Emergency contraception: a review of current oral options

Unintended pregnancy is a major public health concern in the United States.Every year about 3.5 million unintended pregnancies occur in this country,half of which result from contraceptive failure or inadequate contraceptivetechnique.¹ The useof emergency contraception (EC) in these women can reduce the number ofunintended pregnancies and consequential abortions substantially. It has beenestimated that three quarters of these situations could be avoided with theuse of EC.²

The method described by Yuzpe a quarter century ago consists of two dosesof ethinyl estradiol (100 μg) plus levonorgestrel (0.5 mg) spaced 12 hoursapart. An alternative option is two doses of ethinyl estradiol (100 μg)plus norgestrel (1 mg), spaced 12 hours apart. The Food and DrugAdministration (FDA) has approved the use of several oral contraceptives aspart of the Yuzpe regimen for EC. Despite FDA approval, the manufacturers havedeclined to submit a new drug application for this indication(table1).^3,4Even though several different methods of EC are available, this reviewaddresses only oral EC medications that have an FDA-labeled indication forEC.

Table 1.

Available oral emergency contraceptives

Commercially availableEC*	Estrogen, μg	Progestin, mg	Tablets per dose, no.(color)†	Average wholesale price$‡
Oral EC products
Ethinyl estradiol-levonorgestrel	50	0.25	2	19.94
Levonorgestrel (Plan B)		0.75	1	21.95
FDA-approved EC drugs§
Alesse/Levlite	20	0.1	5 (pink)	32.95/32.62
Levlen/Nordette	30	0.15	4 (pale orange)	31.93
Trievlen/Triphasic	30	0.125	4 (yellow)	24.52
		Norgestrel
Lo/Ovral	30	0.3	4 (white)	34.04
Ovral	50	0.05	2 (white)	50.10
Ovrette		0.075	20 (yellow)	33.62
FDA = Food and Drug Administration.

^*Trade names are given for information only and are not to be construed asendorsement by either the author or the editors of this journal.

^†Oral hormonal EC consists of two doses. The first dose should be takenwithin 72 hours after unprotected intercourse, followed by a second dose 12hours later.

^‡Price of an intact oral contraceptive package, as some pharmacies may notbreak up the individual package (Facts and Comparisons Price Alert,Indianapolis, IN: January 2002).

^§The manufacturers of these oral contraceptives, Berlex and Wyeth-Ayerst,have declined to submit new drug applications for their products to includeEC; therefore, the package labeling does not include it.

DEFINITION

Emergency contraception refers to any device or drug that is used as anemergency procedure to prevent pregnancy after unprotected sexualintercourse.^5,6Synonymous terms for EC include “the morning-after pill,”postcoital contraception, interception, postovulatory contraception,“visiting pill,” and “vacation pill.” These terms areoften misinterpreted as indicating abortion or are inappropriately associatedwith the abortifacient mifepristone (RU-486). An abortifacient is any deviceor drug that acts after implantation hasoccurred.⁵ Once ablastocyst has implanted in the endometrium, it is defined as the beginning ofpregnancy.⁷ EC isnot effective once implantation has taken place. Because it will not terminatean existing pregnancy, it is, therefore, not an abortifacient.

INDICATION

Emergency contraception is indicated for the prevention of pregnancy inwomen after a known or possible contraceptive failure or unprotected sexualintercourse and for victims of sexual assault. It is not recommended as a formof routine contraception. Although EC reduces the risk of pregnancy, it ismuch less effective than the regular use of standardcontraception.^8,9

THERAPEUTIC OPTIONS

Currently two oral EC products are commercially available in the UnitedStates, one a combination of ethinyl estradiol and levonorgestrel (Preven) andone that is levonorgestrel only (Plan B)(table 1). Both productsrequire a prescription; however, patient access has been facilitated throughvarious protocols, including the Emergency Contraception Hotline(1-888-NOT-2-Late [668-2528]) and the Emergency Contraception web site(ec.princeton.edu). These resources provide information about EC products and localparticipating providers. The web site also provides patient pamphlets invarious foreign languages.

Each tablet of Preven contains levonorgestrel, 0.25 mg, and ethinylestradiol, 0.05 mg. It is available in two different packages—as four ECtablets or as an EC kit, which includes a pregnancy test and a detailedpatient information book. Each Plan B package comprises two tablets, eachcontaining 0.75 mg of levonorgestrel.

