Pharmacy Pearl 24 April 2002

Before we start, this is NOT a philosophical, religious, or political discussion about abortion, birth control, pro-life, pro-choice, etc. Those discussions are abundant elsewhere and will not be duplicated here.

What this pearl will try to do is pass along some useful information about levonorgestrel or Plan B®. Hopefully, you've heard by now, Plan B® was added to the Basic Core Formulary (BCF) at the last DoD P&T committee meeting in Feb 02. The decision was reviewed and affirmed by the Executive Director of the TRICARE Management Activity as being consistent with current TRICARE policy and benefits.

Emergency contraception may be defined as the use of a drug or device soon after sexual intercourse to prevent pregnancy. Its' use was described as early as 1974 when Albert Yuzpe first published information about using 2 doses of ethinyl estradiol (100 mcg) and dl-norgestrel (0.5mg), the first given upon presentation and the second dose 12 hours after presentation within 72 hours of sexual assault, unprotected intercourse, or "contraceptive accident" (i.e slipped or broken condom, failure to take three or more contraceptive tablets during a one month cycle). Most oral contraceptive pills (OCPs) can be dosed similarly and used as emergency contraceptives. The number of tablets will vary with each different oral contraceptive. In 1997, the FDA concluded certain OCPs containing ethinyl estradiol and norgestrel or levonorgestrel are "safe and effective" for emergency contraception. Emergency contraception is NOT meant to take the place of other forms of birth control such as OCPs, condoms, diaphragms, etc.

Some numbers - There's approximately 3 million unintended pregnancies in the US each year. Nearly 50% of these end in abortion. It is estimated at least 225,000 women have used emergency contraception over the past few decades. A 1992 study estimated that emergency contraception may prevent 1.7 million unintended pregnancies and 800,000 abortions a year in the US.

Mechanism of action - the exact mechanism of emergency contraception is unclear. Some postulated mechanisms include:

- Suppression of ovulation by inhibiting or suppression the LH (luteinizing hormone) surge necessary for final follicular growth)

- Interfering with fertilization by impeding movement of egg and/or sperm

- Impeding or preventing transport of the fertilized egg to the uterus

- Impeding or preventing implantation of the blastocyst into the endometrium by making the uterine lining 'unreceptive'.

Emergency contraception will not harm nor disrupt an established pregnancy (Wellbery, 2000, FDA 1997, Glasier 1998).

Plan B® consists of 2 tablets containing levonorgestrel 0.75mg each, taken 12 hours apart. The first dose should be within 72 hours of sexual intercourse. The efficacy of emergency contraception decreases linearly as you progress past the 72 hour window until day 6-7 after intercourse when the regimen becomes completely ineffective.

This agent [Plan B®] has several advantages over the Yuzpe method. The Yuzpe method, although effective, can cause a significant amount of nausea and vomiting, often requiring pre-treatment or post-dose treatment. Meclizine 50mg (single dose) 1 hour before the first dose of the Yuzpe regimen decreased nausea compared to no pre-treatment from 64% to 47%. Plan B® only requires a total of two tablets (1 tablet, then another 12 hours later, starting within 72 hours of sexual intercourse). Vomiting within 1 hour of the dose may necessitate re-dosing. The patient should contact their physician if this occurs for further instruction.

The efficacy of Plan B® in preventing pregnancy when compared to the Yuzpe method was almost identical. The adverse effects of the Yuzpe method vs Plan B® were (respectively): nausea (51% vs 23%), vomiting (19% vs 6%), dizziness (17% vs 11%), and fatigue (29% vs 17%). Like other OCPs, Plan B® will not prevent or treat a sexually transmitted disease (STD).

A theoretical risk of thromboembolism may exist with the Yuzpe method. The short period of therapy makes this risk extremely small, even in smokers. Contraindications to Plan B® include: pregnancy, undiagnosed abnormal genital bleeding, and allergy to levonorgestrel.

