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Home , Chlorotrianisene, Esterified estrogens, Estradiol cypionate, Methyltestosterone

Federal Register / Vol. 68, No. 71 / Monday, April 14, 2003 / Notices 17953

CFR Number of Responses per Avg burden per Total annual reference Data collection respondents respondent response (in hrs.) burden (in hrs.)

73.6 (c–e) Request for exemption ...... 17 1 70/60 20 73.14 ...... Transfer of select agent ...... 1,000 5 1.75 8,750 73.6 (a)(2) Clinical and diagnostic laboratory exemp- 1,000 4 1 4,000 tion report. 73.7(i) ...... Notification of inactivation ...... 6 1 30/60 3 73.8(g) ..... Request expedited review ...... 6 1 30/60 3 73.10(b) ... Documentation of self-inspection ...... 1,000 1 1 1,000 73.13(f) .... Documentation of training ...... 1,000 1 2 8,700 73.18 ...... Administrative review ...... 14 1 4 56 73.15(d) ... Ensure secure recordkeeping system ...... 1,000 1 30/60 4,000

Total ...... 1,000 ...... 34,804

Dated: April 7, 2003. and other comments should be patients not improved by Thomas Bartenfeld, identified with Docket No. 76N–0377 alone.’’ Acting Associate Director for Policy, Planning and submitted to the Dockets In the Federal Register of December and Evaluation, Centers for Disease Control Management Branch (HFA–305), Food 17, 1998 (63 FR 69631), FDA withdrew and Prevention. and Drug Administration, 5630 Fishers approval of estrogen-containing drugs [FR Doc. 03–9019 Filed 4–11–03; 8:45 am] Lane, rm. 1061, Rockville, MD 20852. A insofar as they are indicated for BILLING CODE 4163–18–P request for an opinion on the postpartum because applicability of this notice to a specific have not been shown to be drug product should be directed to the safe for this use. That Federal Register DEPARTMENT OF HEALTH AND Division of New Drugs and Labeling notice included, among others, four of HUMAN SERVICES Compliance (HFD–310), Center for Drug the five NDAs listed above. (NDA 11– Evaluation and Research, Food and 267 was not included because the drug Food and Drug Administration Drug Administration, 5600 Fishers product covered by that application, [Docket Nos. 78N–0377 and 98P–1041; DESI Lane, Rockville, MD 20857. Halodrin Tablets, was not labeled for 7661] use for postpartum breast engorgement.) FOR FURTHER INFORMATION CONTACT: Given this December 17, 1998 notice, David T. Read, Center for Drug Certain Estrogen- the following discussion relates only to Evaluation and Research (HFD–7), Food Combination Drugs; Drugs for Human the second indication found safe and Use; Drug Efficacy Study and Drug Administration, 5600 Fishers effective in the 1972 notice, i.e., ‘‘for the Implementation; Amendment and Lane, Rockville, MD 20857, 301–594– menopausal syndrome in patients not Opportunity for Hearing 2041. improved by estrogen alone.’’ SUPPLEMENTARY INFORMATION: In the Federal Register of September AGENCY: Food and Drug Administration, 29, 1976 (41 FR 43112), the agency HHS. I. Background announced that the menopausal ACTION: Notice. In a notice published in the Federal indication for combination drugs SUMMARY: The Food and Drug Register of September 8, 1972 (37 FR containing an estrogen and an androgen Administration (FDA) is amending a 18225), FDA announced its evaluation was revised to read as follows: previous Federal Register notice to of the various indications claimed for Moderate to severe vasomotor symptoms the following combination drugs that associated with the in those reclassify certain estrogen-androgen patients not improved by estrogen alone. combination drugs as lacking contain an estrogen and an androgen: (There is no evidence that estrogens are substantial evidence of effectiveness for 1. Halodrin Tablets (NDA 11–267), effective for nervous symptoms or the treatment of moderate to severe containing and ethinyl which might occur during menopause, and vasomotor symptoms associated with ; they should not be used to treat these the menopause in those patients not 2. Tylosterone (NDA 8–099), conditions.) 41 FR 43112 at 43113. (emphasis improved by estrogen alone. The agency containing and in original) This action was taken as one part of is taking this action because for this ; a large agency undertaking with respect indication there is not substantial 3. Tylosterone Tablets (NDA 7–661), to the labeling (patient-directed as well evidence of the contribution of each containing diethylstilbestrol and as physician-directed) for all estrogen- component to the effectiveness of these methyltestosterone; containing drug products. The following combination drugs. FDA is offering an 4. Tace with Androgen Capsules documents were also published in the opportunity for a hearing to persons (NDA 10–597), containing Federal Register of September 29, 1976: affected by this action. and (1) 41 FR 43110 (DESI 2238; Certain DATES: Requests for hearings are due on methyltestosterone; Preparations for Vaginal Use); (2) 41 FR or before May 14, 2003. Data in support 5. Deladumone Injection and 43114 (DESI 1543; Certain Estrogen- of hearing requests are due June 13, Deladumone OB Injection (NDA 9–545), Containing Drugs for Oral or Parenteral 2003. containing enanthate and Use); (3) 41 FR 43117 (DESI 740, 1543, ADDRESSES: Communications in . 2238, and 7661; Physician Labeling and response to this notice should be As announced in that 1972 notice, Patient Labeling for Estrogens for identified with the reference number FDA found these drugs to be safe and General Use); and (4) 41 FR 43108 (a DESI 7661 and directed to the attention effective for the ‘‘prevention of proposed rule that would require certain of the appropriate office named below. postpartum breast engorgement and ‘‘for patient-directed labeling for estrogens A request for hearing, supporting data, the menopausal syndrome in those for general use).

