Dale N. Robertson

A five-year clinical trial of levonorgestrel silastic implants (Norplant™)

Abstract Silastic implants containing the progestin, levonorgestrel, were tested as a long-term contraceptive system in 101 women. During five full years of use, no pregnancies occurred. The 5-year continuation rate was 54%. Menstrual irregularities were the most frequent reason for termination of use but only during the first year. More than half of the terminations for this reason were in the first year. Some of the subjects elected to continue use of the implants beyond 5 years, allowing release rate data to be obtained through 6 years. From the second through the sixth year of use, the implants delivered a constant 30 micrograms per day of levonorgestrel to the subjects, and even after six years 57% of the original steroid content remained in the capsules. Return of fertility following removal was essentially immediate and not related to time of use. Medical reasons for removal were infrequent and no pattern was discernible.

Release rates of levonorgestrel from silasticR capsules, homogeneous rods and covered rods in humans

Three forms of subdermal implants containing levonorgestrel are described. These are: capsules, in which the powdered drug is sealed inside of lengths of Medical Grade Silastic tubing; homogeneous rods, in which the drug is uniformly dispersed in Silastic 382 Medical Grade Elastomer; and covered rods, in which a core rod of drug and filler-free polydimethylsiloxane polymer (50:50, Wt:Wt) are sealed inside thin-walled Silastic tubing. Long-term in vivo release rates from human subjects are presented; 6.5 years for capsules, 3.6 years for homogeneous rods and 4 years for covered rods. Sets of six capsules release a decreasing amount of drug through the first few hundred days in situ and after 500 days a fairly constant rate of about 35 micrograms per day is released (2 micrograms/cm). Homogeneous rods deliver a continuously declining amount of drug during the entire time studied. In the first 100 days the release averages 136 micrograms per day from a set of three 3-cm rods (15 micrograms/cm), gradually declining to 30 micrograms per day (3.3 micrograms/cm) from day 800 to day 1300. The covered rods deliver at a constant rate of 17.5 micrograms per day for a 3-cm rod (5.83 micrograms/cm) through 4 years.

A four-year clinical study of NORPLANT implants.

A total of 324 women aged 18-35 began use of NORPLANT subdermal implants in Finland Chile and the Dominican Republic in 1978-79. Through 4 years of 1st segment use the average annual continuation rate was 84/100 women and the 4 year cumulative rate was 49/100. There were no pregnancies in the 1st 2.5 years of use and a total of 2 by the end of 4 years. Single decrement (gross) pregnancy rate cumulated to 1.2/100 users at the end of month 48 and the Pearl index through 4 years was .2/100 woman years. Placement and removal of implants subject women to the risk of infection at the implant site. The use of implants as a practical method of family planning rests in part on the question of whether these relatively simple clinical procedures can be performed with a low infection rate under field conditions. Marked bleeding patterns were a concern. Some women experienced very long bleeding runs. With adequate training and supervision delivery and removal of implants can be done quickly and safely as indicated by the low infection rates (0.3/100 women). The training of personnel in the required skills is apparently no more difficult than was the training for the IUD 2 decades ago. Infection should it occur would tend to have less serious consequences for the woman than does pelvic infection. Perforation of the uterus in delivery of a copper IUD requires abdominal surgery to remove the device. No equally serious sequelae have been associated with improper placement or removal of implants.

Sustained intrauterine release of levonorgestrel over five years.

Two models of levonorgestrel-releasing intrauterine devices were studied. Model A was designed to deliver 20 micrograms/day, and model B was designed to deliver 30 micrograms/day. Plasma concentrations of levonorgestrel were determined in blood samples taken from women who used the levonorgestrel-releasing intrauterine devices (IUDs) and who participated in a clinical trial for more than 5 years. During clinical studies IUDs have been removed for various reasons between 8 and 40 months after insertion. The rate of release of levonorgestrel from the IUDs was calculated by determining the remaining amount of levonorgestrel. Plasma concentrations of levonorgestrel ranged between a mean +/- standard deviation (SD) concentration of 166 +/- 75 pg/ml and 131 +/- 32 pg/ml for the first 18 months of use and between 101 +/- 37 pg/ml and 74 +/- 15 pg/ml at 24 and 60 months after insertion of the IUD. The plasma concentrations from 24 months through 60 months were significantly lower than concentrations measured during initial months of IUD use, but not between the two devices. There was a strong correlation between the time of use and the amount of levonorgestrel lost from the IUDs. The calculated mean daily release of levonorgestrel was 17.6 micrograms for model A and 22.2 micrograms for model B. This gives a calculated lifetime of more than 6 years for a levonorgestrel-releasing IUD.

Clinical chemistry in women treated with levonorgestrel implants (NORPLANT) or a TCu 200 IUD.

Two groups of implant users and two groups of IUD users participated in the study at different times. In the first groups, fractionation of lipoproteins was performed on serum samples from 28 subjects who had used the implants for 37 months and from 26 subjects who had used the Copper TCu 200 for 30 months. Users of the implants had significantly lower levels of total cholesterol, triglycerides and LDL-cholesterol than users of the IUDs. HDL-cholesterol levels were not different between the groups. In the other groups of women, general chemistries and selected hormone assays were carried out on samples from 30 subjects who had used implants for 51 months and from 24 subjects who had used the TCu 200 IUDs for 43 months. The parameters studied were the SM-12 chemistry group profile, estradiol, cortisol, testosterone, triiodothyronine, thyroxine and thyroid stimulating hormone. In the implant group, mean serum glucose levels were statistically significantly elevated and inorganic phosphorus levels were significantly reduced as compared to the IUD group. In both cases all individual measurements were within the normal range for the population. Testosterone and triiodothyronine levels in the implant group were significantly lower than in the IUD group, but no individual values were outside the normal range for the population. Mean values for all other parameters were not significantly different between the groups.

