97-4663. Prescription Drug Products; Certain Combined Oral Contraceptives for Use as Postcoital Emergency Contraception  

  • [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]]
    
    _______________________________________________________________________
    
    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
    
    
    

Document Information

Published:
02/25/1997
Department:
Food and Drug Administration
Entry Type:
Notice
Action:
Notice.
Document Number:
97-4663
Pages:
8610-8612 (3 pages)
Docket Numbers:
Docket No. 96N-0492
PDF File:
97-4663.pdf