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The five applications listed below (59 FR 9989), respectively. The agency improved by estrogen alone. The use of were approved on the basis of the 1976 withdrew approval of NDA 7–661 these combination drug products for any notice, and their approvals are (Tylosterone Tablets) and NDA 8–099 other use, including but not limited to withdrawn in a notice published (Tylosterone Injection), both containing the treatment of other menopausal elsewhere in today’s issue of the diethylstilbestrol and symptoms, will not be considered in Federal Register: methyltestosterone, and NDA 9–545 this proceeding. The effectiveness of 1. NDA 17–968 and ANDA 85–603 (Deladumone OB Injection and estrogen-androgen combination ( 50 milligrams/ Deladumone Injection, each containing products for indications not covered by milliliter (mg/mL) and estradiol and estradiol this proceeding should be addressed cypionate 2 mg/mL injection). valerate) in a notice published in the through the new drug application 2. ANDA 85–860 and ANDA 86–423 Federal Register of October 29, 1998 (63 process. (testosterone enanthate 180 mg/mL and FR 58053). estradiol valerate 8 mg/mL injection). In response to the notice of October II. The Safety and Effectiveness of 3. ANDA 85–865 (testosterone 29, 1998, on November 24, 1998, Solvay Estrogen-Androgen Combination Drug enanthate 90 mg/mL and estradiol Pharmaceuticals submitted a citizen Products for the Treatment of valerate 4 mg/mL injection). petition (Docket No. 98P–1041) Vasomotor Symptoms Associated With In 1981, the Center for Drug requesting that FDA determine that the Menopause in Patients Not Improved Evaluation and Research (CDER) (then products covered by the three by Estrogen Alone the Bureau of Drugs) determined in applications withdrawn in the October The agency took a renewed interest in response to requests from the sponsors 21, 1998, notice were not withdrawn for estrogen-androgen combination drug that the effectiveness finding of the 1976 reasons of safety or effectiveness. As products when concerns were raised DESI 7661 Federal Register notice could FDA is doing for the five estrogen- about the effect of in be applied to two combination drug androgen combination products whose lowering high-density lipoproteins products that were not listed in the 1976 approvals are being withdrawn in a (Refs. notice, but were being marketed at the notice published elsewhere in today’s 1 and 2). It is believed that oral time: (1) and issue of the Federal Register, the agency androgens can reverse the favorable methyltestosterone and (2) esterified is deferring to the outcome of this impact of estrogen on lipoproteins (Ref. estrogens and methyltestosterone. Based proceeding to amend the 1976 notice 3). Other safety concerns were on this finding, FDA filed (i.e., accepted the determination of whether the for review) abbreviated new drug (Refs. 4 and 5) and possible products covered by the three toxicity (Refs. 6, 7, and 8). applications (ANDAs) for these drug applications named in Solvay’s petition products. Wyeth-Ayerst submitted FDA concluded that the negative were withdrawn for reasons of safety or effects androgens may have on lipid ANDA 85–515 for a drug product effectiveness. If the proceeding to containing 0.625 mg conjugated profile may be offset by a potential amend the 1976 notice determines that positive effect on bone mineral density estrogens and 5 mg methyltestosterone, there is substantial evidence of (Refs. 1, 9, and 10). and ANDA 87–824 for a drug product effectiveness of the estrogen-androgen With respect to virilization (i.e., containing 1.25 mg conjugated estrogens combination products for the treatment , , deepening of the voice, and 10 mg methyltestosterone. Reid- of moderate to severe vasomotor alopecia, and ), FDA Provident Laboratories (subsequently symptoms associated with the acquired by Solvay Pharmaceuticals, menopause in those patients not observed that the incidence varied Inc.) submitted ANDA 87–212 for a drug improved by estrogen alone, then the widely in clinical studies and appeared product containing 0.625 mg esterified products covered by the three to be dose and duration dependent. In estrogens and 1.25 mg applications named in Solvay’s petition, a 2–year trial of 33 women treated with methyltestosterone (Estratest H.S.), and as well as the five products referred to methyltestosterone 2.5 mg and esterified ANDA 87–597 for a drug product in a notice published elsewhere in estrogen 1.25 mg daily, 36 percent containing 1.25 mg today’s issue of the Federal Register, reported a hair disorder and 30 percent and 2.5 mg methyltestosterone will be regarded as not withdrawn for reported acne (Ref. 1). In the same 2– (Estratest). reasons of effectiveness. year trial of 33 women treated with In 1996, FDA withdrew Wyeth- As mentioned previously, there are esterified estrogen 1.25 mg daily, 3 Ayerst’s two pending applications two pending ANDAs for Solvay’s percent reported a hair disorder and 6 under 21 CFR 314.65 because the Estratest and Estratest H.S., originally percent reported acne (Ref. 1). In applications had been inactive for many filed in 1981. However, as described in another trial at 24 months, 10 of the 154 years and Wyeth-Ayerst had stopped detail below, FDA no longer believes women treated with methyltestosterone marketing the products. Solvay that estrogen-androgen combination and esterified estrogens and 3 of the 157 continues to market Estratest and drug products are effective for the women treated with esterified estrogens Estratest H.S. The ANDAs for the treatment of moderate to severe reported hirsutism (Ref. 9). Estratest products have not been vasomotor symptoms associated with FDA does not believe there is a approved and are still pending. the menopause in those patients not serious risk for possible liver toxicity at FDA has withdrawn approval of all improved by estrogen alone. FDA, the relatively low doses of androgen five new drug applications (NDAs) therefore, has initiated this proceeding administered in standard oral estrogen- named in the 1972 and 1976 notices. to amend the DESI finding of androgen combination therapies (Refs. The agency withdrew approval of NDA effectiveness for these products. This 11, 12, and 13). 10–597 (Tace with Androgen Capsules proceeding is limited to a determination An agency review of the literature containing chlorotrianisene and of whether there is substantial evidence regarding safety concerns led to scrutiny methyltestosterone) and NDA 11–267 of the effectiveness of estrogen-androgen of the labeled indication, that is, (Halodrin Tablets containing combination drug products for the moderate to severe vasomotor symptoms fluoxymesterone and ethinyl estradiol) treatment of moderate to severe associated with the menopause in those in Federal Register notices of June 25, vasomotor symptoms associated with patients not improved by estrogen 1993 (58 FR 34466), and March 2, 1994 the menopause in those patients not alone.

