8610 Federal Register / Vol. 62, No. 37 / Tuesday, February 25, 1997 / Notices

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 96N–0492]

Prescription Drug Products; Certain

Combined Oral Contraceptives for Use

as Postcoital Emergency

Contraception

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is announcing

that the Commissioner of Food and

Drugs (the Commissioner) has

concluded that certain combined oral

contraceptives containing ethinyl

estradiol and norgestrel or

levonorgestrel are safe and effective for

use as postcoital emergency

contraception, and requests submission

of new drug applications (NDA’s) for

this use. This notice is intended to

encourage manufacturers to make this

additional contraceptive option

available.

ADDRESSES: Submit NDA’s to the Food

and Drug Administration, Center for

Drug Evaluation and Research, Central

Document Room, 12229 Wilkins Ave.,

Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Lisa

D. Rarick, Center for Drug Evaluation

and Research (HFD–580), Food and

Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301–827–

4260.

SUPPLEMENTARY INFORMATION:

I. Background

Combined oral contraceptives, which

contain an estrogen and a progestin,

were first approved in the United States

in 1960 and in many other countries

shortly thereafter. When taken daily for

3 weeks followed by a week without

medication, these drugs provide

effective contraception. They have

become one of the most widely

employed methods of pregnancy

prevention, currently used by an

estimated 11 million American women.

In the period since the introduction of

combined oral contraceptives, the

amounts of estrogen and progestin have

been reduced and explicit labeling

guidance for safe use has been

developed in response to extensive

medical research. Consequently,

combined oral contraceptives are now

accepted as remarkably safe and

effective when used as directed. There

are more than 30 brands of FDAapproved oral contraceptives on the

American market that contain estrogens

and progestins. These products contain

estrogens and progestins in different

amounts and have some differences in

labeling, but all are considered to be

safe and effective.

For several decades, estrogens and

progestins have also been used, either

separately or in combination, to prevent

pregnancy in women who have

unprotected intercourse as a result of

rape, contraceptive failure, or lack of

planning. Such drugs, when used for

this purpose, are known as emergency

contraceptive pills, or postcoital pills, or

morning-after pills.

The best researched regimen for

emergency contraceptive pills was first

described in 1974 by Professor A. Albert

Yuzpe of Canada (Ref. 18). The regimen

consists of two tablets, each tablet

containing 0.05 milligram (mg) of

ethinyl estradiol and 0.50 mg of

norgestrel, taken within 72 hours after

unprotected intercourse; a second

identical dose is to be taken 12 hours

after the first dose. When used in this

manner, the treatment is 75 percent

effective in preventing pregnancy.

This regimen and the very similar

regimens described below are widely

used. The specific regimen described by

Yuzpe is approved for use by the drug

regulatory agencies of the United

Kingdom, Germany, Sweden,

Switzerland, and New Zealand. The

approved products used in this regimen

contain ethinyl estradiol and, as the

progestin, either norgestrel or

levonorgestrel.

The Yuzpe regimen and similar

regimens have been used extensively in

the United States in the last two

decades, even though no products are

approved and labeled for this use. The

drugs are prescribed by hospital

emergency rooms, reproductive health

clinics, and university health centers.

They are also prescribed, although less

widely, by physicians in private

practice. On February 14, 1996, the

Reproductive Health Technologies

Project established a hotline number (1–

800–584–9911) to inform women about

this contraceptive method and about

providers in their local area.

Since the United Kingdom approved

emergency contraceptive pills in 1984,

more than 4 million prescriptions have

been recorded. However, the actual use

is much greater because providers have

found it less expensive to provide

tablets of identical drugs taken from

products packaged as combined oral

contraceptives. The use of combined

oral contraceptives for emergency

contraception in the United States can

only be estimated because they are not

approved for this indication, but the

results of a Kaiser Family Foundation

survey reported at the June 28, 1996,

meeting of FDA’s Advisory Committee

for Reproductive Health Drugs (the

Advisory Committee) suggest that

approximately 225,000 American

women have used the method. A further

indication of the extent of use is that

over 25,000 calls were made to the

hotline number (cited above) in the first

5 months of operation.

In November 1994, the Center for

Reproductive Law & Policy filed a

citizen petition asking FDA to require

manufacturers of certain combined oral

contraceptive products to amend their

labeling and patient package inserts to

include information regarding the use of

these products for postcoital emergency

contraception. Although FDA indicated

that it had the authority to require that

certain conditions of use be included in

a product’s labeling, it declined to

exercise its discretion in this case to

require the relabeling of these products

for emergency contraception, and

denied the petition. However, the

agency decided to present the issue of

the safety and effectiveness of combined

oral contraceptives for postcoital

emergency use to the Advisory

Committee. The Advisory Committee

met on June 28, 1996, to consider this

issue and unanimously concluded that

the four regimens below are safe and

effective for postcoital emergency

contraception. For the reasons described

in section II. below, FDA agrees with

this conclusion.