Mechanism of action

Although the precise mechanism of action of either of these products hasnot been fully elucidated, both work in a similar manner. Several mechanismshave been postulated, depending on when during the menstrual cycle an exposureoccurs. They are thought to act primarily by inhibiting or disruptingovulation. In addition, they may act by interfering with tubal transport ofthe ova and/or sperm, thereby inhibiting fertilization, or by inhibitingimplantation through alteration of theendometrium.^10,11

Adverse effects

Both EC products have comparable adverse effects, the most commonlyreported being nausea, emesis, abdominal pain, headache, menstrualirregularities, fatigue, dizziness, and breast tenderness. The incidence ofnausea, emesis, and fatigue, however, is substantially less withlevonorgestrel alone (PlanB).^12,13Because of the short duration of treatment, long-term adverse effects areextremely unlikely. The use of EC is generally not associated with any seriousadverse effects, even though the doses used are higher than those used forroutine contraception. Compared with oral contraceptives, EC treatment is notassociated with a substantially increased risk for venousthromboembolism.¹⁴For women at risk for venous thromboembolism, a history of thromboembolicdisease, or stroke, levonorgestrel alone may be preferred because evidence islacking that progestins may have procoagulant effects.

Efficacy

Although both agents are effective in reducing the expected number ofpregnancies, comparative trials have shown that levonorgestrel alone (Plan B)is more efficacious in preventingpregnancy.^12,13The use of the ethinyl estradiol-levonorgestrel combination prevents about 74%of pregnancies, whereas the use of levonorgestrel alone prevents about 85% ofpregnancies when administered within 72hours.¹⁵ Factorsaffecting the efficacy of EC include treatment regimen compliance and timefrom failed contraception—known or suspected contraceptive failure orunprotected intercourse—to treatment. Even though the manufacturersrecommend that treatment be initiated within 72 hours of unprotectedintercourse, there is evidence that EC treatment is 72% to 85% effective wheninitiated between 72 and 120 hours after unprotectedintercourse.¹⁶Therefore, women seeking treatment after 72 hours, but within 120 hours,should not be denied treatment if other alternatives are unacceptable.Nevertheless, treatment should be administered as soon as possible afterfailed contraception because the rate of pregnancy increases the longertreatment is delayed from the time of failedcontraception.¹⁷

Drug interactions

Interactions known to occur with combined oral contraceptives andprogestin-only contraceptive drugs may occur with the use of EC. The mostcommon clinically encountered interactions with oral contraceptives, whichhave been shown to reduce their effectiveness, involve the use of antibioticsandanticonvulsants.^18,19With the increased use of nonprescription medications and polypharmacy,prescribers should be aware of possible pharmacodynamic and pharmacokineticinteractions between EC and other medication(table 2).

Table 2.

Possible interactions with oral contraceptive (OC) medication

Agents (trade name) that decrease effectiveness ofOCs*	Agents (trade name) whose effectiveness is decreased byOCs*	Agents (trade name) whose effect is increased byOCs*
Barbiturates	Lorazepam	Alprazolam
Carbamazepine	(Ativan)	(Xanax)
Ethosuximide (Zarontin)	Oxazepam	Ascorbic acid
Griseofulvin	Temazepam	(vitamin C)
Metronidazole	(Restoril)	Beta blockers
Nelfinavir mesylate	Warfarin	Caffeine
(Viracept)	(Coumadin)	Corticosteroids
Oxcarbazepine (Trileptal)	Cyclosporine
Penicillins	Diazepam
Phenytoin (Dilantin)	Selegiline
Primidone	hydrochloride
Rifamycins	Theophylline
Ritonavir (Norvir)	Triazolam
St. John's wort†	(Halcion)
Tetracyclines	Tricyclic
antidepressants
		Warfarin (Coumadin)

^*Trade names are given for information only and are not to be construed asendorsement by either the author or the editors of this journal. Where severalformulations are available, a trade name has not been given.

^†May cause breakthrough bleeding, but has not been reported to result inunexpected pregnancy.

Contraindications and warnings

Emergency contraception is relatively safe, with essentially nocontraindications except pregnancy. It is not known whether the samecontraindications for combined oral contraceptives and progestin-onlycontraceptive drugs apply to the EC products; therefore, caution should betaken in patients using either of them (see Box). The same precautions takenwith combined oral contraceptive and progestin-only contraceptive drugs shouldbe considered with Preven and Plan B,respectively.

