PROPOSED RULES

DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE

Food and Drug Administration

[ 21 CFR Part 130]

DIETHYLSTILBESTROL

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which were reviewed in the Drug Efficacy Study and for which the initial Drug Efficacy Study Implementation announcement was published in the FEDERAL REGISTER of November 10, 1971 (36 FR 21537).

Therefore, pursuant to provisions of the Federal Food, Drug, and Cosmetic Act (sec. 502 (a) and (f), 505, 701(a), 52 Stat. 1050-1053, as amended, 1055, as amended; 21 U.S.C. 352 (a) and (f), 355, 371(a)) and under authority delegated to him (21 CFR 2.120), the Commissioner of Food and Drugs proposes to amend Part 130 in § 130.45 by revising the section heading; redesignating paragraph (a) as subparagraph (1) and adding a new paragraph heading for paragraph (a); redesignating paragraph (b) as subparagraph (2) and adding a new paragraph (b); and redesignating the remainder of the existing paragraphs, subparagraphs, and subdivisions with no change in the existing text. Section 130.45 is revised to read as follows: § 130.45 Preparations for contraception; labeling directed to the patient. (a) Oral contraceptives. (1) The Food and Drug Administration is charged with assuring both physicians and patients that drugs are safe and effective for their

Labeling

The Commissioner of Food and Drugs has concluded that the information now, available supports the effectiveness of diethylstilbestrol for use as a postcoital contraceptive. The agency considers this use of the drug to be safe as an emergency treatment only, and not as a routine method of birth control. Repeated courses of therapy are to be avoided. Because of the nature of the circumstances surrounding such use, the possible adverse effects on the fetus should the patient be pregnant, possible side effects of the drug, and alternative measures available and their hazards, the physician is the proper person to fully discuss such aspects with the patient so that she may participate in an informed way in the decision to use the drug. To further assure that the patient is fully informed, it is concluded that each package of the drug should contain only the number of tablets required for that one occasion, and should contain a printed leaflet, directed to the patient, describing specifically how to use the drug. Imitations on its use, precautions, contraindications, and possible adverse effects.

Diethylstilbestrol intended for this use is regarded as a new drug requiring an approved new drug application for marketing. At present there are no approved new drug applications for this use. The Food and Drug Administration will entertain new drug applications under the conditions described in the proposal below.

formation to physicians concerning such things as the effectiveness, contraindications, warnings, precautions and adverse reactions is an important element in the discharge of this responsibility. In view of this, the Administration has reviewed the oral contraceptive products, taking into account the following factors: The products contain potent steroid hormones which affect many organ systems; they are used for long periods of time by large numbers of women who, for the most part, are healthy and take them as a matter of choice for prophylaxis against pregnancy, in full knowledge of other means of contraception; and there is no present assurance that persons for whom the drugs are prescibed or dispensed are uniformly being provided the necessary information for safe and effective use of the drugs.

(2) In view of the foregoing, it is deemed in the public interest to present to users of the oral contraceptives a brief notice of the nature of the drugs, the fact that continued medical supervision is needed for safe and effective use, that the drugs may cause side effects and are contraindicated in some cases, that the most important complication is abnormal blood clotting which can have a fatal outcome, that the physician recognizes an obligation to discuss the potential hazards of taking the drugs with the patient, that he has available for the patient written material discussing the effectiveness and the hazards of the drugs, and that users of the oral contraceptives should notify their physicians if they notice any unusual physical disturbance or discomfort.

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and these regulations will provide him a balanced discussion of the effectiveness and the risks attendant upon the use of oral contraceptives for his use in discussing the drugs with his patients.

(4) The oral contraceptives are restricted to prescription sale, and their labeling is required to bear information under which practitioners licensed to administer the drugs can use them safely and for the purpose for which they are intended. In addition, in the case of oral contraceptive drugs, the Commissioner conclude that it is necessary in the best interests of users that the following printed information for patients be included in or with the package dispensed to the patient:

(Patient Package Information)

ORAL CONTRACEPTIVES

(Birth Control Pills)

Do Not Take This Drug Without Your - Doctor's Continued Supervision The oral contraceptives are powerful and effective drugs which can cause side effects in some users and should not be used at all by some women. The most serious known side effect is abnormal blood clotting which can be fatal.

Safe use of this drug requires a careful discussion with your doctor. To assist him in providing you with the necessary information, has pre(Firm name) pared a booklet (or other form) written in a style understandable to you as the drug user. This provides information on the effectiveness and known hazards of the drug including warnings, side effects and who should not use it. Your doctor will give you this booklet (or other form) if you ask for it and he can answer any questions you may have about the use of this drug.