The four regimens for postcoital

emergency contraception are as follows:

(1) For tablets that contain 0.05 mg of

ethinyl estradiol and 0.50 mg of

norgestrel, take 2 tablets within 72

hours after unprotected intercourse,

then take 2 more tablets 12 hours after

the first dose;

(2) For tablets that contain 0.03 mg of

ethinyl estradiol and 0.30 mg of

norgestrel, take 4 tablets within 72

hours after unprotected intercourse,

then take 4 more tablets 12 hours after

the first dose;

(3) For tablets that contain 0.03 mg of

ethinyl estradiol and 0.15 of

levonorgestrel, take 4 tablets within 72

hours after unprotected intercourse,

then take 4 more tablets 12 hours after

the first dose; and

(4) For tablets that contain 0.03 mg of

ethinyl estradiol and 0.125 mg of

levonorgestrel, take 4 tablets within 72

hours after unprotected intercourse,

then take 4 more tablets 12 hours after

the first dose.

The appendix to this notice provides

information concerning the use of

emergency contraceptive pills that

might be useful to sponsors in drafting
Federal Register / Vol. 62, No. 37 / Tuesday, February 25, 1997 / Notices 8611

physician and patient labeling for these

products for this use.

II. Discussion

A. Safety

Experience with the approved

products in Europe and New Zealand

has demonstrated the regimens to be

safe. At the Advisory Committee’s June

28, 1996, meeting, Elizabeth Barden

presented information from the British

Medicines Control Agency that only six

serious adverse reactions associated

with these products for this use were

reported to it from 1984 to 1996. Of

these, only one occurred close enough

to the time of administration to indicate

that the reaction might be drug related.

Emergency contraceptive pills are not

effective if the woman is pregnant; they

act by delaying or inhibiting ovulation,

and/or altering tubal transport of sperm

and/or ova (thereby inhibiting

fertilization), and/or altering the

endometrium (thereby inhibiting

implantation). Studies of combined oral

contraceptives inadvertently taken early

in pregnancy have not shown that the

drugs have an adverse effect on the

fetus, and warnings concerning such

effects were removed from labeling

several years ago. There is, therefore, no

evidence that these drugs, taken in

smaller total doses for a short period of

time for emergency contraception, will

have an adverse effect on an established

pregnancy.

B. Effectiveness

There are numerous published

articles that support the effectiveness of

oral contraceptive pills for emergency

use (Refs. 1, 3, 4, 7 through 14, 16 and

18 through 21). In 1996, Trussell,

Ellertson, and Stewart reported a metaanalysis of 10 published articles on

clinical trials of emergency

contraceptive pills in which the number

of pregnancies among women with

regular menstrual cycles who used

emergency contraception was compared

to the expected number of pregnancies

based on the cycle day of intercourse

and published estimates of conception

probabilities by cycle day (Ref. 9).

Defining effectiveness as the percent

reduction in the likelihood of pregnancy

occurring, the authors found a range of

effectiveness of 55.3 percent to 94.2

percent, with an average effectiveness of

74.0 percent. In other words, if 100

women have unprotected intercourse

once during the second or third week of

their menstrual cycle, about 8 will

become pregnant, but if the same

women use emergency contraception

after intercourse, only 2 will become

pregnant.

III. References

The following references have been

placed on display in the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20852, and may be seen by interested

persons between 9 a.m. and 4 p.m.,

Monday through Friday.

1. Bagshaw, S. N., D. Edwards, and A. K.

Tucker, ‘‘Ethinyl Oestradiol and D-Norgestrel

Is an Effective Emergency Postcoital

Contraceptive: A Report of Its Use in 1,200

Patients in a Family Planning Clinic,’’

Australian and New Zealand Journal of

Obstetrics and Gynecology, 28:137–140,

1988.

2. Delbanco, S., ‘‘1995 Kaiser Family

Foundation Surveys on Emergency

Contraceptive Pills: Knowledge and Attitudes

among American Adults and Obstetrician/

Gynecologists,’’ Testimony before the FDA

Reproductive Health Drugs Advisory

Committee, June 28, 1996.

3. Fasoll, M., F. Parazzini, G. Cecchetti,

and C. La Vecchia, ‘‘Post-coital

Contraception: An Overview of Published

Studies,’’ Contraception, 39:459–468, 1989.

4. Glasier, A., ‘‘Postcoital Contraception,’’

Reproductive Medicine Review, 2:75–84,

1993.

5. Glasier, A., et al., ‘‘Mifepristone (RU486)

Compared with High-Dose Estrogen and

Progestogen for Postcoidal Emergency

Contraception,’’ New England Journal of

Medicine, 327:1041–1044, 1992.

