Comparison of Levonorgestrel-releasing Intrauterine System (LNG-IUS) against Laparoscopic Assisted Supracervical Hysterectomy (LASH) for menorrhagia treatment: An economic evaluation.

BACKGROUND: This economic evaluation and literature review was conducted with the primary aim to compare the cost-effectiveness of laparoscopic assisted supracervical hysterectomy (LASH) with NICE's gold-standard treatment of Levonorgestrel-releasing intrauterine system (LNG-IUS) for menorrhagia. MATERIALS AND METHODS: A cost-utility analysis was conducted from an NHS perspective, using data from two European studies to compare the treatments. Individual costs and benefits were assessed within one year of having the intervention. An Incremental Cost-Effectiveness Ratio (ICER) was calculated, followed by sensitivity analysis. Expected Quality Adjusted Life Years (QALYS) and costs to the NHS were calculated alongside health net benefits (HNB) and monetary net benefits (MNB). RESULTS: A QALY gain of 0.069 was seen in use of LNG-IUS compared to LASH. This yielded a MNB between -£44.99 and -£734.99, alongside a HNB between -0.0705 QALYs and -0.106 QALYS. Using a £20,000-£30,000/QALY limit outlined by NICE,this showed the LNG-IUS to be more cost-effective than LASH, with LASH exceeding the upper bound of the £30,000/QALY limit. Sensitivity analysis lowered the ICER below the given threshold. CONCLUSIONS: The ICER demonstrates it would not be cost-effective to replace the current gold-standard LNG-IUS with LASH, when treating menorrhagia in the UK. The ICER's proximity to the threshold and its high sensitivity alludes to the necessity for further research to generate a more reliable cost-effectiveness estimate. However, LASH could be considered as a first line treatment option in women with no desire to have children.

[Efficacy and adverse effects of levonorgestrel-releasing intrauterine system in treatment of adenomyosis].

OBJECTIVE: To evaluate the efficacy and adverse effects of levonorgestrel-releasing intrauterine system (Mirena) in the treatment of adenomyosis. METHODS: The clinical data of 75 patients with adenomyosis who had Mirena insertion in Women's Hospital,Zhejiang University School of Medicine from September 2013 to December 2013 were retrospectively analyzed. The patients were followed up to 39 months. The efficacy and adverse effects were assessed. RESULTS: Pictorial Blood Loss Assessment Chart (PBAC) scores were decreased significantly after Mirena insertion both in patients with menorrhea (118±13 vs. 29±33, P<0.01) and normal menstruation (82±15 vs. 14±13, P<0.01); the patients with menorrhea showed a more significant decrease in PBAC score than those with normal menstruation (90±35 vs. 69±19,P<0.01). The visual analogue scale (VAS) score decreased significantly after Mirena insertion compared with pre-treatment[7(6,7) vs. 1(0,2), P<0.01]. The expulsion of Mirena occurred in 18 cases (24.0%); 9 cases (12.0%) had no effect and 28 cases (37.3%) had changes of menstruation patterns. Multivariate Cox regression analysis showed that the expulsion of Mirena was not associated with post-treatment VAS score, PBAC score before and after treatment or menstrual stabilization time (all P>0.05). CONCLUSIONS: Mirena is effective and safe in the long term management of adenomyosis, but about one third patients may require further treatment because of the expulsion or ineffectiveness of Mirena.

Emergency Contraception for Adolescents: A Political Battle.

The political debate for adolescents to have access to emergency contraception that is available over the counter has been going on for years. Since 1999, Levonorgestrel, Plan B One Step®, has been used in the United States as an emergency contraception but with a prescription at the time. The FDA has done years of research and testing with Barr Laboratories, the manufacture of Plan B One Step®, to make it safe for females of all ages. In 2003, the FDA recommended the over the counter use of Plan B One Step® for all ages, yet this did not occur. In pharmacies across our nation young women find it impossible to purchase this product whether they be of age or not. Politics is making the choices for our young females, not medical evidence. How long are we going to let this continue?

Development and implementation of a quality assurance program for a hormonal contraceptive implant.

BACKGROUND: The importance of the distribution of safe, effective and cost-effective pharmaceutical products in resource-constrained countries is the subject of increasing attention. FHI 360 has developed a program aimed at evaluating the quality of a contraceptive implant manufactured in China, while the product is being registered in an increasing number of countries and distributed by international procurement agencies. The program consists of (1) independent product testing; (2) ongoing evaluation of the manufacturing facility through audits and inspections; and (3) post-marketing surveillance. STUDY DESIGN: This article focuses on the laboratory testing of the product. The various test methods were chosen from the following test method compendia, the United States Pharmacopeia (USP), British Pharmacopeia (BP), International Organization for Standardization (ISO), the American Society for Testing and Materials (ASTM), or lot release tests mandated by Chinese regulatory requirements. Each manufactured lot is independently tested prior to its distribution to countries supported by this program. In addition, a more detailed annual testing program includes evaluation of the active ingredient (levonorgestrel), the final product and the packaging material. RESULTS: Over the first 4 years of this 5-year project, all tested lots met the established quality criteria. CONCLUSIONS: The quality assurance program developed for this contraceptive implant has helped ensure that a safe product was being introduced into developing country family planning programs. This program provides a template for establishing quality assurance programs for other cost-effective pharmaceutical products that have not yet received stringent regulatory approval and are being distributed in resource-poor settings.

