[Federal Register Volume 64, Number 70 (Tuesday, April 13, 1999)]
[Proposed Rules]
[Pages 17985-17988]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-9146]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. 99N-0188]


Progestational Drug Products for Human Use; Requirements for 
Labeling Directed to the Patient

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to revoke 
its regulation requiring patient labeling for progestational drug 
products. This patient labeling is required to inform patients of an 
increased risk of birth defects reported to be associated with the use 
of these drugs during the first 4 months of pregnancy. FDA has 
concluded that, based on a review of the scientific data, such labeling 
for all progestogens is not warranted. In addition, the diversity of 
drugs that can be described as progestational, and the diversity of 
conditions these drugs may be used to treat, make it inappropriate to 
consider these drugs a single class for labeling purposes. This action 
is intended to provide consumers with more appropriate labeling for 
certain drug products.

DATES: Written comments by July 12, 1999. See section VI of this 
document for the proposed effective date of a final rule based on this 
document.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Diane V. Moore, 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

    In the Federal Register of July 22, 1977 (42 FR 37646), FDA 
published a notice setting forth professional labeling for 
progestational drug products, other than progestogen-containing 
products for contraception, and included a box warning recommending 
against use during the first 4 months of pregnancy. The category 
``progestational drug products'' includes natural progesterone and all 
synthetic progestins. The basis for the warning, as stated in the 
notice, was:
    Reports during the past several years have indicated that the 
use of sex hormones during early pregnancy may seriously damage the 
offspring. Several reports suggest an association between 
intrauterine exposure to sex hormone treatment and congenital 
anomalies, including congenital heart defects and limb reduction 
defects.
    Based on these reports, FDA also published in the Federal Register 
of July 22, 1977 (42 FR 37643), a proposed rule to require patient 
labeling for progestational drug products. The final regulation was 
published in the Federal Register of October 13, 1978 (43 FR 47178), 
and it is codified at Sec. 310.516 (21 CFR 310.516). It requires that 
progestational drug products be dispensed with a patient package insert 
containing a ``brief discussion of the nature of the risks of birth 
defects resulting from the use of these drugs during the first 4 months 
of pregnancy'' (Sec. 310.516(b)(4)). The regulation applies to any drug 
product that contains a progestogen, with the exceptions of 
contraceptives and oral dosage forms labeled solely for the treatment 
of advanced cancer\1\ (Sec. 310.516(e)(4)). Texts for patient and 
professional labeling were published at the same time and contained 
essentially the same warning concerning heart and limb defects (see 42 
FR 37646 at 37647 and 37648, July 22, 1977).
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    \1\ The original regulation exempted contraceptives, which were 
required to comply with the labeling requirements of 21 CFR 310.501. 
In 1981 the regulation was amended to exempt advanced cancer drugs 
(46 FR 53656, October 30, 1981).
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    In the late 1980's, FDA evaluated the scientific literature 
concerning the possible teratogenicity of progestational drugs and 
concluded that the labeling for progestational drug products should be 
revised. Available evidence indicated the warning about congenital 
heart defects and limb reduction defects should be deleted. At that 
time, several reports suggested an association between exposure to 
progestational drugs during pregnancy and an increased risk of 
hypospadias in male fetuses and mild virilization of the external 
genitalia in female fetuses.
    Because FDA continued to believe that there was some risk of birth 
defects associated with progestogens, the patient labeling and box 
warning statements were revised. In the Federal Register of January 12, 
1989 (54 FR 1243), FDA published revised guideline texts for patient 
and professional labeling for progestational drug products that deleted 
the warning about possible congenital heart defects and limb reduction 
defects and added a warning about an increased risk of certain genital 
abnormalities. The

[[Page 17986]]

