In that case, they can call toll free 1-888-not-2-late and locate a physician who can prescribe EC. The website Not-2-Late has a searchable database of physicians and facilities able to prescribe EC. In two states, Washington and California, women can get EC directly from their pharmacist. Other states are considering similar bills, including New York. Consult Not-2-Late for updates.

Helpful Websites on Emergency Contraception

Not-2-Late: This site is operated by the Association of Reproductive Health Professionals and the Office of Population Research, Princeton, University.

Searchable database for providers of EC

Hotline: 1-888-NOT-2-LATE

Preven: Drug insert, patient information

Plan B: Drug insert, patient protocol and informed consent. Searchable database of pharmacies carrying EC's.

Association of Reproductive Health Professionals: Good patient care protocol, list of oral contraceptive doses for EC; teaching program, slide set on EC.

Mifepristone, Mifeprex^®, RU486, the "Abortion Pill" and EC

This Cyberounds^® would not be complete without a discussion of the anti-progesterone, mifepristone, and emergency contraception. Mifepristone is a very effective emergency contraceptive. In this capacity, it is not causing an abortion. It is not interrupting a pregnancy; it is preventing a pregnancy. Its efficacy as an emergency contraceptive is primarily due to its effect of delaying ovulation and possibly delaying maturation of the endometrium.

Mifepristone is available in the U.S. only for medical abortions. Its availability is restricted to practices and health facilities doing medical abortions under strict protocols, so off label use for emergency contraception would be difficult. Furthermore, studies have shown that only 1/60 of the dose used for abortion, 10 mg vs. 600 mg, is needed for emergency contraception. No such preparation is available in the U.S.(14)

Large studies have been done worldwide on mifepristone as an emergency contraceptive, and here is what we know:

• Mifepristone is more effective than the Yuzpe regimen and about equally effective as the progestin-only regimen.(15)
• There are very few side effects with mifepristone. Vomiting incidence was 1%, the same as the progestin-only in one large study.(9)
• The dose of mifepristone needed for EC is very low. Ten milligrams was just as effective as the 600 mg used for medical abortions.(14)
• Only a single dose of mifepristone is needed.
• The earlier it is used after exposure the better. In one study, effectiveness was demonstrated out to 120 hours (5 days), as was the progestin-only regimen, though there was a trend toward decreasing effectiveness.(9)
• Mifepristone also blocks corticosteroid receptors, so adrenal insufficiency and chronic treatment with corticosteroids are listed as contraindications in the insert. Porphyria, hemorrhagic disorders and anticoagulant medications are also listed.(16) But the insert cautions refer to the 600 mg dose used for medical abortion, a large dose that stays in the body for a prolonged period. Whether these contraindications are relevant to a 10 mg dose is not known.
• Mifepristone works by delaying ovulation, which can delay the onset of the next menstrual period. This effect is dose related. With the 10 mg dose, the incidence of a delay in menses more than 7 days was 9-18%. The incidence of bleeding apart from menses in the 7 days after the medication was 9%, about half that of the progestin-only (levonorgestrel) in this study.(9) Higher doses of mifepristone caused much longer delays of menses.(14)
• Because of the delay in ovulation, patients must be strongly cautioned to abstain from intercourse or use back up contraception until a normal menstrual period has occurred.

Please refer to the Appendix for further information.