Federal Register / Vol. 64, No. 70 / Tuesday, April 13, 1999 / Proposed Rules 17985

List of Subjects in 14 CFR Part 71 DEPARTMENT OF HEALTH AND Reports during the past several years have HUMAN SERVICES indicated that the use of sex hormones Airspace, Incorporation by reference, during early pregnancy may seriously Navigation (air). Food and Drug Administration damage the offspring. Several reports suggest an association between intrauterine exposure The Proposed Amendment 21 CFR Part 310 to sex hormone treatment and congenital anomalies, including congenital heart defects In consideration of the foregoing, the [Docket No. 99N±0188] and limb reduction defects. Federal Aviation Administration Based on these reports, FDA also proposes to amend 14 CFR part 71 as Progestational Drug Products for published in the Federal Register of follows: Human Use; Requirements for July 22, 1977 (42 FR 37643), a proposed Labeling Directed to the Patient rule to require patient labeling for progestational drug products. The final PART 71ÐDESIGNATION OF CLASS A, AGENCY: Food and Drug Administration, CLASS B, CLASS C, CLASS D, AND HHS. regulation was published in the Federal Register of October 13, 1978 (43 FR CLASS E AIRSPACE AREAS; ROUTES; ACTION: Proposed rule. AND REPORTING POINTS 47178), and it is codified at § 310.516 SUMMARY: The Food and Drug (21 CFR 310.516). It requires that 1. The authority citation for 14 CFR Administration (FDA) is proposing to progestational drug products be part 71 continues to read as follows: revoke its regulation requiring patient dispensed with a patient package insert labeling for progestational drug containing a ‘‘brief discussion of the Authority: 49 U.S.C. 106(g), 40103, 40113, products. This patient labeling is nature of the risks of birth defects 40120; E.O. 10854, 24 FR 9565, 3 CFR, 1959– resulting from the use of these drugs 1963 Comp., p. 389 required to inform patients of an increased risk of birth defects reported during the first 4 months of pregnancy’’ § 71.1 [Amended] to be associated with the use of these (§ 310.516(b)(4)). The regulation applies drugs during the first 4 months of to any drug product that contains a 2. The incorporation by reference in pregnancy. FDA has concluded that, progestogen, with the exceptions of 14 CFR 71.1 of the Federal Aviation based on a review of the scientific data, contraceptives and oral dosage forms Administration Order 7400.9F, Airspace such labeling for all progestogens is not labeled solely for the treatment of Designations and Reporting Points, warranted. In addition, the diversity of advanced cancer1 (§ 310.516(e)(4)). dated September 10, 1998, and effective drugs that can be described as Texts for patient and professional September 16, 1998, is amended as progestational, and the diversity of labeling were published at the same follows: conditions these drugs may be used to time and contained essentially the same treat, make it inappropriate to consider warning concerning heart and limb Paragraph 6005 Class E airspace areas these drugs a single class for labeling defects (see 42 FR 37646 at 37647 and extending upward from 700 feet or more 37648, July 22, 1977). above the surface of the earth. purposes. This action is intended to provide consumers with more In the late 1980’s, FDA evaluated the * * * * * appropriate labeling for certain drug scientific literature concerning the AWP AZ E5 Taylor, AZ [NEW] products. possible teratogenicity of progestational drugs and concluded that the labeling DATES: Written comments by July 12, Taylor Municipal Airport, AZ for progestational drug products should (Lat. 34°27′17′′N, long. 110°06′89′′W) 1999. See section VI of this document for the proposed effective date of a final be revised. Available evidence indicated Show Low Municipal Airport, AZ the warning about congenital heart ° ′ ′′ ° ′ ′′ rule based on this document. (Lat. 34 15 56 N, long. 110 00 17 W) defects and limb reduction defects That airspace extending upward from 700 ADDRESSES: Submit written comments should be deleted. At that time, several feet above the surface within a 6.5-mile to the Dockets Management Branch reports suggested an association radius of the Taylor Municipal Airport, (HFA–305), Food and Drug between exposure to progestational excluding the portion within the Show Low, Administration, 5630 Fishers Lane, rm. drugs during pregnancy and an AZ, Class E airspace area. That airspace 1061, Rockville, MD 20852. increased risk of hypospadias in male extending upward from 1,200 feet above the FOR FURTHER INFORMATION CONTACT: fetuses and mild virilization of the surface within 5 miles southeast and 8 miles Diane V. Moore, Center for Drug external genitalia in female fetuses. northwest of the 041° bearing from the Taylor Evaluation and Research (HFD–580), Because FDA continued to believe Municipal Airport, extending from the Taylor Food and Drug Administration, 5600 that there was some risk of birth defects Municipal Airport to the southern boundary Fishers Lane, Rockville, MD 20857, associated with progestogens, the of V–264. 