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Estrogen-alone drug products are between the two treatments. The 15 Other authors affirm the conclusion approved for the treatment of moderate menopausal symptoms evaluated were that estrogen-androgen combination to severe vasomotor symptoms hot flushes, cold sweats, vaginal drug products are not superior to associated with the menopause. dryness, cold hands and feet, breast estrogen in reducing vasomotor Vasomotor symptoms associated with pain or tenderness, numbness and symptoms (Refs. 3, 20 through 23). the menopause are, simply put, ‘‘hot tingling, crawls, , increased Rosenberg summarized the evidence flushes.’’ A hot flush is a sudden feeling facial or , voice deepening, concerning the alleviation of vasomotor of heat, usually on the face, neck, acne, trouble sleeping, pounding of the symptoms as follows: ‘‘Studies suggest shoulders, and chest. Hot flushes have heart, dizzy spells, and pressure or that estrogen is primarily responsible for been described as ‘‘recurrent, transient tightness in the head or body. A 2–year, reductions in vasomotor symptoms and periods of flushing, sweating, and a multicenter, double-blind, randomized, that the addition of androgen neither sensation of heat, often accompanied by parallel group study (Ref. 9) comparing improves nor detracts from this palpitation, feeling of anxiety, and the effects of 2 doses of conjugated beneficial effect’’ (Ref. 24, p. 400). sometimes followed by chills’’ (Ref. 14). and 2 doses of esterified III. FDA’s Conclusions Concerning the When hot flushes occur at night, they estrogen plus methyltestosterone in a Safety and Effectiveness of Estrogen- are often called night sweats. total of 311 surgically menopausal Androgen Combination Drug Products The indication for estrogen-androgen women found no differences among the combination drug products is limited to groups in relief of hot flashes, sweats, For the reasons discussed previously, that subset of women with ‘‘moderate to and vaginal dryness. FDA no longer regards combination severe vasomotor symptoms associated drug products containing estrogen(s) Clinical studies that evaluated the with the menopause’’ that are ‘‘not and androgen(s) as having been shown effect of estrogen-androgen combination improved by estrogen alone’’ (emphasis to be effective for the treatment of therapy specifically on hot flushes added). The precise wording of the moderate to severe vasomotor symptoms found that the combination does not indication quite narrowly defines the associated with the menopause in those reduce the frequency of vasomotor intended population. Thus, to be found patients not improved by estrogen symptoms more than estrogen alone. effective for this narrow indication, alone. The agency has closely examined Watts et al. (Ref. 1) compared treatment there would need to be reliable evidence the data and information that formed with esterified estrogens alone and that estrogen-androgen combination the basis for the 1976 finding that such treatment with esterified estrogens and products are effective in treating the combinations were effective for this population of menopausal women methyltestosterone in a 2–year, indication, as well as the subsequent whose vasomotor symptoms are not multicenter, double-blind, randomized, literature, and has determined that there relieved by estrogen alone. parallel group study conducted in 66 is a lack of substantial evidence that this FDA believes that substantial surgically menopausal women. The combination is effective for ‘‘moderate evidence is lacking that the addition of authors found no significant difference to severe vasomotor symptoms an androgen can improve the in the mean reduction from baseline in associated with the menopause in those effectiveness of estrogen alone in the the number of hot flushes between the patients not improved by estrogen treatment of vasomotor symptoms (i.e., two groups. Sarrel et al. (Ref. 17) found alone.’’ hot flushes). An early randomized, no meaningful differences in relief from IV. References placebo-controlled, five-arm, two-period hot flushes when 20 postmenopausal crossover by Sherwin and women were treated for 8 weeks with The following references have been Gelfand (Ref. 15) compared the effects esterified estrogens or an esterified placed on display in the Dockets on surgically menopausal women of estrogens-androgen combination in a Management Branch (HFA–305), Food immediate postoperative parenteral single-center, double-blind, and Drug Administration, 5630 Fishers administration of estrogen alone (n=11), randomized, parallel group study. Lane, rm. 1061, Rockville, MD 20852, androgen alone (n=10), estrogen and Burger (Ref. 18) administered and may be seen by interested persons androgen in combination (n=12), and subcutaneous implants of estradiol and between 9 a.m. and 4 p.m., Monday placebo (n=10) to hysterectomy controls testosterone to 17 menopausal women through Friday. (n=10) and found that the androgen who complained that symptoms 1. Watts, N. B. et al., ‘‘Comparison of Oral alone, estrogen-androgen combination, persisted, particularly loss of , Estrogens and Estrogens Plus Androgen on despite treatment with conjugated Bone Mineral Density, Menopausal and control hysterectomy groups had Symptoms, and Lipid-Lipoprotein Profiles in lower (i.e., lower frequency and equine estrogens. There was no Surgical Menopause,’’ Obstetrics & severity) menopausal somatic symptoms statistically significant change from Gynecology, 85:529–537, 1995. scores than the estrogen alone and baseline in hot flushes after treatment. 2. Hickok, L. R., C. Toomey, and L. Speroff, placebo groups. The menopausal Myers et al. (Ref. 19) conducted a 10– ‘‘A Comparison of Esterified Estrogens With somatic symptoms score evaluated a week, double-blind, placebo controlled, and Without Methyltestosterone: Effects on constellation of symptoms including hot parallel group study in 40 naturally Endometrial Histology and Serum flushes, cold sweats, , menopausal women comparing 4 Lipoproteins in Postmenopausal Women,’’ treatments: Conjugated estrogens alone, Obstetrics & Gynecology, 82:919–924, 1993. rheumatic pains, cold hands and feet, 3. Kaunitz, A. M., ‘‘The Role of Androgens breast pains, , numbness and conjugated estrogens and in Menopausal Hormonal Replacement,’’ tingling, and skin crawls. A single- medroxyprogesterone, conjugated Endocrinology and Clinics of center, double-blind randomized, 6– estrogens and androgen, and placebo. North America, 26(2):391–397, 1997. month study by Hickok, Toomey, and The study found that the estrogen and 4. ACOG Committee on Gynecologic Speroff (Ref. 2) compared the effects of estrogen/medroxyprogesterone groups Practice, ‘‘Committee Opinion: Androgen treating surgically menopausal women had significantly fewer hot flashes than Treatment of Decreased Libido,’’ 2002 with esterified estrogens alone (n=13) or the estrogen/androgen or placebo Compendium of Selected Publications, American College of Obstetricians and in combination with methyltestosterone groups. The authors concluded: ‘‘This Gynecologists, Washington, DC, pp. 5–6, (n=13) on a similar constellation of result is consistent with other studies 2002. menopausal symptoms, but found no showing no effect of androgen alone on 5. Gelfand, M. M., and B. Wiita, ‘‘Androgen statistically significant difference hot flashes’’ (Ref. 19, p. 1129). and Estrogen-Androgen Hormone

