Federal Register

Tuesday
February 25, 1997

Part V

Department of
Health and Human
Services

Food and Drug Administration

Prescription Drug Products; Certain
Combined Oral Contraceptives for Use as
Postcoital Emergency Contraception;
Notice

[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 FDA-
approved 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
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
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: Ovral
Pill Color: white
Number of pills to swallow within 72 hours after unprotected sex: 2
Number of pills to swallow 12 hours later: 2

Brand Name: Lo/Ovral
Pill Color: white
Number of pills to swallow within 72 hours after unprotected sex: 4
Number of pills to swallow 12 hours later: 4

Brand Name: Nordette
Pill Color: light orange
Number of pills to swallow within 72 hours after unprotected sex: 4
Number of pills to swallow 12 hours later: 4

Brand Name: Levlen
Pill Color: light orange
Number of pills to swallow within 72 hours after unprotected sex: 4
Number of pills to swallow 12 hours later: 4

Brand Name: Triphasil
Pill Color: yellow
Number of pills to swallow within 72 hours after unprotected sex: 4
Number of pills to swallow 12 hours later: 4

Brand Name: Tri-Levlen
Pill Color: yellow
Number of pills to swallow within 72 hours after unprotected sex: 4
Number of pills to swallow 12 hours later: 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