The effect of fluconazole on circulating ethinyl estradiol levels in women taking oral contraceptives.

OBJECTIVE: This open-label, two-period, crossover study was conducted to evaluate the effect of a single 150 mg dose of fluconazole on the pharmacokinetics of ethinyl estradiol in healthy female subjects. STUDY DESIGN: Ten subjects regularly taking Ortho-Novum 7/7/7 (Ortho Pharmaceutical, Raritan, N.J.) and 10 subjects regularly taking Triphasil (Wyeth-Ayerst Laboratories, Philadelphia), which contain ethinyl estradiol 35 microg and 30 microg during days 1 to 6, respectively, were randomly assigned to receive a single 150 mg dose of fluconazole 2 hours before the oral contraceptive, on pill day 6 of one of two menstrual cycles. Ethinyl estradiol serum concentrations were measured at baseline and up to 24 hours after oral contraceptive intake. No fluconazole was administered during the other menstrual cycle, which served as the control. RESULTS: Mean serum concentrations of ethinyl estradiol were increased after fluconazole administration in both oral contraceptive groups. Maximum observed serum concentration and area under the concentration-time curve values were significantly (p < 0.05) greater during the fluconazole regimens (vs regimens without fluconazole) for both oral contraceptive groups and for combined values of the two oral contraceptive groups. The mean time to reach the maximum concentration was not altered by concomitant fluconazole administration. CONCLUSIONS: These findings suggest that there is a potential for a clinically significant interaction between coadministration of fluconazole and ethinyl estradiol in oral contraceptives.

PIP: The effect of a single dose of the imidazole antifungal agent fluconazole on circulating ethinyl estradiol levels in oral contraceptive (OC) users was investigated in an open-label, two-period, crossover study. 10 regular users of Ortho-Novum 7/7/7 and 10 women regularly taking Triphasil were randomly assigned to receive 150 mg of fluconazole 2 hours before OC ingestion on pill day 6 of one of two menstrual cycles. Mean serum concentrations of ethinyl estradiol were increased after fluconazole administration in both OC groups. Maximum observed serum concentration and area under the concentration time curve values were significantly greater during the fluconazole cycle for both OC groups and for the combined values of the two groups (p 0.05). The mean time to reach the maximum concentration was not altered by concomitant fluconazole administration. Mean serum ethinyl estradiol concentrations were greater at all time points in Ortho-Novum 7/7/7 users than Triphasil users. These findings suggest there is potential for a clinically significant drug interaction between co-administration of fluconazole and ethinyl estradiol. The most likely site of this drug interaction is the hepatic cytochrome P450 enzyme system. Since a single dose of 150 mg of fluconazole is standard treatment for common vaginal yeast infections, such concomitant therapy is likely in OC users at some point and its implications should be considered by prescribing clinicians.

Peripheral progesterone (P) levels and endometrial response to various dosages of vaginally administered P in estrogen-primed women.

OBJECTIVE: To compare the pharmacokinetics and pharmacodynamics of 100 mg/d, 200 mg/d, and 400 mg/d (200 mg two times per day) of P administered vaginally for 14 days to estrogen-primed postmenopausal women. DESIGN: Randomized, open-label, three-way crossover study. SETTING: Two university-based investigative sites. PATIENT(S): Twenty healthy postmenopausal women with histologically normal endometria. INTERVENTION(S): Oral 17 beta-E2 was given each day of a 28-day cycle; a P vaginal suppository was inserted daily according to the randomization schedule during days 15-28 of each cycle; blood samples were collected; an endometrial biopsy was obtained on day 25; and patients were crossed over to the next treatment cycle after a washout period of at least 30 days. MAIN OUTCOME MEASURE(S): Mean P blood levels, endometrial dating/conversion. RESULT(S): There was good vaginal absorption of P for all dosages. Endometrial conversion occurred in all 200- and 400-mg/d P-dosed cycles, whereas the 100-mg/d dosage failed to convert primed endometria consistently. There also was a significantly increased tendency for earlier bleeding and spotting with the 100-mg/d dosage. CONCLUSION(S): Both the 200- and 400-mg/d dosage regimens consistently convert an estrogen-primed endometrium, and yield appropriate endometrial dating and bleeding patterns. However, the 400-mg/d dosage attains the highest sustained blood levels and may be the best dosage regimen for further study.

Lack of interaction between magnetic resonance imaging and the copper-T380A IUD.

