P&T News: September 1999

Emergency Contraception: Focus On Emergency Contraceptive Pills

Mary B. Ross, R.Ph., M.B.A. e
Peer Review Status: Internally Peer Reviewed by Kevin Ault, M.D., Assistant Professor, Department of Obstetrics and Gynecology.

High-dose combination oral contraceptives have been used since the 1970s for emergency contraception and are commonly known as the Yuzpe regimen, postcoital contraception, or the "morningafter pill."2 In 1997, the FDA declared certain combination oral contraceptives containing esthinyl estradiol with norgestrel or levonorgestrel as safe and effective for use as emergency contraception. However, prescribing of the appropriate dose and successful completion of the regimen are complicated by the numerous marketed brands of oral contraceptives that contain a variety of agents and doses. In addition, oral contraceptive packets often contain placebo or iron supplements, and active and placebo tablets lack standardized colors for ready identification. Recently, the FDA approved the marketing of a standardized emergency contraceptive kit (Preven[R] - Gynetics) to facilitate appropriate dosing and timing of drug administration.'* High-dose combination oral contraceptive pills for emergency contraception will be the focus of this article.

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*Addendum: Only July 28,1999, the FDA approved the marketing of a progestin-only tablet for emergency contraception (Plan B[R] - Woman's Capitol Corporation). Plan B[R] consists of two 0.75 mg tablets of levonorgestrel. The first tablet is taken within 72 hours of unprotected intercourse; the second tablet is taken 12 hours later. Initially, Plan B[R] will be available through Planned Parenthood Clinics; widespread commercial distribution is not planned until late 1999.

Efficacy of Emergency Contraceptive Pills (ECPs)
The mechanism of action of ECPs in preventing pregnancy is still unclear. They may inhibit or delay ovulation to prevent fertilization. Other possible mechanisms include alterations of the endometrium which may prevent implantation, or alterations of the tubal transport of sperm, egg, or embryo .4 It is important to note that ECPs do not interrupt an established pregnancy (i.e., implantation has occurred); and therefore, ECPs are not abortifacients.

Table 1. Situations in Which Emergency Contraception May Be Appropriate

No contraceptive was used when intercourse took place. A male condom slipped, broke, or leaked. A women's diaphragm or cervical cap was inserted incorrectly, dislodged during intercourse, was removed too early, or was found to be torn. A woman has missed two or more of the first seven combined oral contraceptive pills, or she has missed four or more pills during the second week (pills 8 to 14). Because combined pills act by suppressing ovulation, the risk of conception occurs some days after the missed pills when follicular development, freed from the inhibition by the oral contraceptive, is sufficient to allow ovulation. Ovulation is unlikely if only a few pills have been missed during a cycle. Nevertheless, treatment is reasonable if the woman is worried or wishes to avoid even a small risk of pregnancy. A woman has missed one or more progestin-only pills. In contrast to combined pills, ovulation is not consistently suppressed by progestin-only pills, and the risk of pregnancy after missing progestinonly pills is greater and more immediate than is the case with missed combined pills. A female condom was inserted or removed incorrectly leading to spillage of semen, or the penis was inserted mistakenly between the female condom and the vaginal wall resulting in intravaginal ejaculation. The couple erred in practicing coitus interruptus (ejaculation in vagina or on external genitalia). An IUD was partially or totally expelled. A woman was exposed to a possible teratogen such as a live vaccine or cytotoxic drug when she was not protected by effective contraception. A woman was raped.

Adapted from Contraceptive Technology.2

The doses of ethinyl estradiol in combination with levonorgestrel (norgestrel) recognized as effective doses for emergency contraception are 100 mcg to 120 mcg of ethinyl estradiol with 0.5 mg to 0.6 mg of levonorgestrel.2 Norgestrel contains two isomers, only one of which (levonorgestrel) is active; therefore, the amount norgestrel in each dose is twice the amount of levonorgestrel. A number of combination oral contraceptive products can be prescribed for emergency contraception; however, the number of tablets necessary to achieve the appropriate dose ranges from 2 to 5 tablets depending upon the product selected.

