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

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