To determine if the CuT380A (ParaGard) IUD is affected by magnetic resonance imaging (MRI), in vitro studies utilizing a CuT380A IUD (ParaGard), a copper-bearing IUD, and a Signa 1.5T HR system were used to evaluate whether the dynamic magnetic forces generated by the MRI resulted in movement, torque, or heat when the IUD was exposed to the magnetic field generated by the MRI. There was no deflection, turning motion (torque), or temperature change when the IUD was exposed to a magnetic field. There appears to be no reason to exclude women with IUDs of the type examined from an MRI system or its environs.

Irregular bleeding, body mass index and coital frequency in Norplant contraceptive users.

Seventy-five women with a mean age of 27.5 years who requested Norplant implants for contraception were studied over a five-year period. The patients kept daily diaries of their vaginal bleeding and coital frequency, and were seen at least every six months at which time their weight was measured. This study examines the impact of Norplant implants use on menstrual regularity, body mass index and coital frequency. Irregular bleeding was most prevalent during the first two years of Norplant implants use and accounted for the primary reason for discontinuation of this method. No increase in Body Mass Index (BMI) was noted in Norplant implants users over the five-year study period. Women with irregular bleeding did not have a higher or lower BMI compared to women with regular bleeding and irregular bleeding patterns did not impact on coital frequency. Over five years, four pregnancies occurred during Norplant implant use. Norplant implants are a highly effective contraceptive method and women using this method should not expect an increase in body weight. Irregular bleeding is most frequent during the first two years of use and menstrual cyclicity resumes in the majority of women by the third year of use and continues to the fifth year of use.

PIP: Medical researchers recruited 75 women to participate in a 5-year prospective study of Norplant use that examined their bleeding patterns, changes in Body Mass Index (BMI), the effect BMI had on the bleeding pattern, and the effect irregular bleeding had on coital frequency. Clinicians took a complete medical and sexual history and performed a physical and pelvic examination. Follow up visits occurred at 1, 3, 6, and 12 months after insertion of the Norplant contraceptive implant and every 6 months thereafter until removal at 5 years. The clients maintained a daily record of coital activity and bleeding/spotting patterns. Thirty women completed 5 years of Norplant use. Irregular bleeding occurred most frequently during the 1st 2 years of Norplant use. Its frequency decreased as duration of Norplant use increased. For example, 22.35% of the women experienced spotting and bleeding between menstrual periods in the 1st year, 12.25% in the 2nd year, and 3.1% at 5 years. BMI was similar for women with and without irregular bleeding patterns. BMI did not change significantly over the 5 years. Irregular bleeding did not affect coital frequency. The mean coital frequency for the women was 18-20 acts of sexual intercourse per month. Irregular bleeding (32%) and planned pregnancy (12%) were the leading reasons for discontinuation of Norplant. Most of the women who quit using Norplant for irregular bleeding reasons did so during the 1st 2 years. Just 5 pregnancies occurred during Norplant use. These results suggest that clinicians should adequately counsel potential Norplant users about irregular bleeding to reduce discontinuation for irregular bleeding.

Future directions in contraception.

Although contraceptive research has markedly decreased in the United States, it has continued in other countries. The emphasis has been on the development of long-acting, noncoitally related contraceptives, including the progestogen-only and progestogen-estrogen vaginal rings. The levonorgestrel-releasing intrauterine device is highly effective and, like other contraceptives, may contribute to a decrease in the incidence of pelvic inflammatory disease. There is a great need for more effective, acceptable barrier contraceptives. The vaginal condom does not appear to be acceptable to many couples. Studies continue to demonstrate couples' lack of adherence to plans for abstinence and poor utilization of the present barrier contraceptives. The potential for the development of a male contraceptive utilizing gonadotrophin hormone-releasing hormone agonists or antagonists in conjunction with testosterone may hold promise in the future.

Noncontraceptive health benefits and risks of steroidal contraception.