The probability of conception after unprotected intercourse varies according to the number of days before ovulation. The rate of pregnancy 3 days prior to ovulation is about 15%, 30% 1 to 2 days before ovulation, and 12% on the day of ovulation .2 The chance of pregnancy approaches zero at more than two days post-ovulation. When ECPs are taken within 72 hours after intercourse, their effectiveness approaches 75% (i.e., there is a 75% reduction in the expected rate of pregnancy).5

Safety of Emergency Contraceptive Pills
The most frequently reported adverse effects associated with the use of ECPs are nausea (50%) and vomiting (20%).2,3 Routine use of an antiemetic (e.g., meclizine, trimethobenzamide, dimenhydrinate) I hour prior to the 2 first ECP dose may reduce the frequency of nausea and vomiting. Other commonly reported adverse effects include menstrual irregularities, breast tenderness, headache, abdominal pain/cramps, dizziness, fatigue, and headache.3

While the FDA-approved labeling for the ECPs contains all of the same contraindications and warnings as the daily cyclical combination oral contraceptive pill, it is not known whether these contraindications and warnings 2 also apply to the ECP regimen of four oral contraceptive pills taken within a 12-hour period. Both the World Health Organization' and the International Planned Parenthood Federation 7 have stated that there are no absolute contraindications to the use of ECPs except known pregnancy. ECPs are contraindicated in pregnancy because they are ineffective once pregnancy is established, not because they are harmful/teratogenic to the fetus.4

Patient Management
Although pregnancy can only occur during the time period of 6 days before and I day after ovulation, any woman requesting emergency contraception after unprotected intercourse should be offered treatment unless there are good medical reasons for not doing so. By reviewing the menstrual cycle day when unprotected intercourse occurred, one can determine whether the risk of pregnancy is high or low; however, the overriding factor should be how the woman feels about her risk.2

First, exclude the possibility that the woman is not already pregnant. The Preven'[R] Emergency Contraception Kit contains a urine pregnancy test. This test is used to verify an existing pregnancy that occurred earlier in the current menstrual cycle or the previous cycle. If a positive pregnancy test result is obtained, the patient should be instructed not to take the ECPs.

The patient should be counseled regarding potential adverse effects, particularly nausea and vomiting. A prescription for antiemetic therapy should also be provided to the patient or recommendations should be made for over-the-counter antiemetics (Table 2).8 The patient should also be instructed that if vomiting occurs within I hour of taking either dose of medication, she should contact her prescriber to assess the need for a repeat dose.

Table 2. Anti-emetic Treatment 0ptions
Drug	Dose	Timing of Administration
Non-prescription Drugs
Meclizine (Dramamine II[R], Bonine[R])	One or two 25 mg tablets	1 hour before first ECP dose; repeat if needed in 24 hours
Diphenhydramine (Benedryl[R])	One or two 25 mg capsules	1 hour before first ECP dose; repeat as needed every 4 to 6 hours
Dimenhydrinate (Dramamine[R])	One or two 50 mg tablets or 4 to 8 teaspoons liquid	30 minutes to 1 hour before first ECP dose; repeat as needed every 4 to 6 hours
Cyclizine (Marezine[R])	One 50 mg tablet	30 minutes before first ECP dose; repeat as needed every 4 to 6 hours
Prescription Drugs
Meclizine (Antivert[R])	One or two 25 mg tablets	1 hour before first ECP dose; repeat if needed in 24 hours
Trimethobenzamide (Tigan[R])	One 250 mg capsule or 200 mg suppository	1 hour before first ECP dose; repeat as needed 4 to 6 hours
Promethazine (Phenergan[R])	One 25 mg tablet or suppository	30 minutes to I hour before first ECP dose; repeat as needed every 8 to 12 hours
Adapted from reference.