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Replacement Therapy: A Review of the of the Menopause,’’ Journal of Clinical It is the responsibility of every drug Safety Literature, 1941 to 1996,’’ Clinical Endocrinology and Metabolism, 10:1547– manufacturer or distributor to review Therapeutics, 19(3):383–399, 1997. 1558, 1950. this notice to determine whether it 6. Westaby, D. et al, ‘‘Liver Damage from 21. McNagny, S. E., ‘‘Prescribing Hormone covers any drug product that the person Long-Term Methyltestosterone,’’ Lancet, Replacement Therapy for Menopausal manufactures or distributes. Any person 2:262–263, 1977. Symptoms,’’ Annals of Internal , 7. Turani, H. et al., ‘‘Hepatic Lesions in 131(8):605–616, 1999. may request an opinion of the Patients on Anabolic Androgenic Therapy,’’ 22. Barlow, D. H. et al., ‘‘Long-Term applicability of this notice to a specific Israel Journal of Medical Sciences, 19:332– Hormone Implant Therapy—Hormonal and drug product by writing to the Division 337, 1983. Clinical Effects,’’ Obstetrics & Gynecology, of New Drugs and Labeling Compliance 8. Lucey, M. R., and R. H. Moseley, ‘‘Severe 67:321–325, 1986. (see ADDRESSES). Cholestasis Associated With 23. Rymer, J., and E. Morris, ‘‘Menopausal A request for a hearing may not rest Methyltestosterone: A Case Report,’’ Symptoms,’’ Clinical Evidence, 5: 1308–1310, upon mere allegations or denials but American Journal of Gastroenterology, June 2001. must set forth specific facts showing 82:461–462, 1987. 24. Rosenberg, M. J., T. D. N. King, and M. that a genuine and substantial issue of 9. Barrett-Connor, E. et al, ‘‘A Two-Year, C. Timmons, ‘‘Estrogen-Androgen for fact requires a hearing, together with a Double-Blind Comparison of Estrogen- Hormone Replacement: A Review,’’ Journal Androgen and Conjugated Estrogens in of Reproductive Medicine, 42(7):394–404, well-organized and full factual analysis Surgically Menopausal Women,’’ Journal of 1997. of the clinical and other investigational Reproductive Medicine, 44:1012–1020, 1999. data that the objector is prepared to 10. Raisz, L. G. et al, ‘‘Comparison of the V. Amendment prove in a hearing. Any data submitted Effects of Estrogen Alone and Estrogen Plus Based on the findings discussed in in response to this notice must be Androgen on Biochemical Markers of Bone previously unsubmitted and include Formation and Resorption in section II of this document, FDA is amending the Federal Register notice of data from adequate and well-controlled Postmenopausal Women,’’ Journal of Clinical clinical investigations as described in 21 Endocrinology and Metabolism, 81:37–43, September 29, 1976 (41 FR 43112), to 1996. reclassify estrogen-androgen CFR 314.126. This notice of opportunity for hearing 11. Gitlin, N., P. Korner, and H. Yang, combination drugs as lacking encompasses all issues relating to the ‘‘Liver Function in Postmenopausal Women substantial evidence of effectiveness for legal status of the drug products subject on Estrogen-Androgen Hormone moderate to severe vasomotor symptoms to it (including identical, related, or Replacement Therapy: A Meta-Analysis of associated with the menopause in those Eight Clinical Trials,’’ Menopause, 6(3):216– similar drug products as defined in patients not improved by estrogen 224, 1999. § 310.6), e.g., any contention that any alone. 