[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