A 1998 UK study by Glasier and Baird evaluated the usage patterns in women who had emergency contraception available at home (treatment group) vs. women who had to visit a doctor to obtain emergency contraception at the time they needed it (control group). A large percentage of women in both the treatment and control groups did NOT use emergency contraception during the one year trial (53% and 73%, respectively). As expected, there were more women who used emergency contraception ONCE in the treatment group vs the control group (36% vs 14%, respectively). The number of patients in both groups that used emergency contraception more than once was small and not statistically different. Emergency contraception kept by women at home was not misused. It did not appear to be used in place of other forms of birth control.

Additional information from MICROmedex:

FDA APPROVAL: Adult, yes; pre-menarchal, no

EFFICACY: Adult, effective

DOCUMENTATION: Adult, good

2. SUMMARY:

- Oral levonorgestrel-only is indicated in preventing pregnancy after known or suspected contraceptive failure or unprotected intercourse

3. ADULT:

Drug consult on emergency contraception from MICROMEDEX:

Emergency contraception is defined as the use of a drug or device to prevent pregnancy after sexual intercourse has occurred (Glasier , 1997; Gold, 1999; Wellbery, 2000; Wertheimer, 2000). The administration of emergency contraception is indicated in instances such as sexual assault, unprotected intercourse, and contraceptive accident (a slipped or broken condom or failure to take three or more oral contraceptive tablets during one cycle) (Wellbery, 2000). It is intended for use in emergency situations when the possibility of pregnancy cannot be ruled out and the female does not wish to become pregnant.

In 1994 it was estimated that 2.65 million women in the United States experienced an unintended pregnancy, with 54% of these ending in abortion (Henshaw, 1998). A survey conducted in 1997 found that 11% of American females understood the basic facts regarding emergency contraception and approximately 1% of women aged 18-44 years had used it (Kaiser Family Foundation, 1997). The use of emergency contraception may prevent an estimated 1.7 million unintended pregnancies and 800,000 abortions in the United States annually (Trussell et al, 1992).

High dose estrogen was the first form of emergency contraception introduced in the 1960s (Gold, 1999). However, the frequent occurrence of nausea and vomiting have diminished its use (Van Santen & Haspels, 1985). The Yuzpe regimen (estrogen combined with progestin, currently available in a kit form under the trade name Preven(R)) was initially studied as postcoital contraception in 1974 (Yuzpe et al, 1974). In 1976, the copper containing intrauterine device (IUD) was introduced as an alternative for emergency contraception (Lippes et al 1976). An IUD may be inserted up to five days post-unprotected intercourse and may be left in place as ongoing contraception for up to 10 years (Wellbery, 2000). Use of an IUD in females who are at risk for acquiring or currently have a sexually transmitted disease may cause pelvic inflammatory disease, which can result in infertility (Wertheimer, 2000). Danazol [Danocrine®] has also been used as an emergency contraceptive with questionable efficacy.

The exact mechanism of action of the estrogen combined with progestin (Yuzpe) regimen and the progestin only regimen remains unclear (Rivera et al, 1999). Postulated mechanisms include prevention or delay of ovulation, creation of a cervical environment unfavorable to sperm transport, and impeding implantation (Trussell & Raymond, 1999). The use of emergency contraception once implantation has occurred will not disrupt an established pregnancy (Wellbery, 2000).