301–827–4260. patient labeling and box warning * * * * * SUPPLEMENTARY INFORMATION: statements were revised. In the Federal Register of January 12, 1989 (54 FR Issued in Los Angeles, California, on I. Background March 31, 1999. 1243), FDA published revised guideline In the Federal Register of July 22, Leonard A. Mobley, texts for patient and professional 1977 (42 FR 37646), FDA published a labeling for progestational drug Acting Manager, Air Traffic Division, notice setting forth professional labeling products that deleted the warning about Western-Pacific Region. for progestational drug products, other possible congenital heart defects and [FR Doc. 99–9134 Filed 4–12–99; 8:45 am] than progestogen-containing products limb reduction defects and added a BILLING CODE 4910±13±M for contraception, and included a box warning about an increased risk of warning recommending against use certain genital abnormalities. The during the first 4 months of pregnancy. The category ‘‘progestational drug 1 The original regulation exempted products’’ includes natural progesterone contraceptives, which were required to comply with the labeling requirements of 21 CFR 310.501. and all synthetic progestins. The basis In 1981 the regulation was amended to exempt for the warning, as stated in the notice, advanced cancer drugs (46 FR 53656, October 30, was: 1981).

VerDate 23-MAR-99 08:20 Apr 12, 1999 Jkt 183247 PO 00000 Frm 00003 Fmt 4702 Sfmt 4702 E:\FR\FM\A13AP2.198 pfrm03 PsN: 13APP1 17986 Federal Register / Vol. 64, No. 70 / Tuesday, April 13, 1999 / Proposed Rules revised patient labeling, which is still in medroxyprogesterone, megestrol, of female masculinization are use, is as follows: norethindrone, norethynodrel, methyltestosterone, methandriol, and Progesterone or progesterone-like drugs norgestrel, and progesterone. The notice danazol (Ref. 2). have been used to prevent miscarriage in the made clear that this list was Thus, there are significant differences first few months of pregnancy. No adequate nonexhaustive and that the warning among progestational drugs. evidence is available to show that they are would apply to all progestational agents, Accordingly, FDA concludes that, based effective for this purpose. Furthermore, most cases of early miscarriage are due to causes including drugs later approved. In 1989, on a review of the scientific data, a which could not be helped by these drugs. when the guideline texts for patient and warning of an increased risk of birth There is an increased risk of minor birth professional labeling were revised to defects on all progestogen labeling is not defects in children whose mothers take this warn about hypospadias and virilization warranted. Class labeling for drug during the first 4 months of pregnancy. of the female genitalia, the warning progestogens is also inappropriate Several reports suggest an association continued to apply to progestogens as a because it applies without regard to the between mothers who take these drugs in the class. indication for which the drug is first trimester of pregnancy and genital FDA has recently reviewed the prescribed. abnormalities in male and female babies. The At the time patient labeling was first risk to the male baby is the possibility of evidence suggesting that progestogen being born with a condition in which the use during pregnancy is associated with required for progestational drugs, opening of the penis is on the underside an increased risk of genital progestogens had been commonly used rather than the tip of the penis (hypospadias). abnormalities. The notion that as hormonal pregnancy tests, as a Hypospadias occurs in about 5 to 8 per 1,000 progestogens are associated with an treatment for habitual or threatened male births and is about doubled with increased risk of hypospadias comes abortion, and for the treatment of exposure to these drugs. There is not enough from compiling cases from secondary amenorrhea and abnormal information to quantify the risk to exposed heterogeneous sources, largely case uterine bleeding. Since that time, some female fetuses, but enlargement of the clitoris reports. Hypospadias has been reported of these uses have been abandoned and and fusion of the labia may occur, although rarely. to be associated with seven new uses have emerged. Hormonal Therefore, since drugs of this type may progestational agents, although for pregnancy tests are