ARCHER, DAVID F. MD
The use of contraceptive modalities has continued to grow both in the United States and internationally. This reflects change in economics with the increase in family income and need to reduce the costs associated with childbearing and childrearing. Within the past 2 years, (and within the next 1 to 2 years we are going to see) we have seen an increasing number of new contraceptive modalities available in the United States marketplace. Many of these are nothing more than new delivery systems for existing steroidal hormones. Several new spermicidal compounds that appear to have both virucidal and bactericidal activity are undergoing clinical trials. This overview provides the reader with some of the new products that are or will be available and their use-effectiveness, and, in some instances, side effect profiles.
NEW PROGESTATIONAL AGENTS
We have introduced in the United States the use of desogestrol and norgestimate as progestational agents in oral contraceptive formulations. 1,2 These products have undergone some changes in terms of their delivery. Specifically, desogestrel and levonorgestrel have joined norethindrone acetate and are currently available in 20-μg ethinyl estradiol (EE) formulations. An exception to the rule of 21 days of hormone and 7 days of placebo is 150 μg of desogestrel, which has 21 days of 20 μg of EE, 2 days of placebo, and 5 days of 10 μg EE in a 28-day pack. This latter product, known as Mircette (Organon, West Orange, NJ), is designed to reduce the incidence of escape ovulation and to reduce midcycle breakthrough bleeding. The addition of the extra days of EE neither increases the effectiveness nor improves the occurrence of breakthrough bleeding. The bridge of the extra days of EE is of interest because there is a move to an increased duration of use of the combination oral contraceptives.
A possible new product is undergoing a current clinical trial in the United States. It contains 30 μg of EE with 150 μg of levonorgestrel, known as Seasonale. Seasonale is designed to extend the duration of the active steroidal medication to between 8 to 12 weeks. This reduces the number of bleeding episodes (menses) to approximately four per year. The use of a continuous EE and progestin has been described in the past. The major problem with this approach has been the erratic onset of escape or breakthrough bleeding that occurs sometime after 6 to 7 weeks of continued use. 3,4 The extent of vaginal bleeding with this new product remains to be seen.
A new progestin, drospirenone, coupled with EE has been investigated in the United States. 5 This progestational agent is a derivative of spironolactone. Drospirenone has a progestational, antimineralocorticoid, and antiandrogenic activity. The combination oral contraceptive contains 3 mg of drospirenone and 30 μg of EE and is called Yasmin (Berlex Laboratories, Montville, NJ). The pearl index of drospirenone with EE in the US clinical trial was 0.407, and the bleeding profile in this published report appeared to be acceptable, with breakthrough bleeding alone for all cycles occurring in 1% and spotting alone in 9.3% of the cycles.
Ethinyl estradiol/drospirenone is reported to have minimal influence on body weight over the course of the clinical trial. More recently, in a placebo-controlled study investigating the effects on acne (20 μg of EE and 100 μg of levonorgestrel [Alesse; Wyeth-Ayerst Laboratories, St. David’s, PA]), no difference in weight gain between the active oral contraceptive and the placebo was found during a 6-month period. 6 The actual weight gain with placebo was 1.2 kg over the course of the 6-month period of time, which was equivalent to 1.2 kg of weight gain in the group using 20 μg of EE with 100 μg of levonorgestrel. These data indicate that the combination oral contraceptive formulations currently available on the US market do not significantly increase weight of the average consumer.
PROGESTIN ONLY IMPLANTS
Although the six-rod Norplant system is currently available, it continues to have only a small niche in the United States market. Women are particularly happy with the extended duration of action and the low-motivation associated with its use-effectiveness.
Norplant II, which is two covered rods that contain levonorgestrol, has been approved by the US Food and Drug Administration. The difference in Norplant II compared with Norplant is that there are only two rods, which are slightly longer, but there is no difference in diameter, with a release profile and clinical use-effectiveness providing 3 years of contraception. 7 Whether this product will be marketed in the United States at the present time remains to be seen.
A second implant, with a duration of action of 3 years, contains 3-ketodesogestrol (69 mg of etonogestrel). It is called Implanon (Organon, The Oss, Netherlands). This product has undergone clinical trials in the United States and in Europe. The European trials show that it has a high level of effectiveness with almost complete suppression of ovulation. During a 3-year trial period, no pregnancies were found in the women in this trial. 8 No serious adverse effects were found, but there were bleeding changes that appeared to be similar to those reported with the use of Norplant. The convenience factor of one implant versus six implants in terms of insertion and removal is obvious.
INJECTABLE MONTHLY PROGESTIN/ESTROGEN
A monthly injectable combining estradiol valerate and medroxyprogesterone acetate (Lunelle; Pharmacia, Peapack, NJ) has been approved in the United States. The pregnancy rate is less than 1.0 per 100 woman-years of use. A monthly withdrawal-bleeding pattern has been found. The withdrawal-bleeding episode occurs 2 weeks after the injection, which corresponds to the elimination pattern of the estradiol valerate. This slight change in bleeding patterns appears to be acceptable to the consumer. 9 An extensive discussion of this product by Dr. Andrew Kaunitz is elsewhere in this symposium.
