Contraceptive options to seek FDA approval
Monthly injectable, IUS move toward acceptance
Pending their approval by the U.S. Food and Drug Administration, two contraceptive methods, the combined monthly injectable and the levonorgestrel intrauterine system (IUS), soon may be available to American women.
Pharmacia & Upjohn of Bridgewater, NJ, has filed an amended New Drug Application with the FDA for Lunelle, a combined hormonal injection method, confirms Kristin Elliott, public relations director for the company’s diversified products division.
The amended application includes information from a recently completed clinical trial, whose findings were scheduled to be presented at the annual Clinical Meeting of the American College of Obstetricians and Gynecologists in Philadelphia in May. (For details on the clinical trial, see Contracep tive Technology Update, January 1998, p. 3.)
"We are very hopeful that the chronology on this will move forward, that we would receive an approval as early as this fall, and the launch would follow that," says Elliott.
Berlex Laboratories of Wayne, NJ, is evaluating the levonorgestrel IUS and expects to file with the FDA later this year, says Wendy Neininger, company director of corporate communications. Berlex is an American subsidiary of Schering AG, a global pharmaceutical company in Berlin, Germany. Schering acquired the levonorgestrel IUS technology when it purchased the Finnish company Leiras Oy in 1996. Leiras and the New York City-based Population Council served as co-developers of the hormonal contraceptive device.
Neininger declined to give a time frame for the company’s filing with the FDA. While the levonorgestrel IUS is approved for use in other companies, such approval does not mean an automatic endorsement from the U.S. regulatory agency, she notes.
Different from Depo
Family planners may recognize Lunelle as Cyclofem, which was developed by the United Nations Development Programme/United Nations Population Fund/World Health Organ ization/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction in Geneva, Switzer land. The drug contains 25 mg of depot medroxyprogesterone acetate (Depo-Provera, or DMPA) and 5 mg of estradiol cypionate, and it is administered once a month via injection.
Pharmacia & Upjohn, which holds U.S. marketing rights to the drug, filed its original application with the FDA in September 1997. The amended application now contains the results of the U.S. clinical trial, which enrolled more than 1,160 women in more than 40 sites.
Lunelle administered monthly
In amending the new drug application, Pharmacia & Upjohn also changed the brand name of the drug from Cyclo-Provera to Lunelle. The name change offers a clear distinction from DMPA, another method marketed by the company, and the new monthly injectable.
DMPA and Lunelle are very different drugs, notes Elliott. DMPA is a progestin-only method and is administered four times a year. Lunelle contains both an estrogen and a progestin and is administered on a monthly basis. While Lunelle contains the same progestin as DMPA, the dose received over time is much lower. (Read more about monthly combined injectables in CTU, June 1996, p. 71.)
Medical eligibility criteria issued by the World Health Organization (WHO) in Geneva, Switzerland, lists Cyclofem as appropriate for most women who want effective, reversible contraception and who are not at risk for most cardiovascular complications.1 Its estrogen has a shorter lifespan and is less potent than those found in combined oral contraceptives, so its restrictions vary somewhat from those for oral contraceptives.
For example, the WHO guidelines say the advantages outweigh the risks for smokers under age 35 or for light smokers over 35, as well as for those with mild hypertension (blood pressure below 160/100), current or medically treated gallbladder disease, or mild cirrhosis (compensated). However, the WHO states that the risks outweigh the advantages for heavy smokers (more than 20 cigarettes daily) over 35, those with a history of hypertension or blood pressure 160/100 or 180/110, and those with severe cirrhosis (decompensated), or liver tumors (benign).
Contraceptive efficacy is extremely high with Lunelle, with failure rates of approximately 0.2%,2 says Andrew Kaunitz, MD, professor and assistant chair of the Department of OB/GYN at the University of Florida Health Sciences Center in Jacksonville. In contrast to DMPA, users often experience regular cycles2 and a rapid return to fertility,3 he notes.
Multiple benefits of IUS
The levonorgestrel IUS, marketed as the Mirena in European and Asian countries, is a T-shaped device with a hollow barrel filled with 52 mg of levonorgestrel. The device is approved for five years in the markets in which it is now available. (CTU provided a complete overview of the IUS in January 1997, p. 4.)
Aside from providing exceptional contraception, the levonorgestrel IUS has several exciting potential therapeutic applications, says David Grimes, MD, vice president of biomedical affairs at Family Health International in Research Triangle Park, NC.
"It has been shown to be effective in treating idiopathic menorrhagia [heavy bleeding]4 as well as dysfunctional uterine bleeding [without underlying pathology].5 It has been found useful in treating abnormal bleeding associated with adenomyosis of the uterus," he says.6
In addition, the levonorgestrel IUS has been used as part of hormone replacement therapy, providing the progestin directly to the endometrium, rather than systemically, Grimes says.7
References
1. Program for Appropriate Technology in Health. WHO eligibility criteria for contraceptive use: Combined injectables and sterilization. Outlook 1996; May:2-3.
2. Hall PE. New once-a-month injectable contraceptives, with particular reference to Cyclofem/Cyclo-Provera. Int J Gynaecol Obstet 1998; 62 Suppl 1:S43-56.
3. Bahamondes L, Lavin P, Ojeda G, et al. Return of fertility after discontinuation of the once-a-month injectable contraceptive Cyclofem. Contraception 1997; 55:307-310.
4. Irvine GA, Campbell-Brown MB, Lumsden MA, et al. Randomised comparative trial of the levonorgestrel intra uterine system and norethisterone for treatment of idiopathic menorrhagia. Br J Obstet Gynaecol 1998; 105:592-598.
5. Lahteenmaki P, Haukkamaa M, Puolakka J, et al. Open randomised study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy. BMJ 1998; 316:1,122-1,126.
6. Fedele L, Bianchi S, Raffaelli R, et al. Treatment of adenomyosis-associated menorrhagia with a levonorgestrel-releasing intrauterine device. Fertil Steril 1997; 68:426-429.
7. Suhonen S, Holmstrom T, Lahteenmaki P. Three-year follow-up of the use of a levonorgestrel-releasing intrauterine system in hormone replacement therapy. Acta Obstet Gynecol Scand 1997; 76:145-150.
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