revised patient labeling, which is still in use, is as follows:
    Progesterone or progesterone-like drugs have been used to 
prevent miscarriage in the first few months of pregnancy. No 
adequate evidence is available to show that they are effective for 
this purpose. Furthermore, most cases of early miscarriage are due 
to causes which could not be helped by these drugs.
    There is an increased risk of minor birth defects in children 
whose mothers take this drug during the first 4 months of pregnancy. 
Several reports suggest an association between mothers who take 
these drugs in the first trimester of pregnancy and genital 
abnormalities in male and female babies. The risk to the male baby 
is the possibility of being born with a condition in which the 
opening of the penis is on the underside rather than the tip of the 
penis (hypospadias). Hypospadias occurs in about 5 to 8 per 1,000 
male births and is about doubled with exposure to these drugs. There 
is not enough information to quantify the risk to exposed female 
fetuses, but enlargement of the clitoris and fusion of the labia may 
occur, although rarely.
    Therefore, since drugs of this type may induce mild 
masculinization of the external genitalia of the female fetus, as 
well as hypospadias in the male fetus, it is wise to avoid using the 
drug during the first trimester of pregnancy.
    These drugs have been used as a test for pregnancy but such use 
is no longer considered safe because of possible damage to a 
developing baby. Also, more rapid methods for testing for pregnancy 
are now available.
    If you take (name of drug) and later find you were pregnant when 
you took it, be sure to discuss this with your doctor as soon as 
possible.
    At the time patient labeling was first required for progestational 
drugs, there was concern that all sex hormones might be teratogenic. 
This concern was based on a diverse collection of literature reports, 
including reports on androgens, estrogens, and progestogens, often in 
combination. It was frequently unclear what drug or combination of 
drugs the women had taken. In 1976, FDA published the text of patient 
labeling for estrogens that included a warning about congenital heart 
defects and limb reduction defects (see 41 FR 43117, September 29, 
1976). In the Federal Register notice of July 22, 1977 (42 FR 37646 at 
37647), setting forth professional labeling for progestational drug 
products, FDA described the category of ``progestational drug 
products'' and noted the need for appropriate warnings for these drugs 
in the belief that all sex hormones, including all progestogens, had 
teratogenic potential. The notice listed the following drugs, and their 
salts and esters, as examples of progestational drugs: Dimethisterone, 
dydrogesterone, ethinylestrenol, ethynodiol, hydroxyprogesterone, 
medroxyprogesterone, megestrol, norethindrone, norethynodrel, 
norgestrel, and progesterone. The notice made clear that this list was 
nonexhaustive and that the warning would apply to all progestational 
agents, including drugs later approved. In 1989, when the guideline 
texts for patient and professional labeling were revised to warn about 
hypospadias and virilization of the female genitalia, the warning 
continued to apply to progestogens as a class.
    FDA has recently reviewed the evidence suggesting that progestogen 
use during pregnancy is associated with an increased risk of genital 
abnormalities. The notion that progestogens are associated with an 
increased risk of hypospadias comes from compiling cases from 
heterogeneous sources, largely case reports. Hypospadias has been 
reported to be associated with seven progestational agents, although 
for several of these progestogens, only one case has been reported. The 
data include cases where women were exposed to other hormones or drugs 
in addition to progestogens. The reasons for progestogen exposure 
varied, including: Hormonal pregnancy tests, treatment of threatened or 
habitual abortion, luteal phase deficiency, and contraception; yet 
studies often failed to control for the condition being treated. One 
study included infants who were genetically predisposed to hypospadias 
(Refs. 1 through 3).
    As discussed previously, the warning concerning an association 
between progestogens and hypospadias was based on heterogeneous 
sources. Since the early reports suggesting teratogenicity, several 
progestational agents have been thoroughly investigated. The reliable 
evidence, particularly from controlled studies, shows no increase in 
congenital anomalies, including genital abnormalities in male or female 
infants, from exposure during pregnancy to progesterone (Refs. 4 
through 7) or hydroxyprogesterone (Refs. 4 through 7, 9 and 10).
    Analysis of the literature associating progestogen use during 
pregnancy with virilization of the genitalia in female infants 
indicates that most cases involved high doses of androgen-derived 
progestins, particularly ethisterone and norethindrone (Refs. 2, 11, 
and 12). Norethindrone in doses ranging from 10 to 40 milligrams per 
day (mg/d), and sometimes as much as 120 mg/d, was used in the 1950's 
and 1960's as a treatment for threatened abortion (Ref. 13). The other 
drugs that account for most of the recorded cases of female 
masculinization are methyltestosterone, methandriol, and danazol (Ref. 
2).
    Thus, there are significant differences among progestational drugs. 
Accordingly, FDA concludes that, based on a review of the scientific 
data, a warning of an increased risk of birth defects on all 
progestogen labeling is not warranted. Class labeling for progestogens 
is also inappropriate because it applies without regard to the 
indication for which the drug is prescribed.
    At the time patient labeling was first required for progestational 
drugs, progestogens had been commonly used as hormonal pregnancy tests, 
as a treatment for habitual or threatened abortion, and for the 
treatment of secondary amenorrhea and abnormal uterine bleeding. Since 
that time, some of these uses have been abandoned and new uses have 
emerged. Hormonal pregnancy tests are no longer available in the United 
States. Progestational drugs have been labeled as ineffective for the 
prevention of spontaneous abortion for 20 years.
    Medroxyprogesterone in combination with estrogen is now widely 
prescribed to postmenopausal women for hormone replacement therapy. By 
definition, postmenopausal women cannot become pregnant, yet the 
current regulation requires that they receive a warning about use in 
pregnancy.
    The use of progesterone for luteal phase support with in vitro 
fertilization has become routine. FDA recently approved a progesterone 
gel for progesterone supplementation or replacement as part of an 
Assisted Reproductive Technology program for infertile women. The 
American College of Obstetricians and Gynecologists has objected to the 
progestational patient labeling requirement as applied to progesterone 
because ``there are no data to indicate that the use of progesterone 
causes any teratologic effects, and the FDA warning is disturbing to 
infertility patients taking progesterone.''\2\
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    \2\ Letter from Stanley Zinberg, dated December 31, 1996.
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    Because of the diversity of the drugs that can be described as 
progestational, the lack of reliable scientific evidence linking most 
of these drugs to an increased risk of birth defects, and the diversity 
of the conditions these drugs may be used to treat, FDA believes it is 
inappropriate to require that progestational drug products be dispensed 
with patient labeling that warns of an increased risk of birth defects. 
Therefore, FDA is proposing to remove this requirement.