Two clinical trials have compared the Yuzpe regimen (estrogen combined with progestin) with progestin alone for efficacy and tolerability as emergency contraception. In a randomized, prospective trial, levonorgestrel was compared with the Yuzpe regimen in 880 healthy females who presented to a family planning clinic within 48 hours of unprotected coitus (Ho & Kwan, 1993). Participants were randomized to receive the Yuzpe regimen (100 mcg ethinyl estradiol and 0.5 mg levonorgestrel) orally at presentation and an identical dose 12 hours later or levonorgestrel alone (0.75 mg) orally at presentation and an identical dose 12 hours later. The pregnancy rates for the Yuzpe and levonorgestrel regimens were determined to be 2.7% and 2.4%, respectively. The difference in pregnancy rates between groups was not statistically significant. The reported incidences of nausea, vomiting, and fatigue were all significantly higher in the Yuzpe regimen group compared to the levonorgestrel group (p less than 0.001). Nausea was experienced by 46.5% and 16.1% of patients in the Yuzpe regimen and levonorgestrel groups, respectively (p less than 0.001). Approximately equal percentages in each group experienced similar changes in pattern of menses. Those who took either medication within 24 hours of unprotected intercourse had lower pregnancy rates compared to women who received emergency contraception between 24 and 48 hours postcoitus.

A larger randomized, multicenter, double blind, prospective trial compared the efficacy and tolerability of levonorgestrel versus the Yuzpe regimen as emergency contraception (Anon, 1998). A total of 1,998 healthy females presenting within 72 hours of unprotected coitus were randomized to receive either oral levonorgestrel (0.75 mg) at presentation and again 12 hours later or the Yuzpe regimen (100 mcg ethinyl estradiol and 0.5 mg levonorgestrel) orally at presentation and 12 hours later. Levonorgestrel alone prevented 85% of the expected pregnancies (pregnancy rate of 1.1%), and the Yuzpe regimen was effective at preventing 57% of the expected pregnancies (pregnancy rate of 3.2%) (p value not reported). The efficacy of both regimens was significantly greater the earlier each medication was taken (pregnancy rates were lower within 24 hours of coitus compared to 49-72 hours postcoitus; p=0.01). The occurrence of nausea, vomiting, dizziness, and fatigue was significantly less in the levonorgestrel regimen compared to the Yuzpe regimen (p less than 0.05). Nausea was experienced by 50.5% and 23.1% of patients in the Yuzpe regimen and levonorgestrel groups, respectively (p less than 0.01). Menstrual pattern alterations were similar in each group, with 57% of all trial participants menstruating within three days of their expected cycle.

A theoretical concern exists regarding the administration of the Yuzpe regimen (estrogen and progestin) to females at risk for developing thrombosis. However, the duration of ethinyl estradiol therapy used in the Yuzpe regimen is brief (less than 24 hours) and appears to have no effect on clotting factors (Webb & Taberner, 1993).

CONCLUSION:

The Yuzpe regimen (100 mcg ethinyl estradiol and 0.5 mg levonorgestrel taken orally within 72 hours of unprotected intercourse and again 12 hours later) is the current standard for emergency contraception and is available in a kit form under the trade name Preven(R). Results from two well designed clinical trials have demonstrated that levonorgestrel is significantly better tolerated for emergency contraception compared to the Yuzpe regimen with resultant pregnancy rates of 1.1% in the levonorgestrel group and 3.2% in the Yuzpe regimen group. The earlier either regimen of emergency contraception was administered, the more efficacious it was. However, nausea and vomiting occurred significantly more frequently in the Yuzpe regimen treatment group in each study.

The levonorgestrel regimen (0.75 mg orally upon presentation and again 12 hours later) should be considered first line for emergency contraception in female patients who present within 72 hours of unprotected intercourse. Nausea may occur in 16% to 23% of women receiving levonorgestrel as emergency contraception. Patients receiving emergency contraception should expect to menstruate within 21 days of taking the medication. If this does not occur, a pregnancy test should be performed. Antiemetics (such as meclizine 50 mg taken orally one hour prior to administration of the Yuzpe regimen) may be considered as prophylaxis for nausea and vomiting secondary to emergency contraception.

REFERENCES:

1. Anon: An emergency contraceptive kit. Med Lett Drugs Ther 1998; 40(1038):102-103.

2. Anon: Comparison of three single doses of mifepristone as emergency contraception: a randomised trial. Task Force on Postovulatory Methods of Fertility Regulation. Lancet 1999; 353(9154):697-702.

