SIDE EFFECTS The association of varying degrees of masculinization of the female fetus with the administration of progesterone or progesterone-like compounds to gravidas was first pointed out by Wilkins and Jones. Subsequent reports by Wilkins, Grumbach, Jones' and others have assuciated the occurrence of this anomaly with the administration of newer progesterone-like substances including Norlutin. A review of available reports revealed a number of cases associated with Norlutin therapy. Wilkins also reports cases associated with other substances including ethinyltestosterone, the combination of norethyndrel and 17-ethiny! estradiol 3-methyl ether, testosterone or other androgens, progesterone. and diethylstilbestrol, in addition to several cases in which no therapy was given. Kupperman has cautioned against the assumption th these masculinizing effects are due primarily to progestational therap. during pregnancy. He and others have observed similar changes in newborn baby girls whose mothers had received no hormonal therapy what soever during pregnancy. In addition, tremendous doses of stilbestrol have been used in the past in habitual abortion without any apparent fetal abnormalities. Because of these considerations, the author feels that the physician should first rule out other factors, such as the chromatin pattern, before attributing these phenomena to the use of progestational agents. Although masculinization of the female fetus has been associated with a number of cases of progestational therapy in the pregnant woman, the etiologic factor or factors have not been clearly demonstrated. Although such reports make some physicians understandably hesitant to recommend this type of therapy in the pregnant woman, there are others who believe these compounds are therapeutically effective in salvaging fetuses* many of whom would not otherwise have been born. In brief, medical opinion differs widely as to how, when and whether progestational agents should be used in the pregnant human female and each physician must decide for himself on the merits of each case. When one of these agents is used to conserve a pregnancy, the physician would be well advised to follow carefully the recommended dosage schedules. He should also be on the alert for any evidence of virilizing effects such as voice change or hirsutism as possibly indicative of mas culmizing processes, even though these processes in the fetus may take with no apparent maternal symptoms. Other untoward effects have not been a problem with either the acetate ester or Norlutin. Spotting before the calculated onset or after ter mination of menstruation, transient lethargy and nausea, hirsutism and acne have been reported, but have not ordinarily caused significant problems. Jaundice was reported in one patient who had received 40 mg. daily of the parent compound, though the condition slowly dis appeared following discontinuation of medication Another patient reported as receiving a smaller dosage had a three-plus cephalin flocculation test result a year after receiving medication. CLINICAL DISCUSSION The uulity of Norlutin in a variety of gynecologic disorders has been established. Norlutate can be used interchangeably for the same indica. tions. According to all available laboratory and clinical data, the only difference between the two compounds is one of potency, the acetate ester being approximately twice as potent as Norlutin. For that reason, the recommended dosage for Norlutate is half that for Norlutin. Because of the fact that both compounds have comparable inherent estrogenic activity, estrogen-priming is usually unnecessary. However, in those cases in which the patient's endogenous estrogen is considered by the physician to be totally inadequate, estrogen-priming may be employed at his discretion. All commonly used estrogens are compatible with either compound, and the choice of estrogen depends upon the preference of the physician and the tolerance of the patient. Norlutin and Norlutate are often useful in the treatment of patients with menstrual irregularities. In amenorrheic patients whose condition esults from irregular hormonal control of the menstrual cycle, Norlutin may re-establish the normal cyclic pattern. In those whose condition results from ovarian agenesis, Norlutin in conjunction with estrogen therapy may aid in establishing a menstrual rhythm as long as therapy is continued. Recurrent anovulatory bleeding responded well" to the use of several progestins, including Norlutin. Norethindrone acetate has been found equally effective, usually at about half the dosage for Norlutin.' In women who are being treated for infertility, the action of Norlutin tends to stabilize cyclic rhythm; thereby, permitting more accurate prediction of the time of ovulation. Therapy with Norlutin aids in preparing the endometrium for implantation of the ovum and inhibits arborization of cervical mucus which may act as a barrier to sperm penetration. The compound has been described as a highly potent, orally effective progestational agent, which can delay menstruation beyond the calculated day, but which is uniformly followed by bleeding after cessation of therapy. Administration of Norlutin" or one of several congeners to women with a history of infertility was followed by conception in 7 of 50 patients within five months of cessation of therapy. Additional reports of beneficial effect from progestational therapy in previously infertile women have been published. 13, 14 Norlutate has been found to be similarly effective in patients with infertility at doses approximating half those used with Norlutin.