6. Haspels, A. A., and M. R. Van Santen,

‘‘New Aspects in Post-coital Contraception,’’

in ‘‘Future Aspects in Contraception,’’ edited

by B. Runnebaum, T. Rabe, and L. Kiesel,

MTP Press Limited, Boston, 1985.

7. Ho, P. C., and M. S. W. Kwan, ‘‘A

Prospective Randomized Comparison of

Levonorgestrel with the Yuzpe Regimen in

Post-coital Contraception,’’ Human

Reproduction, 8:389–392, 1993.

8. Percival-Smith, R. K. L., and B.

Abercrombie, ‘‘Postcoital Contraception with

dl-Norgestrel/Ethinyl Estradiol Combination:

Six Years Experience in a Student Medical

Clinic,’’ Contraception, 36:287–293, 1987.

9. Trussell, J., C. Ellertson, and F. Stewart,

‘‘The Effectiveness of the Yuzpe Regimen of

Emergency Contraception,’’ Family Planning

Perspectives, 28:58–87, 1996.

10. Trussell, J., and F. Stewart, ‘‘The

Effectiveness of Postcoital Hormonal

Contraception,’’ Family Planning

Perspectives, 24:262–264, 1992.

11. Trussell, J., et al., ‘‘Emergency

Contraceptive Pills: A Simple Proposal to

Reduce Unintended Pregnancies,’’ Family

Planning Perspectives, 24:269–273, 1992.

12. Tully, B., ‘‘Postcoital Contraception—A

Study,’’ British Journal of Family Planning,

8:119–124, 1983.

13. Van Look, P. F. A., and H. von Hertzen,

‘‘Emergency Contraception,’’ British Medical

Bulletin, 49:158–170, 1993.

14. Van Santen, M. R., and A. Haspels,

‘‘Interception II: Postcoital Low-Dose

Estrogens and Norgestrel Combination in 633

Women,’’ Contraception, 31:275–293, 1985.

15. Webb, A., ‘‘Safety and Medical

Contraindications,’’ in ‘‘The Provision of

Emergency Hormonal Contraception,’’ edited

by D. Paintin, ch. 4, RCOG Press, London,

1995.

16. Webb, A., J. Russell, and M. Elstein,

‘‘Comparison of Yuzpe Regimen, Danazol,

and Mifepristone (RU486) in Oral Postcoital

Contraception,’’ British Medical Journal,

305:927–931, 1992.

17. Webb, A., and D. Taberner, ‘‘Clotting

Factors After Emergency Contraception,’’

Advances in Contraception, 9:75–82, 1993.

18. Yuzpe, A. A., et al., ‘‘Post Coital

Contraception—A Pilot Study,’’ Journal of

Reproductive Medicine, 13:53–58, 1974.

19. Yuzpe, A. A., R. Percival Smith, and A.

Rademaker, ‘‘A Multicenter Clinical

Investigation Employing Ethinyl Estradiol

Combined With dl-Norgestrel as a Postcoital

Contraceptive Agent,’’ Fertility and Sterility,

37:508–513, 1982.

20. Yuzpe, A. A., and W. J. Lancee,

‘‘Ethinylestradiol and dl-Norgestrel as a

Postcoital Contraceptive,’’ Fertility and

Sterility, 28:932–936, 1977.

21. Zuliani, G., U. F. Colombo, and R.

Molla, ‘‘Hormonal Postcoital Contraception

with an Ethinylestradiol-Norgestrel

Combination and Two Danazol Regimens,’’

European Journal of Obstetrics & Gynecology

and Reproductive Biology, 37:253–260, 1990.

IV. Conclusions

The Commissioner has concluded that

combined oral contraceptives, taken

initially within 72 hours of unprotected

intercourse and providing a total of 0.10

or 0.12 mg of ethinyl estradiol and 0.50

or 0.60 mg of levonorgestrel in each of

2 doses separated by 12 hours, are safe

and effective for use as postcoital

emergency contraception. The

Commissioner bases this conclusion on

FDA’s review of the published literature

concerning this use (listed above),

FDA’s knowledge of the safety of

combined oral contraceptives as

currently labeled, and on the

unanimous conclusion that these

regimens are safe and effective made by

the agency’s Advisory Committee for

Reproductive Health Drugs at its June

28, 1996, meeting. Because such

combined oral contraceptives have not

been labeled for this use or this dosage

regimen, the Commissioner finds that

these products are new drugs as defined

in section 201(p)(1) and (p)(2) of the

Federal Food, Drug, and Cosmetic Act

(the act) (21 U.S.C. 321(p)(1) and (p)(2)).

Accordingly, approved NDA’s are

required as a condition of marketing.