3. Anon: Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Task Force on Postovulatory Methods of Fertility Regulation. Lancet. 1998a; 352(9126):428-433.

4. Glasier A: Emergency postcoital contraception. N Engl J Med 1997; 337(15):1058-1064.

5. Glasier A, Thong KJ, Dewar M et al: Mifepristone (RU486) compared with high-dose estrogen and progestogen for emergency postcoital contraception. N Engl J Med 1992; 327(15):1041-1044.

6. Gold: Prescribing and managing oral contraceptive pills and emergency contraception for adolescents. Pediatr Clin N Am 1999; 46(4):695-718.

7. Henshaw SK: Unintended pregnancy in the United States. Fam Plann Perspect 1998; 30(1):24-29, 46.

8. Ho PC & Kwan MS: A prospective randomized comparison of levonorgestrel with the Yuzpe regimen in post-coital contraception. Hum Reprod 1993; 8(3):389-392.

9. Kaiser Family Foundation: Emergency contraception: Is the secret getting out? 1997 National survey of Americans and helath care providers on emergency contraception. Available at: http://www.kff.org/content/archive/1352/contraception.pdf (cited 04/10/01).

10. Lippes J, Malik T & Tatum HJ: The postcoital copper-T. Adv Plan Parent 1976; 11(1):24-29.

11. Raymond EG, Creinin MD, Barnhart KT et al: Meclizine for prevention of nausea associated with use of emergency contraceptive pills: a randomized trial. Obstet Gynecol 2000; 95(2):271-277.

12. Rivera R, Yacobson I, Grimes D: The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices. Am J Obstet Gynecol 1999; 181(5 Pt 1):1263-1269.

13. Trussell J & Raymond EG: Statistical evidence about the mechanism of action of the Yuzpe regimen of emergency contraception. Obstet Gynecol 1999; 93(5 Pt 2):872-876.

14. Trussell J, Stewart F, Guest F et al: Emergency contraceptive pills: a simple proposal to reduce unintended pregnancies. Fam Plann Perspect 1992; 24(6):269-273.

15. Van Santen MR & Haspels AA: A comparison of high-dose estrogens versus low-dose ethinylestradiol and norgestrel combination in postcoital interception: a study in 493 women. Fertil Steril 1985; 43(2):206-213.

16. Webb A & Taberner D: Clotting factors after emergency contraception. Adv Contracept 1993; 9(1):75-82.

17. Webb A, Russell J & Elstein M: Comparison of Yuzpe regimen, danazol, and mifepristone (RU486) in oral postcoital contraception. BMJ 1992; 305:927-931.

18. Wellbery C: Emergency contraception. Arch Fam Med 2000; 9(7):642-646.

19. Wertheimer RA: Emergency postcoital contraception. Am Fam Physician 2000; 62(10):2287-2292.

20. Yuzpe AA, Thurlow HJ, Ramzy I et al: Post coital contraception--A pilot study. J Reprod Med 1974; 13(2):53-58.

Food and Drug Administration. Prescription drug products; certain combined oral contraceptives for use as post-coital emergency contraception. Fed register 1997;62:8610-12

Glasier A, Baird D. The effects of self-administering emergency contraception. N Engl J Med 1998;339:1-4.

Product Information: Plan B(TM), levonorgesterel. Women's Capital Corp., Bellevue, WA, 1999.

Anon: Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet 1998; 352:428-433.

This Pearl is meant for academic and educational purposes only. This Pearl is meant to raise important points regarding the safe and cost-effective pharmacotherapy of patients. It is not meant to be the definitive reference for the treatment or prophylaxis of various diseases. Although every effort is taken to ensure this Pearl is correct and factual, errors may occur. The Pharmacoeconomic Center assumes no liability for incorrect information or harm that may occur from the use of the information included in this Pearl.