Each tablet in the Preven[R] Emergency Contraceptive Kit contains 0.25 mg levonorgestrel and 50 mcg ethinyl estradiol. The patient should be instructed to take the first two tablets (0.5 mg of levonorgestrel and 100 mcg of ethinyl estradiol) as soon as possible, but within 72 hours of unprotected intercourse. (Note: An equivalent dose can also be achieved by taking two tablets of Ovral[R] for each dose. Each white tablet of Ovral[R] contains norgestrel 0.5 mg and 50 mcg of ethinyl estradiol.) The second dose of two tablets is taken 12 hours later.3

Patients should be informed that ECPs do not protect from pregnancy if unprotected intercourse occurs during the days or weeks following treatment. In addition, since ECPs are not completely effective in preventing pregnancy, in the event of a missed menstrual period, patients should be instructed to contact their physician for a physical exam and pregnancy test.2

Summary
ECPs are a useful method to prevent unintended pregnancy. They have numerous applications beyond the management of sexual assault. While a number of combination oral contraceptives can be prescribed for emergency contraception, the ready accessibility to the correct dose of ECPs, a pregnancy test, and patient information provided in the Preven[R] Emergency Contraceptive Kit may be of benefit to many patients.

References
1. Fam Plann Perspect. 1998;30:24-9, 46.
2. Contraceptive Technology. Chapter 12. 171 edition. New York: Ardent Media. 1998.
3. Gynetics Inc., Preven Emergency Contraceptive Kit package insert. Somerville, NJ. 1998 September.
4. N Engl J Med. 1997;337:1058-64.
5. Contraception. 1998;57:363-9.
6. World Health Organization. 1996:31-3 (WHO/FRH/FPP96.9).
7. IPPF Med Bull. 1994;28(6):1-2.
8. Emergency contraception: a resource manual for providers. Seattle: Program for Appropriate Technology in Health, 1997.

CYTARABINE, LIPOSOME Intrathecal Injection: 50 mg per vial Cytarabine liposome (DepoCyt[R]SkyPharma) injection is indicated for intrathecal treatment of lymphomatous meningitis.

HYALURONATE SODIUM Injection: 16 mg per 2 ml Hyaluronate sodium (Synvisc[R]-Wyeth-Ayerst) intra-articular injection is indicated for the treatment of pain in osteoarthritis of the knee in patients who have failed to respond to conservative nonpharmacologic therapy and simple analgesics.

METHOXSALEN Sterile solution: 20 mcg per ml Methoxsalen (Uvadex[R] -Therakos) sterile solution is indicated for extracorporeal administration with photopheresis in the palliative treatment of cutaneous T-cell lymphoma.

ROSIGLITAZONE Tablets: 2 mg, 4 mg, 8 mg Rosiglitazone (Avandia[R]-SmithKIine Beecham) is an oral antidiabetic agent that increases insulin sensitivity. It is indicated for management of type 2 diabetes mellitus, either alone or in combination with metformin. NOTE: Asa precautionary measure, liver enzymes must be measured prior to the initiation of therapy, every two months for the first 12 months, and periodically thereafter. Pharmacy staff will verify liver function tests have been performed prior to dispensing rosiglitazone.

SODIUM FERRIC GLUCONATE COMPLEX Injection: 62.5 mg per 5 ml This product (Ferrlecit[R]Schein) is indicated for the treatment of iron deficiency in patients undergoing chronic hemodialysis who are receiving supplemental erythropoetin therapy. NOTE: The use of sodium ferric gluconate complex injection is restricted to patients who have a documented hypersensitivity to iron dextran injection.

ADDITIONAL ACTIONS

CARBAMAZEPINE EXTENDED-RELEASE CAPSULES The Carbatrol[R] brand of 200 mg and 300 mg extended-release carbamazepine capsules has been added to stock.

GLIPIZIDE (GLUCOTROL XL[R]) EXTENDED-RELEASE TABLETS 5 mg and 10 mg extended-release tablets have been added to stock.

HAEMOPHILUS b CONJUGATE WITH HEPATITIS B (COMVAX[R]) VACCINE This combination vaccine was added to stock because it does not contain thimerosal. Note: The cost following each brief monograph is the UIHC inpatient acquisition cost.

DRUGS DELETED FROM STOCK

ALATROFLOXACIN INJECTION AND TROVAFLOXACIN TABLETS Deleted due to reports of severe hepatotoxicity. Levofloxacin and other antibiotics are available.

HYALURONATE SODIUM (HYALGAN[R]) INJECTION The Hyalgan[R] brand is deleted from stock; it will be replaced by the Synvisc[R] brand of hyaluronate sodium injection.

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