12. Ettinger, B., ‘‘Letter: Estrogen-Androgen such drug product is not a new drug ,’’ American Journal of Drug products covered by this notice because it is generally recognized as safe Obstetrics and Gynecology, 178(3):627–628, (i.e., estrogen-androgen combination and effective within the meaning of 1998. drugs) are regarded as new drugs section 201(p) of the act or because it is 13. Phillips, E., and C. Bauman, ‘‘Safety (section 201(p) of the Federal Food, exempt from part or all of the new drug Surveillance of Esterified Estrogens- Drug, and Cosmetic Act (the act) 21 Methyltestosterone (ESTRATEST and provisions of the act under the U.S.C. 321(p)). An approved NDA is exemption for drug products marketed ESTRATEST HS) Replacement Therapy in required for marketing. the ,’’ Clinical Therapeutics, before June 25, 1938, in section 201(p) 19(5):1070–1084, 1997. VI. Notice of Opportunity for a Hearing of the act, or under section 107(c)of the 14. Kronenberg, F., ‘‘Hot Flashes: Drug Amendments of 1962, or for any Epidemiology and Physiology,’’ Annals of the Any manufacturer or distributor of a other reason. With respect to the issue New York Academy of Sciences, 592:52–86, drug product affected by this notice is of effectiveness, however, this notice is 1990. hereby offered an opportunity for a limited to whether there is substantial 15. Sherwin, B., and M. Gelfand, hearing to show why estrogen-androgen evidence of the effectiveness of ‘‘Differential Symptom Response to combination drugs should not be Parenteral Estrogen and/or Androgen estrogen-androgen combination drug reclassified as lacking substantial products for the treatment of moderate Administration in the Surgical Menopause,’’ evidence of effectiveness for moderate American Journal of Obstetrics and to severe vasomotor symptoms Gynecology, 151(2):153–160, 1985. to severe vasomotor symptoms associated with the menopause in those 16. Barrett-Connor, E., ‘‘Efficacy and Safety associated with the menopause in those patients not improved by estrogen of Estrogen/Androgen Therapy,’’ Journal of patients not improved by estrogen alone. The use of these drug products Reproductive Medicine, 43(8–Suppl.):746– alone. for any indication other than for the 752, 1998. This notice applies to the particular treatment of moderate to severe 17. Sarrel, P. et al., ‘‘Estrogen and Estrogen- estrogen-androgen combination drugs vasomotor symptoms associated with Androgen Replacement in Postmenopausal named in this notice and to any the menopause in those patients not Women Dissatisfied with Estrogen-Only identical, related, or similar drug Therapy,’’ Journal of Reproductive Medicine, improved by estrogen alone will not be 43(10):847–856, 1998. product under § 310.6 (21 CFR 310.6), considered in this proceeding. 18. Burger, H. et al., ‘‘The Management of whether or not it is the subject of an Any person subject to this notice who Persistent Menopausal Symptoms with approved NDA or ANDA. Estrogen- decides to seek a hearing shall file: (1) Oestradiol-Testosterone Implants: Clinical, androgen combination drugs subject to On or before May 14, 2003, a written Lipid and Hormonal Results,’’ Maturitas, this notice include, but are not limited notice of appearance and request for 6:351–358, 1984. to, the following combination drugs: hearing, and (2) on or before June 13, 19. Myers, L. S. et al., ‘‘Effects of Estrogen, fluoxymesterone and ethinyl estradiol; 2003, the data, information, and Androgen and Progestin on Sexual diethylstilbestrol and analyses relied on to demonstrate that Psychophysiology and Behavior in methyltestosterone; chlorotrianisene there is a genuine issue of material fact Postmenopausal Women,’’ Journal of Clinical Endocrinology and Metabolism, 70(4):1124– and methyltestosterone; testosterone to justify a hearing. Any other interested 1131, 1990. enanthate and estradiol valerate; person may also submit comments on 20. Greenblatt, R. B. et al., ‘‘Evaluation of testosterone cypionate and estradiol this notice. The procedures and an Estrogen, Androgen, Estrogen-Androgen cypionate; and esterified estrogens and requirements governing this notice of Combination, and a Placebo in the Treatment methyltestosterone. opportunity for a hearing, a notice of