Table 3.

Contraindications to oral contraceptive drugs
Combined oral contraceptives (Preven)
Known or suspected pregnancy Pulmonary embolism Ischemic heart disease History of cerebrovascular accident Valvular heart disease with complications Severe uncontrolled hypertension Diabetes with vascular involvement Headaches with focal neurologic symptoms Major surgery with prolonged immobilization Known or suspected carcinoma of the breast or personal history of breastcancer Active liver tumors (benign and malignant) or liver disease Known hypersensitivity to any component of the product
Progestin-only contraceptives (Plan B)
Known or suspected pregnancy Hypersensitivity to any component of the product Undiagnosed abnormal genital bleeding

Pregnancy is a contraindication to EC because EC is ineffective if a womanis pregnant. There is no significant increase of teratogenic risk on fetaldevelopment associated with the long-term use of oral contraceptivesadministered before pregnancy or taken inadvertently during earlypregnancy.^20,21Nonetheless, no studies have been conducted regarding the teratogenic effectsassociated with the use of EC. Health care professionals, however, should bealert to the possibility of ectopic gestation in women who become pregnant orwho have lower abdominal pain after taking EC because it does not preventextrauterinepregnancies.²²

Dosage and administration

The first dose of either EC product(table 1) should be takenwithin 72 hours after failed contraception, followed by a second dose 12 hoursafter the first dose. Although a second dose at 12 hours is preferred, up to16 hours should be reasonably effective. According to the product labeling,women using the Preven EC kit should use the supplied pregnancy test toidentify an existing pregnancy. If a positive result is obtained, EC shouldnot be administered. The pregnancy test could be saved to check for apregnancy if menses do not occur in 21 days.

Should emesis occur within 1 hour after taking either dose, a replacementdose should be given. There are no set guidelines as to when a dose should berepeated. It seems reasonable to assume that if gastrointestinal symptoms areEC-mediated due to an effect on the central nervous system, absorption of thedose should have occurred beforeemesis.²³ Providingpatients with a refill on the EC prescription would not be unreasonable if awoman has a history of frequent drug-induced nausea or emesis or contact withthe prescriber is limited. To prevent emesis and the need to give areplacement dose, meclizine hydrochloride or an antiemetic could beprescribed. Meclizine, an antihistamine with antiemetic properties, is theonly non-prescription antiemetic available in the United States. One dose ofmeclizine, 50 mg, 1 hour before the first dose of EC has been shown tosignificantly reduce nausea and emesis associated with use ofEC.²⁴ If anantiemetic drug is prescribed, the patient should be instructed to take it 1hour before each EC dose, depending on the specific agent's duration ofaction.

Health care practitioners should counsel patients on the correct use of EC,possible adverse effects, effective contraceptive methods, the risk forsexually transmissible diseases, safer sex practice, and the possibility oftreatment failure. Patients should be advised to seek medical attention ifmenses have not begun within 3 weeks after EC treatment for the evaluation ofpregnancy. Each patient should have some type of follow-up care, even if bytelephone.

In Washington State, pharmacists working within a collaborative protocolwith a physician are able to provide EC treatment to the community. This hasboth increased access to EC and reduced unwanted pregnancy rates in thestate.²⁵ EffectiveJanuary 1, 2002, pharmacists in California have been able to provide the sameservices. In addition, the manufacturers of both Preven and Plan B areapplying for nonprescription status.

CONCLUSION

Although EC is not intended for routine contraceptive use, its use afterfailed contraception could minimize the number of unanticipated pregnancies,preventing the physical and emotional burden of an unwanted pregnancy, inaddition to reducing health care costs. The use of EC, however, is limited bythe lack of patient and practitioner awareness and treatment accessibility.Despite the primarily positive attitudes toward EC, patients and practitionerlack detailed knowledge of EC. For example, the misnomer morning-after pillgives the false perception that EC treatment must be initiated immediatelyafter failed contraception. Furthermore, medical consultation after failedcontraception may be challenging to arrange and embarrassing for womenrequesting EC. A movement is growing to make EC available without aprescription and to promote public awareness, in the hope of increasingpatient accessibility.

Figure 1.

Emergency contraception effectively reduces the risk of pregnancy aftercontraceptive failure