no longer available induce mild masculinization of the external several of these progestogens, only one in the United States. Progestational genitalia of the female fetus, as well as case has been reported. The data drugs have been labeled as ineffective hypospadias in the male fetus, it is wise to include cases where women were for the prevention of spontaneous avoid using the drug during the first trimester exposed to other hormones or drugs in abortion for 20 years. of pregnancy. addition to progestogens. The reasons Medroxyprogesterone in combination These drugs have been used as a test for for progestogen exposure varied, with estrogen is now widely prescribed pregnancy but such use is no longer including: Hormonal pregnancy tests, to postmenopausal women for hormone considered safe because of possible damage to a developing baby. Also, more rapid treatment of threatened or habitual replacement therapy. By definition, methods for testing for pregnancy are now abortion, luteal phase deficiency, and postmenopausal women cannot become available. contraception; yet studies often failed to pregnant, yet the current regulation If you take (name of drug) and later find control for the condition being treated. requires that they receive a warning you were pregnant when you took it, be sure One study included infants who were about use in pregnancy. to discuss this with your doctor as soon as genetically predisposed to hypospadias The use of progesterone for luteal possible. (Refs. 1 through 3). phase support with in vitro fertilization At the time patient labeling was first As discussed previously, the warning has become routine. FDA recently required for progestational drugs, there concerning an association between approved a progesterone gel for was concern that all sex hormones progestogens and hypospadias was progesterone supplementation or might be teratogenic. This concern was based on heterogeneous sources. Since replacement as part of an Assisted based on a diverse collection of the early reports suggesting Reproductive Technology program for literature reports, including reports on teratogenicity, several progestational infertile women. The American College androgens, estrogens, and progestogens, agents have been thoroughly of Obstetricians and Gynecologists has often in combination. It was frequently investigated. The reliable evidence, objected to the progestational patient unclear what drug or combination of particularly from controlled studies, labeling requirement as applied to drugs the women had taken. In 1976, shows no increase in congenital progesterone because ‘‘there are no data FDA published the text of patient anomalies, including genital to indicate that the use of progesterone labeling for estrogens that included a abnormalities in male or female infants, causes any teratologic effects, and the warning about congenital heart defects from exposure during pregnancy to FDA warning is disturbing to infertility and limb reduction defects (see 41 FR progesterone (Refs. 4 through 7) or patients taking progesterone.’’2 43117, September 29, 1976). In the hydroxyprogesterone (Refs. 4 through 7, Because of the diversity of the drugs Federal Register notice of July 22, 1977 9 and 10). that can be described as progestational, (42 FR 37646 at 37647), setting forth Analysis of the literature associating the lack of reliable scientific evidence professional labeling for progestational progestogen use during pregnancy with linking most of these drugs to an drug products, FDA described the virilization of the genitalia in female increased risk of birth defects, and the category of ‘‘progestational drug infants indicates that most cases diversity of the conditions these drugs products’’ and noted the need for involved high doses of androgen- may be used to treat, FDA believes it is appropriate warnings for these drugs in derived progestins, particularly inappropriate to require that the belief that all sex hormones, ethisterone and norethindrone (Refs. 2, progestational drug products be including all progestogens, had 11, and 12). Norethindrone in doses dispensed with patient labeling that teratogenic potential. The notice listed ranging from 10 to 40 milligrams per warns of an increased risk of birth the following drugs, and their salts and day (mg/d), and sometimes as much as defects. Therefore, FDA is proposing to esters, as examples of progestational 120 mg/d, was used in the 1950’s and remove this requirement. drugs: Dimethisterone, dydrogesterone, 1960’s as a treatment for threatened ethinylestrenol, ethynodiol, abortion (Ref. 13). The other drugs that 2 Letter from Stanley Zinberg, dated December 31, hydroxyprogesterone, account for most of the recorded cases 1996.