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appearance and request for a hearing, All submissions under this notice of ACTION: Notice. information and analyses to justify a opportunity for a hearing are to be filed hearing, other comments, and a grant or in four copies. Except for data and SUMMARY: The Food and Drug denial of a hearing are contained in information prohibited from public Administration (FDA) is withdrawing § 314.200 (21 CFR 314.200) and in 21 disclosure under 21 U.S.C. 331(j) or 18 approval of one new drug application CFR part 12. U.S.C. 1905, the submissions may be (NDA) and four abbreviated new drug The failure of any person subject to seen in the Dockets Management Branch applications (ANDAs). The holders of this notice to file a timely written notice (address above) between 9 a.m. and 4 the applications notified the agency in of appearance and request for hearing, p.m., Monday through Friday. writing that the drug products were no as required by § 314.200, constitutes an This notice is issued under the election by that person not to use the longer marketed and requested that the Federal Food, Drug, and Cosmetic Act approval of the applications be opportunity for a hearing concerning the (secs. 502, 505, 21 U.S.C. 352, 355) and withdrawn. action proposed and a waiver of any under authority delegated to the contentions concerning the legal status Director of the Center for Drug EFFECTIVE DATE: May 14, 2003. of that person’s drug product(s). Any Evaluation and Research (21 CFR 5.100). new drug product marketed without an FOR FURTHER INFORMATION CONTACT: approved new drug application is Dated: April 4, 2003. David T. Read, Center for Drug subject to regulatory action at any time, Janet Woodcock, Evaluation and Research (HFD–7), Food but any person subject to this notice Director, Center for Drug Evaluation and and Drug Administration, 5600 Fishers Research. who files a timely written notice of Lane, Rockville, MD 20857, 301–594– appearance and request for hearing and [FR Doc. 03–9065 Filed 4–10–03; 8:45 am] 2041. who remains a party to this proceeding BILLING CODE 4160–01–S will not be subject to regulatory action SUPPLEMENTARY INFORMATION: The for matters covered by this notice until holders of the applications listed in the the conclusion of this proceeding. If it DEPARTMENT OF HEALTH AND table in this document have informed conclusively appears from the face of HUMAN SERVICES FDA that these drug products are no the data, information, and factual Food and Drug Administration longer marketed and have requested that analyses in the request for hearing that FDA withdraw approval of the there is no genuine and substantial issue [Docket Nos. 98N–0718 and 76N–0377] applications. The applicants have also, of fact to justify a hearing, or if a request by their requests, waived their for hearing is not made in the required Pharmacia & Upjohn et al.; Withdrawal opportunity for a hearing. format or with the required analyses, the of Approval of One New Drug Commissioner of Food and Drugs will Application and Four Abbreviated New enter summary judgment against the Drug Applications person(s) who requests the hearing, making findings and conclusions, and AGENCY: Food and Drug Administration, denying a hearing. HHS.

