[Federal Register Volume 62, Number 37 (Tuesday, February 25, 1997)]
[Notices]
[Pages 8610-8612]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-4663]



[[Page 8609]]

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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

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

[[Page 8610]]



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 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

[[Page 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 meta-analysis 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 Sec. 314.50 may be met by citing the

[[Page 8612]]

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.

------------------------------------------------------------------------
                                             Number of                  
                                             pills to        Number of  
                                          swallow within     pills to   
     Brand Name           Pill Color      72 hours after    swallow 12  
                                            unprotected     hours later 
                                                sex                     
------------------------------------------------------------------------
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