PIP: From the extensive research conducted over the past 28 years, there is a clear picture that the noncontraceptive benefits of steroidal contraceptives are considerable and the benefits outweigh the risks. The risks associated with the increased incidence of thromboembolic disease have reduced with lower doses of both estrogen and progesterone. Also, the increased risk of hepatocellular carcinoma is very low, compared with the benefits. One benefit is the reduction in primary dysmenorrhea which was discovered in 1940. This occurs due to the suppression of ovulation and decrease in endometrial growth. Ovarian cysts resolve spontaneously; 3500 fewer hospitalizations due to ovarian cysts are reported for 1982. 11,000 fewer cases of ectopic pregnancy/year are a result of oral contraceptive (OC) use. Retrospective case studies have found that pelvic inflammatory disease (PID) is prevented by use of OCs. This happens because the cervical mucus remains thick throughout the menstrual cycle with OC use, and thus prevents transportation of bacteria by sperm from the lower to the upper genital tract. Another reason is the decreased amount of blood flow at the time of withdrawal provides a less conducive environment for bacteria growth. 15,000 annual hospitalizations for PID are estimated to have been prevented by OC use. The data on breast cancer are conflicting, but most do not show a link between OCs and breast cancer. In fact, benign breast disease may be reduced by 23,000 annual hospitalizations due to OC use. Another benefit of OC use is the decreased incidence of endometrial and ovarian cancer. The relative risk among OC users in 1987 was estimated at P = 0.6 for primary endometrial cancer. This beneficial effect continues after OC use is discontinued. There is a 40% reduction in the incidence of ovarian cancer among OC users compared with nonusers, and is related to duration of use, but the protective effect continues after OC use discontinuation. Bone mass is increased in women who use OCs, although further study is required to determine whether the increased bone mass protects from osteoporosis after menopause.^ieng

Oral contraceptives: significance of their effects in man and relationship to findings in animal models.

Combination oral contraceptives have been available since 1960. They contain both an estrogen and a progestogen and have been studied extensively in both lower animals and humans and have been the subject of special regulatory requirements for toxicological and clinical studies. The initial oral contraceptives, by today's standards, contained very high levels of both hormones. There has been a continuous decrease in the dose of both the estrogen and the progestogen during the past quarter century, with continued maintenance of high degree of effectiveness. This decrease of dosage has been stimulated by findings from prospective clinical trials and retrospective case control trials. As additional information has been gained with oral contraceptives, new benefits beyond their effectiveness as contraceptives have been realized. Today's oral contraceptives provide a high degree of effectiveness, low incidence of nuisance side effects, and low incidence of major adverse effects.

PIP: A historical review of the 28-year history of oral contraceptives from the viewpoint of correlation or lack thereof between drug toxic and pathologic effects seen in laboratory animals and those seen clinically is presented. Early high dose pills were expected to cause growth of uterine fibroids, but instead they had the unexpected effect of an estrogen dose-related venous thrombosis risk. Work on rats predicted that pills would cause liver cancers, but instead to slightly increase the incidence of being liver adenomas in women. Similarly, rat research predicted pituitary microadenomas. Pituitary effects in women, while rare, are thought to be due to prescription of pills to women with irregular cycles of pituitary origin. Progestins of the 17-acetoxy series were considered likely to produce breast cancers, as they had in beagle dogs. They apparently have not done so in women. They were reports in the mid-1970s that sequential pills containing 100 mcg ethinyl estradiol cause endometrial carcinoma. These pills have been discontinued. Recent evidence has been accumulating that low-dose pills containing levonorgestrel increase blood pressure and possible LDL-cholesterol. Risk of death from vascular disease, however, seems to be concentrated in women who smoke, especially those over 35.

A double-blind, placebo-controlled study comparing three single-dose regimens of piroxicam with ibuprofen in patients with primary dysmenorrhea.

Sixty-eight women with primary dysmenorrhea were randomly assigned to one of five four-times-daily treatment groups for a minimum of three days and a maximum of five days. Three of the groups received different initial single-daily doses of piroxicam, which were followed on each treatment day with placebo for the second through fourth doses, namely, piroxicam 20 mg daily for five days (piroxicam 20 mg for five days); piroxicam 40 mg on Day 1, followed by piroxicam 20 mg on Days 2 through 5 (piroxicam 40 mg for one day); and piroxicam 40 mg on Days 1 and 2, followed by piroxicam 20 mg on Days 3 through 5 (piroxicam 40 mg for two days). The fourth group received ibuprofen 400 mg four times per day, and the fifth group received placebo four times per day. Patients determined the severity of overall discomfort and pelvic-abdominal pain at baseline and prior to each dose using a four-point numerical scale. Supplemental ibuprofen, 400 mg four times per day, was provided for those patients requiring additional pain relief. Patients also made a global determination of overall relief at the end of the study. At 24 hours, the results revealed that piroxicam 40 mg for two days, piroxicam 20 mg for five days, and ibuprofen provided significantly more relief of overall discomfort compared with placebo (p = 0.003, p = 0.018, and p = 0.026, respectively). All four active treatment groups also experienced significantly more relief of pelvic-abdominal pain compared with placebo: piroxicam 40 mg for two days followed by three days of 20 mg (p = 0.002), piroxicam 40 mg for one day followed by four days of 20 mg (p = 0.023), piroxicam 20 mg for five days (p = 0.012), and ibuprofen (p = 0.011). A significantly smaller percentage of patients treated with piroxicam 40 mg for two days required supplemental medication as compared with those treated with piroxicam 20 mg for five days (p = 0.035) and patients treated with placebo (p = 0.010). A greater amount of overall relief was obtained by patients treated with piroxicam 40 mg for two days compared with patients treated with piroxicam 40 mg for one day (p = 0.041) and placebo-treated patients (p = 0.001). It was concluded that single daily doses of piroxicam 20 mg and 40 mg were as effective as ibuprofen, 400 mg four times per day, for the relief of primary dysmenorrhea.