* The use of progestational agents in habitual and threatened abortion has received support from a number of investigators.-17 In one study, 15 42 of 67 gravidas in whom abortion appeared imminent were delivered of viable infants following a schedule of therapy with Norlutin. Another study recorded a fetal salvage rate of 42.3 per cent with Norlutin ta 45 obstetric patients with threatened abortion. Norlycate has been similarly used therapeutically for threatened and habitual abortion at about half the dose for Norlutin. tion. A number of investigators ascribe premenstrual symptoms to an estrogen-progesterone imbalance caused by deficient progesterone secreA similar endocrine imbalance may also be a contributory factor in some patients with dysmenorrhea. By administration of Norlutin or Norlutate in the pre-ovulatory phase of the cycle some patients may be benefited when a normal cycle is allowed to occur. Norethindrone and forethindrone acetate have both proved beneficial in treatment of patients with endometriosis., 10, 19, 20 Norethindrone or norethindrone acetate can be employed successfully to build up the endometrium and prevent the onset of menses for as long as the normal period of gestation. Cessation of therapy is then followed by with drawal bleeding and frequently by prolonged periods of freedom from pain and discomfort. A test for pregnancy consists of administering 5 mg. of Norlutate or 10 mg. of Norlutin daily for three consecutive days to a woman whose conceptual status is in doubt. If she is not pregnant, withdrawal bleeding should occur within two to four days after cessation of therapy; if she is pregnant, no such bleeding will occur. REFERENCES 1. Djerassi, C.; Miramontes, L.; Rosenkranz, G.; and Sondheimer, F.: J. Am. Chem. Soc. 76:4092, 1954; Abstracts, Papers American Chemical Society, 121st Meeting, 18J, 1952. 2. Junkmann: Unpublished report cited by H. Werner-Boschann, Ann. New York Acad. Sc. 71:727, 1958. 3. McGinty, D. A.: Unpublished data. Research Laboratories, Parke, Davis & Company. 4. Personal Communications to the Department of Clinical Investigation, Research Division, Parke, Davis & Company. 5. Wilkins, L.; Jones, H. W., Jr.; Holman, O. H.; and Stempfel, R. S., Jr.: J. Clin. Endocrinol. & Metab. 18:559, 1958. 6. Jones, H. W., Jr.: Obst. & Gynec. Surv. 12:433, 1957. 7. Wilkins, L.: J.A.M.A. 172:1028, 1960. 8 Grumbach, H. M.; Ducharme, J. R.; and Moloshok, R. E.: J. Clin. Endocrinol. & Metab. 19:1369, 1959. 9. Jones, H. W., Jr. and Wilkins, L.: Fertility and Sterility 11:148, 1960. 10. Kupperman, H. S.: Federation Pru 18:1071, 1959. 11. Southam, A. L.: Ann. New York Acad. Sc. 71:666, 1958. 12. Rock, J.; Pincus, G.; and Garca, C. R.: Science 124:891, 1956. 13. Greenblatt, R. B.: J. Clin. Ende crinol. & Metab. 16:869, 1956. 14. Tyler, E. T. and Olson, H. J.: Am New York Acad. Sc. 71:704, 1958. 15. Abramson, D.: Ann. New York Acad. Sc. 71:759, 1958. 16. Hodgkinson, C. P.; Igna, E. J.; and Bukeavich, A. P.: Ann. New York Acad. Sc. 71:753, 1958. 17. Boschann, H.: Ann. New York Acad. Sc. 71:727, 1958. 18. Morton, J. H.: Internat. Rec. Mod. & Gen. Pract. Clin. 166:505, 1953. 19. Kistner, R. W.: Clin. Pharm. & Therapeutics 1:525, 1960. 20. Greenblatt, R. B. and Jungck, E. C.: J.A.M.A. 166:1461, 1958. 169, No. 11 EXHIBIT 52 (Council of Drugs, Vol. 169, No. 11) COUNCIL ON DRUGS orethindrone (Norlutin).— 17a-Ethinyl-19-norsterone.-The structural formula of norethinme may be represented as follows: CICH -OH ctions and Uses.-Norethindrone, sometimes reed to as norethisterone, is a highly potent, orally ve, progestational agent which was introduced mercially in 1957. It produces the typical phyogical and anatomic effects of progesterone and derivatives, i. e., induction of a secretory endorium, luteal changes in the vaginal epithelium, -ppearance of cervical fern, increases in basal y temperature, and withdrawal bleeding from estrogen-primed endometrium. When given n the 5th to the 25th day of the menstrual cycle, drug is believed to inhibit ovulation. Continuadministration of norethindrone can also delay struation for prolonged periods, with only oconal instances of breakthrough bleeding. The udopregnancy thus induced is presumably an vulatory amenorrhea. In terms of weight of g required for progestational effects, norethinne is one of the most potent agents known. Its et and duration of action are about the same as h parenterally administered progesterone; if givfor five days to amenorrheic women after estroic stimulation, the drug will generally induce hdrawal bleeding within 24 to 72 hours after its continuance. Animal experiments indicate that ethindrone has slight estrogenic effects; there no evidence of androgenic activity. However, lies in animals are not adequate to estimate the ent to which observed histological changes may due to the estrogenic activity of the drug. The g is apparently not metabolized in the same aner as progesterone, since its administration s not cause an increase in the urinary excretion 17-ketosteroids. Norethindrone has been used in the treatment of mary and secondary amenorrhea. The drug will induce secretory changes in the endometrium, h subsequent menstruation, unless there has n adequate estrogenic stimulation. Hence, in ients with inadequate endogenous estrogen protion, as determined by vaginal cytology, estro1 priming is necessary. In women with menstrual gularity or secondary amenorrhea due to inquate corpus luteum activity, the monthly emyment of norethindrone may help in reestablisha normal cyclic pattern. This effect may be pful in the management of patients with inferty problems, since it permits a more accurate diction of the time of