Three-year experience with NORPLANT subdermal contraception.

NORPLANTTM (Laboratorios Gutfol, S.A., Mexico City, Mexico) subdermal implants containing levonorgestrel were accepted by 816 women in a two-phase study initiated in 1975 and augmented in 1978. Through 3 years of first-segment use, acceptors experienced five pregnancies, a cumulative net rate of 0.7 per 100, and a gross pregnancy rate of 1.1 per 100. First-segment continuation at 3 years was at the rate of 44.6 per 100, an annual average of 76 per 100. NORPLANT users experienced irregular menstruation, with high interindividual variation, but with normal average numbers of bleeding days and of bleeding episodes. Hemoglobin levels increased moderately during implant use. The incidence of systolic blood pressure readings above 145 mm Hg or diastolic readings above 95 mm Hg was similar to that observed among users of the TCu 200 intrauterine device enrolled under the same selection criteria in the same clinics between the two phases of the NORPLANT study. Comparative data on pregnancy and other rates are also given for these intrauterine device acceptors.

Contraception with long acting subdermal implants: I. An effective and acceptable modality in international clinical trials

This paper presents results of a double blind, multi-centered and multi-national study of two progestin only subdermal implants used for contraception. A regimen of six capsules of levonorgestrel (Ng) used by 492 women had a net cumulative 12-month pregnancy rate of 0.6 percent and a continuation rate of 74.6 percent. 498 women used six capsules of norgestrienone (R2010) and experienced a net cumulative 12-month pregnancy rate of 3.5 percent and a continuation rate of 79.4 percent. The difference in the pregnancy rate was significant at P less than 0.01, while there was no significant difference in the continuation rates. Menstrual problems were the principal reason for termination of the levonorgestrel regimen, accounting for approximately half of all terminations. There were significantly fewer menstrual problems among users of the norgestrienone (R2010) capsules; the net cumulative 12-month termination rate for this reason was 4.3 percent. Results are compared with continuation and termination rates for acceptors of the Copper T 200 at the same clinics. The low pregnancy rate and reasonably high continuation rate of the norgestrel implants coupled with the fact that the expected effective lifetime of a set of capsules is of the order of 3-5 years appears to warrant further development of this contraceptive regimen.

Cholesterol and HDL-cholesterol values in women during use of subdermal implants releasing levonorgestrel.

Plasma concentrations of cholesterol, HDL-cholesterol, and levonorgestrel were determined in two groups of women using levonorgestrel-releasing subdermal implants. One group used six capsules (NORPLANT)*; the other six covered rods. Plasma concentrations of levonorgestrel among NORPLANT users averaged 700 pg/ml in the first two weeks of use, decreased to 300 pg/ml at 8 weeks, and to about 230 pg/ml by 50 weeks. Concentrations among covered rod users were 1.4 to 1.7 times higher at comparable time periods. Total serum cholesterol and HDL-cholesterol were decreased as compared with controls at all sampling intervals during the 114 weeks of the trial, although the differences did not meet tests of significance at all time periods. Decreases during the test period were of the order of 10 percent, except for total cholesterol among covered rod users where the decrease was less. Cholesterol to HDL-cholesterol ratios did not differ significantly from control values at any sampling period.

Lipoprotein patterns in women in Santo Domingo using a levonorgestrel/estradiol contraceptive ring.

Ten healthy, normally menstruating women attending a family planning clinic in Santo Domingo Participated in a study to determine the effects on plasma lipid levels of levonorgestrel and estradiol released from a contraceptive ring. A schedule of 21 days of use followed by 7 days of non-use was followed for 6 cycles. During the first two cycles of use, concentrations of cholesterol, HDL cholesterol, triglycerides and LDL cholesterol declined significantly from control levels, up to 25% for cholesterol, 28% for HDL cholesterol, 45% for friglycerides and 24% for LDL cholesterol. There were no subsequent changes with continued use. These declines are similar in direction but of lesser magnitude than those reported from clinics in other countries where pretreatment plasma levels of the same lipids are considerably higher. There was no significant change in the total cholesterol to HDL cholesterol ratio during treatment.

First year clinical experience with six levonorgestrel rods as subdermal contraception.

Previous clinical experience with six levonorgestrel subdermal capsules showed a very good contraceptive effectiveness and continuation rate, but with a high proportion of bleeding disturbances, particularly of increased bleeding. It was hypothesized that bleeding could be reduced by higher plasma levels of the steroid, using subdermal rods instead of capsules, as rods have been shown to have a release rate 3 or 4 times that of the capsules. Fifty volunteers were enrolled in a study of the clinical performance of 6 subdermal levonorgestrel rods. Results were compared with a previous experience with 100 volunteers who wore 6 levonorgestrel capsules for a year in the same clinic. Requirement for volunteers to enter the study were the same for capsules and rods. The proportion of women wearing 6 subdermal rods who had increased bleeding was about one half as for the women using 6 levonorgestrel capsules. On the other hand, women using rods had about twice the incidence of amenhorrea, and about four times more hypomenorrhea (4 days or less of bleeding in a 90-day period). There were no pregnancies among the rod users and the discontinuation rate for medical reasons was not higher than for capsule users in the same clinic.