Norplant contraceptive implants: rods versus capsules.

Norplant contraceptive implants are silastic implants containing levonorgestrel. When placed subcutaneously in the medial aspect of the upper arm, they release low levels of levonorgestrel in a constant manner over an extended period of time. Comparative studies of two silastic rods versus six capsules containing levonorgestrel were studied in 250 subjects for 4,464 months of use. Only one pregnancy occurred during the study. Side effect patterns were similar in both groups; the major side effect being irregular uterine bleeding. The bleeding, however, was well tolerated by subjects in both groups and discontinuation rate was very low. The two-rod system offers the advantages of easier insertion technique and shorter insertion time as well as ease of removal as compared to the six-capsule system. Norplant contraceptive implants offer a highly effective means of contraception which is particularly suited for women who are concerned about failure and compliance with oral contraceptives. This type of contraception should become well accepted, not only in underdeveloped countries, but in developed countries as well.

PIP: The efficacy and side effects of Norplant contraceptive implants (6 capsules) versus silastic rods were compared in 250 women for 4464 months of use. Both systems were found to be highly effective and well tolerated. There was only 1 pregnancy, and this occurred during the 27th month of use in a woman who had received the Norplant implants. 34 patients (14%) discontinued the study during the 3-year study period because of side effects. Irregular uterine bleeding (either prolonged or too frequent) accounted for 50% of these removals in both groups. Other reasons for removal included mood swings, excessive weight gain, headaches, and ovarian cyst. The total drop-out rate for all reasons was only 20%, indicating that the Norplant method is highly acceptable to US women. Many subjects indicated they were willing to tolerate the bleeding problems associated with Norplant in order to have a convenient longterm method of contraception. 4 of the 8 women who had the implants removed to become pregnancy had achieved this goal by 4 months after removal, indicating that restoration of fertility is not a problem. In general, the 2-rod system has the advantages of easier insertion technique and shorter insertion time, as well as ease of removal, compared to the 6-capsule system.

[Clinical and biological justifications for the use of Triella]. / Justifications cliniques et biologiques de l'emploi de Triella.

PIP: The principal preclinical studies of the biological properties of norethisterone and the clinical research leading up to development of the low dose triphasic oral contraceptive (OC) Triella are described. Triella mimics the natural cycles of women, allowing effective contraception with a small dose of estrogen and progesterone and excellent cycle control. Preclinical studies demonstrated that norethisterone is an active progestin whose luteo-mimetic and antiovulatory activity are equivalent to those of other progestins. Unlike levonorgestrel, norethisterone shows no notable androgenic activity in experiments with rats and does not modify serum levels of SHBG in rabbits. These findings support the conclusion that norethisterone effectively inhibits ovulation without androgenic secondary effects. The increased intermenstrual bleeding experienced by early users of low-dose formulations necessitated new protocols for evaluation. Each user noted on a daily calendar whether the pill was taken or forgotten and whether "bleeding" requiring sanitary protection or "staining" not requiring protection had occurred on that day. A formulation combining 35 mcg of ethinyl estradiol (EE) and .5 mg norethisterone was effective but caused frequent intermenstrual bleeding, especially during the 2nd phase of cycles and in the 1st cycles of use. Research was then directed toward finding a multiphasic mode of administration to reduce the norethisterone dose to the lowest possible level that would be effective and still permit good cycle control. Several biphasic combinations showed bleeding in the middle of the cycle. The Triella formulation therefore contains 3 levels of norethisterone for the 21 days of treatment: .5 mg for the first 7 days, .75 mg for the following 7 days, and 1 mg for the last 7 days. The EE dose is constant at 35 mcg/daily for the 21 treatment days. Midcycle bleeding was eliminated and the frequency of late cycle bleeding was minimized. Tolerance to Triella equalled that of Ortho-novum 1/35 despite its much smaller total dose. Later studies showed that intermenstrual bleeding in the early cycles of Triella use later diminished.^ieng

Rationale for a new triphasic oral contraceptive.