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For the reasons discussed previously, 9. Katz, Z. et al., ‘‘Teratogenicity of on a substantial number of small FDA believes that it is no longer Progestogens Given During the First entities. Because the proposed rule does appropriate for professional labeling to Trimester of Pregnancy,’’ Obstetrics and not impose any mandates on State, contain a box warning recommending Gynecology, 65:775–780, 1985. local, or tribal governments, or the 10. Varma, T. R., and J. Morsman, against the use of progestational drug ‘‘Evaluation of the Use of Proluton-Depot private sector that will result in a 1-year products during the first 4 months of (Hydroxyprogesterone Hexanoate) in Early expenditure of $100 million or more, pregnancy. There is also no need to Pregnancy,’’ International Journal of FDA is not required to perform a cost- contraindicate progestogens as a Gynaecology and Obstetrics, 20:13–17, 1982. benefit analysis under the Unfunded diagnostic test for pregnancy because 11. Wilkins, L., ‘‘Masculinization of Mandates Reform Act of 1995. hormonal pregnancy tests are no longer Female Fetus Due to Use of Orally Given The proposed rule would remove available in the United States. In a Progestins,’’ Journal of the American Medical certain information from the notice published elsewhere in this issue Association, 172:1028–1032, 1960. professional labeling of affected drug 12. Wilson, J. G., and R. L. Brent, ‘‘Are of the Federal Register, FDA is products. The revised labeling may be Female Sex Hormones Teratogenic?’’ filed in the next annual report. The announcing its intent to revoke its American Journal of Obstetrics and previously issued guidance texts for Gynecology, 141:567–580, 1981. agency has identified 13 sponsors and physician and patient labeling for 13. Jacobson, B. D., ‘‘Hazards of 16 distinct professional labeling inserts progestational drug products. When this Norethindrone Therapy During Pregnancy,’’ that would need to be changed to proposed rule concerning patient American Journal of Obstetrics and comply with this rule. Using a labeling becomes final, holders of Gynecology, 84:962–968, 1962. pharmaceutical labeling cost model approved applications for progestational III. Environmental Impact developed for the agency, the average drug products will be required to revise cost for this labeling change is $1,317 The agency has determined under 21 the labeling of such products by per insert, assuming a compliance CFR 25.30(h) that this action is of a type removing the text for patient labeling. In period of 1 year. Applying this cost to that does not individually or addition, at that time, holders of the 16 professional labeling inserts cumulatively have a significant effect on approved applications should revise the results in a one-time cost of compliance the human environment. Therefore, professional labeling to remove the box of $21,000. There will also be an neither an environmental assessment warning and the contraindication as a additional minor cost of lost inventory. nor an environmental impact statement diagnostic test for pregnancy. These Of the 13 sponsors affected, fewer than is required. labeling revisions will not require a 5 would meet the Small Business supplemental application, but may be IV. Analysis of Impacts Administration definition of small. No reported in the next annual report, as additional burdens are imposed upon FDA has examined the impacts of the manufacturers. provided for in 21 CFR 314.70(a) and proposed rule under Executive Order (d). 12866, the Regulatory Flexibility Act (5 V. Paperwork Reduction Act of 1995 II. References U.S.C. 601–612) and the Unfunded FDA tentatively concludes that this The following references have been Mandates Reform Act of 1995 (Pub. L. proposed rule contains no collections of placed on display in the Dockets 104–4). Executive Order 12866 directs information. The proposal would Management Branch (address above) agencies to assess all costs and benefits remove certain information from the and may be seen by interested persons of available regulatory alternatives and, labeling of affected drug products. The between 9 a.m. and 4 p.m., Monday when regulation is necessary, to select revised labeling may be filed in the next through Friday. regulatory approaches that maximize annual report, which is already required 1. Raman-Wilms, L. et al., ‘‘Fetal Genital net benefits (including potential under FDA’s regulations and is already Effects of First-Trimester Sex Hormone economic, environmental, public health approved by the Office of Management Exposure: A Meta-Analysis,’’ Obstetrics and and safety, and other advantages; and Budget (OMB) as a collection of Gynecology, 85:141–149, 1995. distributive impacts; and equity). Under information, OMB control