Notify your doctor if you notice any unusual physical disturbance or discomfort.

(5) Providing the patient package in

formation to users may be accomplished by including it in each package of the type intended for the user as follows:

(i) If such package includes additional printed materials for the patient (e.g., dosage schedules), the text of the information in subparagraph (4) of this paragraph shall be an integral part of the

printed material and be in boldface type

set out in a box, preceding all other printed text.

(ii) If such package does not include other printed material for the patient, the text of the information in subpara

graph (1) of this paragraph shall be provided as a printed leaflet in boldface type.

(ii) Include in each bulk package intended for multiple dispensing, a sufficient number of the patient package information leaflet, with instructions to the pharmacist to include one with each prescription dispensed.

(6) Written, printed, or graphic materials on the use of a drug that are disseminated by or on behalf of the manufacturer, packager, or distributor and are intended to be made available to the patient, are regarded as labeling. The commissioner also concludes that it is necessary that information in lay language, concerning effectiveness, contraindications, warnings, precautions, and

PROPOSED RULES

adverse reactions be incorporated prominently in the beginning of any such materials, and that such labeling must be made available to physicians for all patients who may request it. Such labeling shall be substantially as follows, based on the approved package insert for prescribers of the oral contraceptives, and shall include the following points:

(1) A statement that the drug should be taken only under continued supervision of a physician.

(ii) A statement regarding the effectiveness of the product.

(iii) A warning regarding the serious side effects with special attention to thromboembolic disorders and stating the estimated morbidity and mortality in users vs nonusers. Other serious side effects to be mentioned include mental depression, edema, rash, and jaundice. The possibility of infertility following discontinuation of the drug should be mentioned.

(iv) A statement of contraindications. (v) A statement of the need for special supervision of some patients including those with heart or kidney disease, asthma, high blood pressure, diabetes, epilepsy, fibroids of the uterus, migraine, mental depression or history thereof.

(vi) A statement of the most frequently encountered side effects such as spotting, breast changes, weight changes, skin changes, and nausea and vomiting.

(vii) A statement of the side effects frequently reported in association with the use of oral contraceptives, but not proved to be directly related such as nervousness, dizziness, changes in appetite, loss of scalp hair, increase in body hair, and increased or decreased libido.

(viii) A statement regarding metabolic effects such as on blood sugar and cholesterol setting forth our current lack of knowledge regarding the long term significance of these effects.

(ix) Instructions in the event of missed menstrual periods.

(x) A statement cautioning the patient to consult her physician before resuming the use of the drug after childbirth, especially if she intends to breastfeed the baby, pointing out that the hor

mones in the drug are known to appear in the milk and may decrease the flow.

(xi) A statement regarding production of cancer in certain animals. This

may be coupled with a statement that

beings. there is no proof of such effect in human

(xi) A reminder to the patient to report promptly to her physician any unusual change in her general physical condition and to have regular examinations.

Optionally, the booklet may also contain factual information on family planning, the usefulness and hazards of other available methods of contraception, and the hazards of pregnancy. This material shall be neither false nor misleading in any particular and shall follow the material presented above.

(7) The marketing of oral contraceptives may be continued if all the following conditions are met within 90 days of

the date of publication of this section in the FEDERAL REGISTER.

(1) The labeling of such preparations shipped within the jurisdiction of the Act is in accord with paragraphs (a) (4) and (5), and (6) of this section.

(i) The holder of an approved newdrug application for such preparation submits a supplement to his new-drug application under the provisions of § 130.9 (d) to provide for labeling as described in paragraphs (a) (5) and (6) of this section. Such labeling may be put into use without advance approval of the Food and Drug Administration.

(ii) Existing stocks may be shipped without the package insert for a period of 90 days, provided the labeling booklet is prepared and disseminated as prompetly as possible.

(b) Oral postcoital contraceptives. (1) Diethylstilbestrol orally for postcoital contraception. Studies conducted with this drug have shown its effectiveness in contraception when administered under restricted conditions. The Commissioner, having considered comments by members of the Food and Drug Administration's Obstetrics and Gynecology Advisory Committee, concludes that the drug is safe and effective as an emergency treatment only, and not as a routine method of birth control. Repeated courses of therapy are to be avoided. The effectiveness of diethylstilbestrol in preventing pregnancy depends upon the time lapse after coitus and administration of the drug. The recommended dosage is one 25 milligram tablet twice a day, for 5 consecutive

days beginning, preferably, within 24 hours and not later than 72 hours after exposure. When this dosage is given within the specified time interval, the drug is highly effective in preventing conception. Its use, however, will not terminate pregnancy.