[[Page 17987]]

    For the reasons discussed previously, FDA believes that it is no 
longer appropriate for professional labeling to contain a box warning 
recommending against the use of progestational drug products during the 
first 4 months of pregnancy. There is also no need to contraindicate 
progestogens as a diagnostic test for pregnancy because hormonal 
pregnancy tests are no longer available in the United States. In a 
notice published elsewhere in this issue of the Federal Register, FDA 
is announcing its intent to revoke its previously issued guidance texts 
for physician and patient labeling for progestational drug products. 
When this proposed rule concerning patient labeling becomes final, 
holders of approved applications for progestational drug products will 
be required to revise the labeling of such products by removing the 
text for patient labeling. In addition, at that time, holders of 
approved applications should revise the professional labeling to remove 
the box warning and the contraindication as a diagnostic test for 
pregnancy. These labeling revisions will not require a supplemental 
application, but may be reported in the next annual report, as provided 
for in 21 CFR 314.70(a) and (d).

II. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Raman-Wilms, L. et al., ``Fetal Genital Effects of First-
Trimester Sex Hormone Exposure: A Meta-Analysis,'' Obstetrics and 
Gynecology, 85:141-149, 1995.
    2. Schardein, J. L., ``Chemically Induced Birth Defects,'' 
Marcel Dekker, Inc., New York, 1993.
    3. Scialli, A. R., The REPROTOX System, Reproductive Toxicology 
Center, Washington, DC.
    4. Check, J. H. et al., ``The Risk of Fetal Anomalies as a 
Result of Progesterone Therapy During Pregnancy,'' Fertility and 
Sterility, 45:575-577, 1986.
    5. Heinonen, O. P., D. Slone, and S. Shapiro, ``Birth Defects 
and Drugs in Pregnancy,'' Publishing Sciences Group, Littleton, MA, 
1977.
    6. Michaelis, J. et al., ``Prospective Study of Suspected 
Associations Between Certain Drugs Administered During Early 
Pregnancy and Congenital Malformations,'' Teratology, 27:57-64, 
1983.
    7. Resseguie, L. J. et al., ``Congenital Malformations Among 
Offspring Exposed In Utero to Progestins, Olmsted County, MN,'' 
Fertility and Sterility, 43:514-519 1985.
    8. Rock, J. A. et al., ``Fetal Malformations Following 
Progesterone Therapy During Pregnancy: A Preliminary Report,'' 
Fertility and Sterility, 44:17-19, 1985.
    9. Katz, Z. et al., ``Teratogenicity of Progestogens Given 
During the First Trimester of Pregnancy,'' Obstetrics and 
Gynecology, 65:775-780, 1985.
    10. Varma, T. R., and J. Morsman, ``Evaluation of the Use of 
Proluton-Depot (Hydroxyprogesterone Hexanoate) in Early Pregnancy,'' 
International Journal of Gynaecology and Obstetrics, 20:13-17, 1982.
    11. Wilkins, L., ``Masculinization of Female Fetus Due to Use of 
Orally Given Progestins,'' Journal of the American Medical 
Association, 172:1028-1032, 1960.
    12. Wilson, J. G., and R. L. Brent, ``Are Female Sex Hormones 
Teratogenic?'' American Journal of Obstetrics and Gynecology, 
141:567-580, 1981.
    13. Jacobson, B. D., ``Hazards of Norethindrone Therapy During 
Pregnancy,'' American Journal of Obstetrics and Gynecology, 84:962-
968, 1962.

III. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

IV. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612) and the 
Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Order 
12866 directs agencies to assess all costs and benefits of available 
regulatory alternatives and, when regulation is necessary, to select 
regulatory approaches that maximize net benefits (including potential 
economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Under the Regulatory 
Flexibility Act, unless an agency certifies that a rule will not have a 
significant impact on small entities, the agency must analyze 
regulatory options that would minimize the impact of the rule on small 
entities.
    The Unfunded Mandates Reform Act of 1995 (in section 202) requires 
that agencies prepare an assessment of anticipated costs and benefits 
before proposing any rule that may result in an expenditure in any 1 
year by State, local, and tribal governments, in the aggregate, or by 
the private sector, of $100 million or more (adjusted annually for 
inflation).
    The agency has reviewed this proposed rule and has determined that 
it is consistent with the regulatory philosophy and principles 
identified in Executive Order 12866, and these two statutes. With 
respect to the Regulatory Flexibility Act, the agency certifies that 
the rule will not have a significant effect on a substantial number of 
small entities. Because the proposed rule does not impose any mandates 
on State, local, or tribal governments, or the private sector that will 
result in a 1-year expenditure of $100 million or more, FDA is not 
required to perform a cost-benefit analysis under the Unfunded Mandates 
Reform Act of 1995.
    The proposed rule would remove certain information from the 
professional labeling of affected drug products. The revised labeling 
may be filed in the next annual report. The agency has identified 13 
sponsors and 16 distinct professional labeling inserts that would need 
to be changed to comply with this rule. Using a pharmaceutical labeling 
cost model developed for the agency, the average cost for this labeling 
change is $1,317 per insert, assuming a compliance period of 1 year. 
Applying this cost to the 16 professional labeling inserts results in a 
one-time cost of compliance of $21,000. There will also be an 
additional minor cost of lost inventory. Of the 13 sponsors affected, 
fewer than 5 would meet the Small Business Administration definition of 
small. No additional burdens are imposed upon manufacturers.

V. Paperwork Reduction Act of 1995

    FDA tentatively concludes that this proposed rule contains no 
collections of information. The proposal would remove certain 
information from the labeling of affected drug products. The revised 
labeling may be filed in the next annual report, which is already 
required under FDA's regulations and is already approved by the Office 
of Management and Budget (OMB) as a collection of information, OMB 
control no. 0910-0001. Therefore, clearance by OMB under the Paperwork 
Reduction Act of 1995 is not required.

VI. Proposed Effective Date

    FDA proposes that any final rule based on this proposal be 
effective 1 year after its date of publication in the Federal Register.

VII. Request for Comments

    Interested persons may, on or before July 12, 1999, submit to the 
Dockets Management Branch (address above) written comments on this 
proposal. Two copies of any comments are to be submitted, except that 
individuals may submit one copy. Comments are to be identified with the 
docket number found in brackets in the heading of this document. 
Received comments may be seen in the Dockets Management Branch between 
9 a.m. and 4 p.m., Monday through Friday.

[[Page 17988]]

List of Subjects in 21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 310 be amended as follows:

PART 310--NEW DRUGS

    1. The authority citation for 21 CFR part 310 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 
360j, 360hh-360ss, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 
242(a), 262, 263b-263n.


Sec. 310.516  [Removed]

    2. Section 310.516 Progestational drug products; labeling directed 
to the patient is removed.

    Dated: March 25, 1999.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 99-9146 Filed 4-12-99; 8:45 am]
BILLING CODE 4160-01-F