ovulation. Although the imate value of progestogens in the treatment of nale infertility remains to be determined, agents has norethindrone might theoretically be of 139/1193 value in establishing conditions conducive to pregnancy by reason of their inhibiting effect on the arborization of cervical mucus (which may act as a barrier to sperm penetration) and by preparing the endometrium for implantation of the ovum. Like other progestogens, norethindrone may be tried in the treatment of functional uterine bleeding, provided that genital malignancy has been ruled out and that curettage has established the diagnosis of benign endometrial hyperplasia. Because it can induce a state of amenorrhea for as long as its daily administration is continued, norethindrone has been suggested as a means of temporary delay of the menstrual period for honeymoon, vacation, and athletic events. However, the use of a potent hormone to inhibit a normal physiological function, simply for patient convenience, should be discouraged. The menstrual-inhibiting property of the drug may, however, serve a useful purpose in alleviating the symptoms of endometriosis and causing a regression of endometrial implants. Norethindrone, as well as other progestogens, has been tried in a more or less empirical manner for the treatment of threatened or habitual abortion. At present, there is a dearth of convincing evidence that any agent of this type can reduce the incidence of fetal loss. There is likewise insufficient evidence at hand to establish the proposed use of norethindrone for the treatment of premenstrual tension or dysmenorrhea. The clinical use of norethindrone has not been associated with any appreciable toxicity. In occasional instances, mild nausea, lethargy, and spotting before the calculated onset or after termination of menstruation have been reported. In young animals, prolonged administration of large doses of the drug causes a decrease in food consumption, with a consequent depression in weight gain; however, anorexia and weight loss have not been a problem clinically. Prolonged therapy with norethindrone generally decreases libido, an effect that would negate its proposed use to delay menstruation during the honeymoon. Dosage.-Norethindrone is administered orally. For amenorrhea, menstrual irregularity, functional uterine bleeding, and infertility, the usual dose is 10 to 20 mg. daily from the 5th to the 23rd day of the menstrual cycle. A five-day period is allowed for withdrawal bleeding to occur. Continuous daily doses of 20 to 30 mg. are usually sufficient to prevent menstruation. For the treatment of premenstrual tension and dysmenorrhea, the proposed dose is 10 mg. once or twice daily, beginning in the preovulatory phase and continuing to the 20th to the 23rd day of the cycle. Pending more evidence to show a beneficial effect, the proposed dosage for these latter purposes is considered experimental. Preparations: tablets 5 mg. Parke, Davis & Company cooperated by furnishing scientific data to aid in the evaluation of norethindrone. 73753 0-61-pt. 2-28 EXHIBIT 53 Reprinted from AMERICAN JOURNAL OF PUBLIC HEALTH, Vol. 51, No. 5, May, 1961 Copyright by the American Public Health Association, Inc., 1790 Broadway, New York, N. Y. The huge proliferation of drugs currently thrown on the market and the inadequate testing that these products receive have created a significant problem. The nature of this problem and the possible ways of dealing with it are reviewed here. THE CLINICAL VALUE OF DRUGS: SOURCES OF EVIDENCE Mindel C. Sheps, M.D., M.P.H., F.A.P.H.A. ELIABLE judgments about the value Rand limitations of a drug in clinical medicine can be made only after careful comparison of its effects with those of alternative methods of treatment, after accumulation of wide experience by many observers, and after dispassionate critical evaluation of the results. The problem of reaching such judgments about today's products must be conIsidered in the context of the number and kinds of drugs being produced currently. After examining the current drug production and prescription pattern, I propose to discuss the methods by which an evaluation of clinical effectiveness is attempted, and the efforts made by organized bodies to deal with existing problems. Current Patterns of Drug Production In recent years, the prescription pattern has changed greatly both quantitatively and qualitatively. The number of prescriptions filled has risen from 182 million in 1939 to 655 million in 1958, to 712 million in 1959, practically a fourfold increase in 20 years.1,2 Further more, whereas in 1939, 80 per cent of prescriptions were compounded by the druggist on the premises, now at least 90 per cent are prefabricated by pharmaceutical houses. Most of the prescriptions are for new drugs, more than 70 per cent of the dollars spent being for products less than ten years old. New products are accepted more rapidly and become obsolete more rapidly. Generally today a new product either soars to popularity within the first few weeks or months after it is launched on the market, or else "the promotional program fails and the product is doomed to mediocrity." A parallel acceleration has occurred in the rate of obsolescence, the life expectancy of a new drug being from about two to five years, or about half of what it was a decade ago. This rapid obsolescence naturally results in pressure for each new drug to go on the market quickly in the hope of a successful run before it is too late. Such pressure militates against deliber ate objective public evaluation of the place in clinical medicine of a new drug before it is released for general use. It |