The association of progestogen and estrogen with certain undesirable effects led investigators to seek oral contraceptive (OC) formulations containing reduced amounts of both. Evidence is presented from studies of the triphasic regimen of 0.5 mg norethindrone plus 35 micrograms ethinyl estradiol on the first seven menstrual cycle days, 0.75 mg norethindrone plus 35 micrograms ethinyl estradiol the second seven days, followed by 1 mg norethindrone plus 35 micrograms ethinyl estradiol for the final seven days. This OC formulation appears to be highly effective and relatively free of the side effects commonly associated with low-dose OC regimens.

Rationale for a triphasic oral contraceptive.

PIP: Clinical observation on the use of various oral contraceptive (OC) formulations and the normal hormonal cycle formed the basis for development of Ortho-Novum 7/7/7, a triphasic with a constant low dose of 35 mcg ethinyl estradiol for all 21 tablets and a trilevel adjustment in the progestin. The 1st 7 pills contain .5 mg of norethindrone to encourage estrogen-promoted endometrial growth, the next 7 pills contain .75 mg of norethindrone, and increase intended to minimize midcycle breakthrough bleeding, and the final 7 days contain 1 mg of norethindrone to provide greater endometrial support. Clinical studies in the US, Canada, and France have shown that Ortho-Novum 7/7/7 is effective and safe, that it reduces midcycle breakthrough bleeding sometimes seen in patients on biphasic therapy, that side effects occur infrequently, and that metabolic impact is low. The combined study population consisted of 619 normal, healthy, nonpregnant women aged 18-38 years. Mean age of US subjects was 24.8 years and 81% had had a previous pregnancy. 63% of the Canadian and 52% of the French subjects had never been pregnant. 2 additional special studies were conducted in Canada, an endometrial biopsy study of 20 subjects to assess suppression of ovulation and a gonadotropin study of 29 subjects to assess effects on serum progesterone and pituitary gonadotropin levels. The results showed that serum progesterone levels were relatively low throughout the cycle and there were no ovulatory peaks in either follicle stimulating hormone or luteinizing hormone level. Results of the endometrial biopsy study showed that Ortho-Novum 7/7/7 was effective in preventing ovulation in all 20 subjects, as evidenced by the absence of secretory endometrium. There was no evidence of any histopathological change in the endometrium following 6 cycles of Ortho-Novum 7/7/7. The rate of breakthrough bleeding was comparable to that with Ortho-Novum 1/35, despite the 25% lower progestin content. The observed with higher dose OCs. The incidence of on-pill amenorrhea was 1.2%. A slight to minimal reduction in menstrual bleeding was observed, as well as a trend toward reduction in the severity of dysmenorrhea and premenstrual tension. No significant differences in body weight were noticed before, during, or after the study period, and no clinically significant changes in mean systolic or diastolic blood pressure occurred. Incidences of side effects reported by subjects were very low. The efficacy of Ortho-Novum 7/7/7 is comparable to that of higher dose OCs, with a Pearl index of .22 or less.^ieng

Evaluation of drugs for arrest of premature labor in a new animal model.

Reported are pharmacologic data from a new animal model used for evaluating drugs from several therapeutic classes for their potential use in the treatment of premature labor. This model measures the spontaneous delivery time between the first and second rat pups in a term pregnancy. In control animals, this averaged 16.3 +/- 4.2 minutes. Ethanol (3.5 gm/kg) and the beta-agonists ritodrine (12.5 mg/kg) and albuterol (0.25 mg/kg) significantly delayed delivery of the second pup. The calcium blockers nifedipine, verapamil, and diltiazem were the most active of all compounds tested in this model. The nonsteroidal anti-inflammatory agents indomethacin and naproxen were inactive at doses as high as 5 and 25 mg/kg, respectively. Metiamide, an H2-antagonist, and dimenhydrinate, an H1-antagonist, were inactive.