Application No. Drug Applicant

NDA 17–968 Depo-Testadiol (testosterone cypionate and Pharmacia & Upjohn Co., 7000 Portage Rd., ) Injection, 50 milli- Kalamazoo, MI 49001–0199. grams/milliliter (mg/mL) and 2 mg/mL.

ANDA 85–603 Testosterone Cypionate-Estradiol Cypionate Steris Laboratories, Inc., 620 North 51st Ave., Injection. Phoenix, AZ 85043–4706.

ANDA 85–860 Testosterone Enanthate and Estradiol Val- Do. erate Injection, 180 mg/mL and 8 mg/mL.

ANDA 85–865 Testosterone Enanthate and Estradiol Val- Do. erate Injection, 90 mg/mL and 4 mg/mL.

ANDA 86–423 Ditate-DS (testosterone enanthate and estra- Savage Laboratories, 60 Baylis Rd., Melville, diol valerate) Injection, 180 mg/mL and 8 NY 11747. mg/mL.

The applications listed in the table in estrogen-androgen combination listed in this notice were withdrawn for this document, all estrogen-androgen products specifically named in the reasons of safety or effectiveness. combination products, were submitted notice proposing to amend the 1976 Therefore, under section 505(e) of the following a finding by the FDA notice, as well as of any products that Federal Food, Drug, and Cosmetic Act published in the Federal Register of are identical, related, or similar (21 U.S.C. 355(e)) and under authority September 29, 1976 (41 FR 43112). (including but not limited to the five delegated to the Director, Center for Elsewhere in today’s issue of the products listed in this notice). The Drug Evaluation and Research (21 CFR Federal Register, FDA is initiating a agency, therefore, is deferring until the 5.105), approval of the applications proceeding in which it proposes to outcome of that proceeding the listed in the table in this document, and amend the 1976 notice. That proceeding determination, under § 314.161 (21 CFR all amendments and supplements will determine if there is substantial 314.161), of whether the five products thereto, is hereby withdrawn, effective evidence of effectiveness of the May 14, 2003.

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