no. 0910– 2. Schardein, J. L., ‘‘Chemically Induced the Regulatory Flexibility Act, unless an 0001. Therefore, clearance by OMB Birth Defects,’’ Marcel Dekker, Inc., New agency certifies that a rule will not have under the Paperwork Reduction Act of York, 1993. a significant impact on small entities, 3. Scialli, A. R., The REPROTOX System, 1995 is not required. the agency must analyze regulatory Reproductive Toxicology Center, VI. Proposed Effective Date Washington, DC. options that would minimize the impact 4. Check, J. H. et al., ‘‘The Risk of Fetal of the rule on small entities. FDA proposes that any final rule Anomalies as a Result of Progesterone The Unfunded Mandates Reform Act based on this proposal be effective 1 Therapy During Pregnancy,’’ Fertility and of 1995 (in section 202) requires that year after its date of publication in the Sterility, 45:575–577, 1986. agencies prepare an assessment of Federal Register. 5. Heinonen, O. P., D. Slone, and S. anticipated costs and benefits before Shapiro, ‘‘Birth Defects and Drugs in proposing any rule that may result in an VII. Request for Comments Pregnancy,’’ Publishing Sciences Group, Interested persons may, on or before Littleton, MA, 1977. expenditure in any 1 year by State, 6. Michaelis, J. et al., ‘‘Prospective Study local, and tribal governments, in the July 12, 1999, submit to the Dockets of Suspected Associations Between Certain aggregate, or by the private sector, of Management Branch (address above) Drugs Administered During Early Pregnancy $100 million or more (adjusted annually written comments on this proposal. Two and Congenital Malformations,’’ Teratology, for inflation). copies of any comments are to be 27:57–64, 1983. The agency has reviewed this submitted, except that individuals may 7. Resseguie, L. J. et al., ‘‘Congenital proposed rule and has determined that submit one copy. Comments are to be Malformations Among Offspring Exposed In it is consistent with the regulatory identified with the docket number Utero to Progestins, Olmsted County, MN,’’ philosophy and principles identified in found in brackets in the heading of this Fertility and Sterility, 43:514–519 1985. 8. Rock, J. A. et al., ‘‘Fetal Malformations Executive Order 12866, and these two document. Received comments may be Following Progesterone Therapy During statutes. With respect to the Regulatory seen in the Dockets Management Branch Pregnancy: A Preliminary Report,’’ Fertility Flexibility Act, the agency certifies that between 9 a.m. and 4 p.m., Monday and Sterility, 44:17–19, 1985. the rule will not have a significant effect through Friday.

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List of Subjects in 21 CFR Part 310 DATES: Written comments regarding this vocational, or practical nurses. Mindful Administrative practice and proposed rule will be accepted until that the au pair program should be procedure, Drugs, Labeling, Medical May 13, 1999. available to families with special needs devices, Reporting and recordkeeping ADDRESSES: Comments regarding this children, the Agency is of the opinion requirements. proposed rule must be presented in that host family participation may be Therefore, under the Federal Food, duplicate and addressed as follows: limited by the number of available au Drug, and Cosmetic Act and under United States Information Agency, pair participants willing to accept such authority delegated to the Commissioner Office of General Counsel, Rulemaking family placements. Further, it appears of Food and Drugs, it is proposed that Clerk, 301 4th Street, S.W., Washington, that au pair participants placed with 21 CFR part 310 be amended as follows: D.C. 20547. families having special needs children FOR FURTHER INFORMATION CONTACT: should be better prepared for the PART 310ÐNEW DRUGS Sally Lawrence, Exchange Visitor demands that may arise from such Program Services, Program Designation placements. With these considerations 1. The authority citation for 21 CFR in mind, the Agency proposes part 310 is revised to read as follows: Branch, United States Information Agency, 301 4th Street, S.W., amendment of § 514.31(e) to ensure that Authority: 21 U.S.C. 321, 331, 351, 352, Washington, D.C. 20547; Telephone both the au pair participant and host 353, 355, 360b–360f, 360j, 360hh–360ss, (202) 401–9810. family are fully apprised of the unique 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, responsibilities that may arise from this SUPPLEMENTARY INFORMATION: The 241, 242(a), 262, 263b–263n. type of placement. To this end, the au Agency has conducted a review of the § 310.516 [Removed] pair will self-identify, and the sponsor consumer aspects of the au pair program will take rasonable steps to verify, his or 2. Section 310.516 Progestational drug and determines that certain regulatory her prior