(2) There is at present no positive evidence that the restricted use of diethylstilbestrol for postcoital contraception carries a significant carcinogenic risk either to the mother or the fetus. However, because existing data support the possibility of delayed appearance of carcinoma in females whose mothers have been given diethylstilbestrol later in pregnancy, and because teratogenic and other adverse effects on the fetus with the very early administration recommended are not well understood, failure of postcoital treatment with the drug deserves serious consideration of voluntary termination of pregnancy. For these reasons, as well as possible adverse effects in the patient, the drug should not be used as a routine method of birth control. A pregnancy test should be performed prior to use of the drug as a postcoital contraceptive. If the test is positive, the drug should not be used.

(3) Because of the nature of the conditions surrounding this use of diethylstilbestrol, the Commissioner concludes that it is in the best interests of the patient that, in addition to receiving specific instructions from her physician, she also receives with her package of the drug a printed leaflet describing how to use

the drug, limitations on its use, its potential for serious effects on the fetus in the event she is pregnant, and possible adverse effects, contraindications and precautions.

(4) Diethylstilbestrol for use as a postcoital contraceptive shall be packaged in containers of 10 tablets, each tablet to contain 25 milligrams diethylstilbestrol. Each drug package of ten tablets shall contain, in addition to information under which the practitioner licensed to administer the drug can use it safely and for the purpose for which it is intended, a brief leaflet for the user to read as follows:

(Patient package information)

Your doctor has prescribed these tablets which contain estrogen (female hormone) as an emergency measure to prevent pregnancy. To be effective the treatment must be started within three days of sexual intercourse and preferably within one day. Also, you must take the full course of tablets (one twice a day for five days) even if some nausea and vomiting occurs. These symptoms are common in patients receiving medicine.

this

You should use this drug only under the direction of your physician. This treatment is not recommended for routine or frequent use as a method of contraception because there is no evidence of safety for this relatively large amount of estrogen taken repeatedly. Before prescribing this drug, your not physician will determine whether or you may be pregnant.

This treatment is highly effective in preventing pregnancy if used as described above. However, this drug will not cause an abortion if you are already pregnant. An important reason for not taking the drug if you are already pregnant is that such usage exposes the fetus to an unnecessary hazard. There is some evidence that, if the growing fetus is a female and the mother is given this drug during pregnancy, the child may have an increased risk of developing cancer of the vagina or cervix later in life. If this drug is not successful in preventing pregnancy, it is recommended that you consult with your physician regarding continuation of the pregnancy. There is no evidence that the mother herself (you) will have an increased risk of developing cancer from this treatment.

These tablets which contain estrogen may cause certain side effects, most of which are not serious. The most common side effects are tenderness and nausea, vomiting, breast swelling. The most serious side effect of estrogens, which is rare but can at times be fatal, is abnormal blood clotting, the symptoms of which may be severe leg or chest pain, coughing up of blood, difficulty in breathing, sudden severe headaches, dizziness or fainting, disturbances in vision or speech or weakness or numbness of an arm or leg. If any of these occur, you should stop taking the tablets and notify your doctor as soon possible.

Women who have or have had blood clotting disorders, serious liver conditions, cancer of the breast or womb, or undiagnosed vaginal bleeding in the past should not take these tablets. Furthermore, you should inform your physician if you have or have had a special health problem, such as migraine, mental depression, fibroids of the uterus, heart or kidney disease, asthma, high blood pressure, diabetes or epilepsy. He may wish to make sure that it is suitable for you to take these tablets.

(5) Diethylstilbestrol for use as a postcoital contraceptive may be marketed

PROPOSED RULES

only on the basis of an approved new drug application (abbreviated applications, 130.4 (f), will be acceptable), except that full information described under items 7 and 8 (composition and methods, facilities, and controls) of the new drug application Form FD-356H (§ 130.4 (c)) is required. Guidelines for labeling directed to the physician are available from the Food and Drug Administration, Bureau of Drugs, Division of Metabolic and Endocrine Drug Products (BD-130), 5600 Fishers Lane, Rockville, MD 20852.

Interested persons may, on or before November 26, 1973. file with the Hearing Clerk, Food and Drug Administration, Rm 6-86, 5600 Fishers Lane, Rockville, MD 20852, written comments (preferably in quintuplicate) regarding this proposal. Comments may be accompanied by a memorandum or brief in support thereof. Received comments may be seen in the above office during working hours Monday through Friday.

Dated: September 12, 1973.

A. M. SCHMIDT, Commissioner of Food and Drugs. [FR Doc.73-20441 Filed 9-21-73;8:45 am)

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