Amenorrhea associated with carotenemia.

Data are presented for ten women with anovulation, nine of them with amenorrhea, who have associated carotenemia. Classic explanations for carotenemia in amenorrheic patients have been weight loss or anorexia nervosa, yet carotenemia in our patients appeared to be diet induced. All patients consumed a pure or predominantly vegetarian diet; there was no intake of red meats. Clinical and laboratory data of the patients are presented. The amenorrhea of the patient is consistent with hypothalamic hypogonadotropic anovulation (HHA). It appeared that diet modification not only led to reduction in carotene levels, but also improved the menstrual status. The association of carotenemia and menstrual disorders is reviewed. The possibility that carotenemia is related to the development of HHA is discussed.

Results of a study to determine the effects of three oral contraceptives on serum lipoprotein levels.

A multicenter, double-blind investigation with random allocations of subjects to Ortho-Novum 1/50 tablets, Ortho-Novum 1/35 tablets, or Modicon tablets (Ortho Pharmaceutical Corporation, Raritan, NJ) was conducted. Each subject remained on the same oral contraceptive (OC) for at least four cycles. Serum high-density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglyceride, and cholesterol were measured prior to the initiation of OC therapy and were repeated after treatment cycles 2 and 4. There were no significant changes in HDL, LDL, or serum cholesterol levels. Triglyceride levels increased but remained significant only with the lowest dose product. These were no significant differences among the three drugs for the four parameters studied.

Optimum dosage of an oral contraceptive. A report from the study of seven combinations of norgestimate and ethinyl estradiol.

A statistically designed study was carried out to determine an optimum combination of norgestimate and ethinyl estradiol as an oral contraceptive, based on efficacy, safety, and side-effect patterns. A total of 1,991 patients were studied for more than two years while they were receiving various dosage combinations of these steroids. There were seven dosage combinations studied as part of a statistically orthogonal experimental design, augmented by three combinations near the center. The data arising from these studies were used to fit approximate functions relating the amount of norgestimate and ethinyl estradiol to the rate of spotting and breakthrough bleeding, gastrointestinal disturbance, and pregnancies. These functions, in turn, helped to identify an optimum dosage (0.125 mg. of norgestimate plus 0.035 mg. of ethinyl estradiol) in the entire range of combinations studied.

A dose-response study with Monistat cream.

A randomized multiregimen clinical study was undertaken using Monistat Cream for the treatment of vulvovaginal candidiasis. The objective of the study was to find if there is a shorter regimen comparable in effectiveness to the currently marketed 14-day regimen. The results indicate that there is no significant difference between the cure rate obtained for 7 days of therapy and for 14 days of therapy.

Clinical experience with a low dose oral contraceptive containing norethisterone and ethinyl oestradiol.

The results are presented of a clinical investigation of an oral contraceptive containing 0.5 mg norethisterone and 0.035 mg ethinyl oestradiol. The medication was administered orally as a 21-day cyclic regimen in 1,168 women. Duration of use was from 1 to 53 cycles with an overall total of 16,345 cycles. When the preparation was taken as directed, no pregnancies occurred. Three women conceived during the course of this study; however, these subjects missed 3, 2, and 1 prescribed tablets, respectively, and their pregnancies are thus judged due to patient failure. The overall pregnancy rate was 0.22 per 100 women years of use calculated as a Pearl Index. Intermenstrual bleeding (spotting and/or breakthrough bleeding) was noted primarily in the early cycles, soon tapering off to a lower and stable level. The overall cumulative cyclic incidence of amenorrhoea was 1.0%.

PIP: Clinical experience with a low dose oral contraceptive (OC) containing .5 mg norethisterone and .035 mg ethinyl estradiol is reported. 1168 sexually active women received the OC as a 21-day cyclic regimen from 1 to 53 cycles with an overall total of 16345 cycles. No pregnancies occurred when the OC was taken as directed. 3 women who conceived during the study missed 3, 2, and 1 prescribed tablets, respectively. The overall pregnancy rate was .22/100 woman years of use calculated as a Pearl index. Spotting and/or breakthrough bleeding was noted primarily in the early cycles. Patient dropout was 14.2% for menstrual disorders and irregularities, and 11.4% for other medically associated complaints or reactions. It is concluded that this OC has proved to be an effective and well-tolerated lower dose OC.