FDA is prepared to accept NDA’s for

combined oral contraceptives

appropriately labeled for use as

postcoital emergency contraception

under section 505(b)(2) of the act (21

U.S.C. 355(b)(2)) and part 314 (21 CFR

part 314). Because of the publicly

available safety and effectiveness data

documenting the drugs’ use, the safety

and effectiveness requirements of

§ 314.50 may be met by citing the
8612 Federal Register / Vol. 62, No. 37 / Tuesday, February 25, 1997 / Notices

published literature listed in the

references in section III. of this

document. The Commissioner advises

that it is unnecessary to submit copies

and reprints of the data cited in section

III. of this document. Both the safety

and effectiveness data upon which the

Commissioner bases the above

conclusions and the minutes of the

Advisory Committee meeting are on file

for public inspection in the Dockets

Management Branch (address above).

The Commissioner invites applicants to

submit any other pertinent studies and

literature of which they are aware.

Dated: February 20, 1997.

David A. Kessler,

Commissioner of Food and Drugs.

Appendix

Use of Emergency Contraceptive Pills (ECP’s)

ECP’s consist of two doses of regular birth

control pills containing estrogen and

progestin. Taking ECP’s provides a short,

strong, burst of hormone exposure.

Depending on where you are in your cycle

and when you had unprotected intercourse,

using ECP’s may prevent ovulation, disrupt

fertilization, or inhibit implantation of a

fertilized egg in the uterus.

How To Use ECP’s

The oral contraceptive pills that can be

used as ECP’s are listed below. Take only one

type of pill, not all of them. For example, if

you use Ovral, you do not need Nordette. If

you are getting your ECP’s from a regular

pack of birth control pills containing 28 pills

(1 for every day), remember that the last 7

(green or pink) pills do not contain any

hormones.

Brand Name Pill Color

Number of pills

to swallow within 72 hours

after unprotected sex

Number of pills

to swallow 12

hours later

Ovral white 2 2

Lo/Ovral white 4 4

Nordette light orange 4 4

Levlen light orange 4 4

Triphasil yellow 4 4

Tri-Levlen yellow 4 4

1. Swallow the first dose no later than 72

hours after having unprotected sex.

Remember that the second dose must be

taken 12 hours after the first dose. Taking the

first dose at 3 p.m. would mean taking the

second dose at 3 a.m. So take the first dose

at a time that will make it convenient to take

the second dose 12 hours later.

2. Swallow the second dose 12 hours after

taking the first dose. Do not swallow any

extra ECP’s. More pills will probably not

decrease the risk of pregnancy any further

and will increase the risk of nausea.

Side Effects of ECP’s

About half the women who take ECP’s

have temporary nausea. It is usually mild and

should stop in a day or so. The risk of nausea

may be reduced if you take a long-acting

nonprescription antinausea medicine (such

as meclizine) 30 minutes to 1 hour before

taking each of the two doses of ECP’s. About

20 percent of women who take ECP’s vomit.

If you vomit within an hour after taking

either dose of ECP’s, call your clinician to

discuss whether to repeat that dose or to take

antinausea medicine.

Before Taking ECP’s

If you think you might have gotten

pregnant last month, see your clinician

before taking ECP’s. Early pregnancy

symptoms can include breast tenderness,

nausea, or a previous period that was not

quite normal.

If you have a serious medical problem, talk

to your clinician before using ECP’s.

After Taking ECP’s

Your next menstrual period may start a few

days earlier or later than usual. If your period

does not start within 3 weeks, see your

clinician for an exam and pregnancy test. If

ECP’s fail, or if you were already pregnant

when you took ECP’s, the fetus would be

exposed to hormones. Studies of women who

continued to take birth control pills after they

unknowingly became pregnant do not show

any evidence of harm to the fetus.

ECP’s may not prevent an ectopic

pregnancy (in the tubes or abdomen). Ectopic

pregnancy is a medical emergency. In ectopic

pregnancies, spotting and cramping pain

usually begin shortly after the first missed

menstrual period. See your clinician

immediately if you experience these

symptoms.

After taking ECP’s, get started as soon as

you possibly can with a method of birth

control you will be able to use every time you

have sex. ECP’s are meant for one-time,

emergency protection. ECP’s are not as

effective as other forms of birth control. If

you want to start or resume use of birth

control pills after taking ECP’s, consult your

clinician. Protect yourself from Acquired

Immune Deficiency Syndrome (AIDS) and

other sexual infections as well as pregnancy.

Use condoms every time you have sex if you

think you may be at risk.

Source: Adapted (with permission) from

Trussell, J., F. Stewart, F. Guest, and R. A.

Hatcher, ‘‘Emergency Contraceptive Pills: A

Simple Proposal To Reduce Unintended

Pregnancies,’’ Family Planning Perspectives,

24:269–273, 1992.

[FR Doc. 97–4663 Filed 2–24–97; 8:45 am]

BILLING CODE 4160–01–F