We currently have Progestasert and the copper T 380 A Paragard (Ortho Pharmaceutical, Raritan, NJ) as available intrauterine devices. A new intrauterine delivery system releasing 20 μg of levonorgestrel per day, known as Mirena (Berlex Laboratories, Montville, NJ), is pending approval. This product is T-shaped and has levonorgestrel contained in the long-arm of the “T.” Mirena has a use-effectiveness of 5 years, with pregnancy rates of 0.71 (pearl index) cumulative over the course of a 5-year period. An advantage of this medicated intrauterine device is a decrease in menstrual blood loss, although there is some irregular bleeding during the first 12 months of use. Many of the women become totally amenorreic after 12 months of use of the medicated intrauterine device.
A unique approach is the administration of hormones through the skin. A transdermal contraceptive delivery system releasing 20 μg of EE per day and norestromin (17 diacetyl norgestimate) has been developed and is known as Evra (Ortho Pharmaceuticals). Evra has undergone clinical trials in the United States and has been reported to have an excellent bleeding profile. The use effectiveness was high, with no follicle greater than 12 mm on ultrasound scanning being reported during the course of a 2-month study. 16 The transdermal system is used for 7 days per week, with 3 weeks of use and 1 week of nonuse. Compliance was 83% in the clinical trial. There was little breakthrough bleeding with this system. These data indicated that the breakthrough bleeding that occurs with combination oral contraceptive use could be related to the pharmacokinetic profile of the steroids in combination oral contraceptive preparations. The transdermal system that delivers a stable blood level of hormones appears to have a much-improved bleeding profile.
An intravaginal ring releasing 60 μg of EE per day and 120 μg of 3-ketodesogestrol has been developed; it is called the Nuva Ring (Organon). This device is designed to have a monthly insertion or a 3-week use with removal for 1 week. It has been shown in clinical trials to have an effective contraceptive approach with, again, low-levels of breakthrough bleeding. 10 This product is not yet on the United States market, although clinical trials in the United States have been completed.
Diaphragm-like or barrier devices represent less than 5% of contraceptives. Barrier contraceptives were at one time thought to deliver their efficacy through obstructing sperm transport through the vagina and into the cervix. Barrier devices are more effective when used with a spermicide. All barrier contraceptives at the present time are to be used with a spermicide, commonly some form of nonoxynol-9, a surface-active detergent.
The Contraceptive Research and Development program (CONRAD, Roslynn, VA) has undertaken multicenter clinical trials of two new barrier devices: Lea’s contraceptive and FemCap. Both of these products have contraceptive failure rates with pearl indexes of approximately 12, comparable with that found with other barrier devices. 11,12 Both devices require the concomitant use of a spermicide.
Lea’s contraceptive is a device designed to fit in the upper part of the vagina and is to be worn for 48 hours. The advantage of the Lea’s contraceptive was thought to be a valve at the base of the device that would allow egress of uterine or cervical fluids, allowing it to maintain itself in place for a longer period of time than that of a standard diaphragm. 12 However, it appears most effective when it is used for no more than 48 hours, based on concerns with the possible colonization of bacteria in the vagina.
FemCap, however, is designed to be obtained over-the-counter. It comes in two sizes that are used based on the obstetric history of the individual patient. 13 The FemCap does not require fitting such as is performed with the standard diaphragm, and it can be used whether the individual is nulliparous or parous and with or without a vaginal delivery. The two sizes attempt to embrace a wide range of cervical sizes and shapes. The device is made of silicone and should fit easily over the cervix. Both of these devices have undergone clinical trial for safety and efficacy and are pending Food and Drug Administration approval in the United States.
Contraceptive spermicide is a topic that has seen a sudden increase of activity. This is because of the fact that there has been concern with the use of nonoxynol-9, a surface-active detergent. Recent reports have indicated that a spermicide used in sexually active individuals throughout the menstrual cycle has a pregnancy rate of approximately 26%. 14 Nonoxynol-9 has been reported in prostitutes to result in an increase in the heterosexual transmission of HIV. 17 The exact mechanism of how this occurs is unknown. It should be stressed that these women are exposed to an increased frequency of coital activity with multiple partners. These partners may have large differences in the shedding of the HIV in their ejaculate. At the present time, recommendations in the United States for the average consumer who is not having intercourse with a partner at-risk for HIV and other disease would be that nonoxynol-9 is safe for use. Several other products undergoing development have a variety of names, such as C31G, polystyrene sulfate, and cellulose sulfate. These products have been found to have bactericidal and virucidal activity in vitro and are undergoing development at the present time in phase I and phase II clinical trials.
Another product known as BufferGel is designed to decrease the vaginal acidity and maintain the vaginal pH in the presence of the alkaline ejaculate. This product has also undergone preliminary clinical trials for safety and efficacy. 15
New contraceptive modalities that are being introduced into the US marketplace reflect many changes in the delivery of existing steroidal products. These products are available now not only as oral medications but also as transdermal, intravaginal, intrauterine, and implantable or injectable devices. Each of these has its own unique profile and enhances the ability of consumers to pick and choose the product that is most acceptable to them.
However, development of new barrier contraceptives, particularly those that have the potential to reduce the heterosexual transmission of HIV or to reduce a bacterial infection such as Chlamydia or Neisseria gonorrhea, continues to be moving forward in clinical trials. These products can have a lower efficacy compared with the steroidal products but, because of their other benefits, may be of significant medical use.
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17. Van Damme L. Abstract presented at International Meeting on HIV, Durban, South Africa, June 20, 2000.
© 2001 Lippincott Williams & Wilkins, Inc.