experience, skills, and training products; labeling directed to the amendments to existing regulations regarding the care of special needs patient is removed. should improve the quality of the children and the host family will be Dated: March 25, 1999. program, enhance child safety, promote required to review and specifically transparency, and generally further the William K. Hubbard, acknowledge their acceptance of such public understanding of this program. Acting Deputy Commissioner for Policy. experience, skills, and training. The Specifically, the Agency has identified a Agency proposes this requirement to [FR Doc. 99–9146 Filed 4–12–99; 8:45 am] systemic program arising from the BILLING CODE 4160±01±F ensure that an au pair participant placed advertising and promotion of the with a special needs child has program. Often, this advertising accurately described any prior promotes au pair participation as an experience and that the au pair and host UNITED STATES INFORMATION opportunity to travel and experience life family are thus fully informed regarding AGENCY in the United States without a full duties and experience. explanation of the significant child care 22 CFR Part 514 As a related au pair placement matter, requirements that underlie the program. the Agency also proposes amendment of Exchange Visitor Program Conversely, the advertising directed § 514.31(e) to require that sponsors not towards American host families often place an au pair with a host family until AGENCY: United States Information promotes only the child care aspects of the host family has interviewed the au Agency. the program and fails to stress the pair by telephone. The Agency is of the ACTION: Proposed rule. educational and cultural benefits that opinion that most host families do in the program should provide to the au fact interview the potential au pair by SUMMARY: The regulations govern pair participant. telephone. To provide additional Agency-designated au pair programs Accordingly, to promote a better assurances to the host family regarding under which foreign nationals are understanding of the program the the au pair’s English speaking ability, afforded the opportunity to live with an Agency is proposing to amend the the Agency believes that this general American host family and participate existing regulations set forth at practice of conducting a telephone directly in the home life of the host §§ 514.31(f)(2) and 514.31(i) to require interview should be made mandatory. family while providing child care that all designated au pair program The Agency is also proposing an services and attending a U.S. post- sponsors provide host families and amendment to § 514.31 (m) to require secondary educational institution. The potential au pairs with a brochure that designated sponsors utilize a Agency’s goal in proposing amendment written by the Agency. This brochure standard management audit format of these existing regulations is to explains fully the program obligations supplied by the Agency. This strengthen the oversight and general for both the au pair and host family management auditing requirement was accountability of the au pair program participants and will enhance the first adopted in 1995 and is designed to and to identify and reduce potential risk overall integrity of the au pair program ensure that designated sponsors are in of injury to program participants. These by providing written notice of these full compliance with Agency amendments will provide greater obligations. regulations. The Agency has now specificity regarding the selection and The question of how best to provide reviewed three years of management orientation of both host family and au for the inclusion of American families audits submitted in response to this pair participants thereby enhancing the with self-identified special needs regulation. The audits vary substantially prospect for more informed children has been raised. Au pairs are in quality and content. Because this participation by both parties. Further not personal attendants or nurses and management audit is crucial to the proposed program enhancements would will not have specialized training in Agency’s oversight of the au pair require disclosure of prior experience nursing. Accordingly, au pairs will not program the public has a vested interest for au pair participants providing child provide child care services relating to in ensuring that the quality, content, care for special needs children. An the care and protection of infants or and integrity of the audit process is amendment to provide for uniform children which are performed by uniform and useful as a management program audits is also proposed. trained personnel such as registered, oversight tool. Accordingly, the Agency

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