Ethinylestradiol and levonorgestrel preparations on the Belgian market: a comparative study.

Preparations formulated as coated or film-coated tablets, containing levonorgestrel and the combination ethinylestradiol/levonorgestrel, were evaluated in a comparative study. This study comprised in vitro dissolution, assay and content uniformity. The analytical methods were previously validated according to international guidelines. All examined products complied with the postulated requirements.

Simultaneous determination of mifepristone and monodemethyl-mifepristone in human plasma by liquid chromatography-tandem mass spectrometry method using levonorgestrel as an internal standard: application to a pharmacokinetic study.

A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously determine mifepristone and monodemethyl-mifepristone in human plasma using levonorgestrel as the internal standard (IS). After solid-phase extraction of the plasma samples, mifepristone, monodemethyl-mifepristone and the IS were subjected to LC-MS/MS analysis using electro-spray ionization (ESI) in the multiple reaction monitoring (MRM) mode. Chromatographic separation was performed on an XTERRA MS C(18) column (150 x 2.1 mm i.d., 5 microm). The method had a chromatographic run time of 4.5 min and linear calibration curves over the concentration ranges of 5-2000 ng/mL for mifepristone and monodemethyl-mifepristone. The recoveries of the method were found to be 94.5-103.7% for mifepristone and 70.7-77.3% for monodemethyl-mifepristone. The method had a lower limit of quantification (LLOQ) of 5.0 ng/mL and a lower limit of detection (LOD) of 1.0 ng/mL for both mifepristone and monodemethyl-mifepristone. The intra- and inter-batch precision was less than 15% for all quality control samples at concentrations of 10, 100 and 1000 ng/mL. These results indicate that the method was efficient with a short run time (4.5 min) and acceptable accuracy, precision and sensitivity. The validated LC-MS/MS method was successfully used in a pharmacokinetic study in healthy female volunteers after oral administration of 25 mg mifepristone tablet.

The levonorgestrel intrauterine system in contraception.

The levonorgestrel intrauterine system (LNG IUS) releases 20 microg/24 h of levonorgestrel from a polymer cylinder mounted on a T-shaped frame and covered with a release rate-controlling membrane. It is approved for 5-year use. The most outstanding features of LNG IUS are its high contraceptive efficacy and reduction of menstrual blood flow. No single mode of action can account for its contraceptive efficacy. The endometrium becomes thin and inactive, and the cervical mucus turns scanty and viscous. Although ovulation may be disturbed to some degree, estradiol production continues normally. The Pearl index for LNG IUS from large clinical trials is 0.1. Extrauterine pregnancies occur in 1 in 5000 users per year. Both the volume of menstrual blood loss and the number of bleeding days are reduced. During the first year of use, 20% of women become amenorrheic. There is an initial increase in the mean number of bleeding and spotting days, but in 3 to 6 months the number of bleeding and spotting days is the same as observed in copper IUD-users. The variation between individuals is wide and unpredictable. There are also additional health benefits secondary to the inactivation of the endometrium: increased hemoglobin, decreased dysmenorrhea, a possible decrease in pelvic inflammatory disease. LNG IUS may also decrease the growth of fibroids. LNG IUS is well accepted by users, with typical annual continuation rates above 80% in clinical studies.

A randomized multicenter study comparing the efficacy and bleeding pattern of a single-rod (Implanon) and a six-capsule (Norplant) hormonal contraceptive implant.

To compare the contraceptive efficacy, tolerability, and bleeding patterns, 200 healthy female volunteers received, in an open, comparative, randomized, multicenter study in China, either a single-rod (Implanon) or a six-capsule (Norplant) contraceptive implant for 2 years with an optional extension of up to 4 years. Women were exposed to Implanon for 341.6 woman-years and Norplant for 329.1 woman-years. There were no pregnancies during the study. Per 90-day reference period, the median number of bleeding/spotting days with Implanon decreased from 33.5 in the first period to 19.0-21.5 days in the last year. Similarly, with Norplant, the median number of bleeding/spotting days decreased from 34.5 to 18.0-23.0 days, respectively. The number of bleeding/spotting episodes during year 1 was 2.0 per 90-day reference period with Implanon and 3.0 per period with Norplant (p < 0.05 for periods 1-4). For the remaining 90-day periods, there was no statistical difference between the two groups. In general, there was less frequent bleeding with Implanon compared with Norplant, whereas the incidences of amenorrhea and infrequent bleeding were higher with Implanon than with Norplant. The mean overall incidence of prolonged bleeding fell markedly during the study, from 66.0% in reference period 1 to 27.3% in period 16 with Implanon and from 69.0% to 21.7% with Norplant, respectively. The most common adverse events were related to disturbed bleeding patterns, which were also the major reasons for discontinuation (Implanon n = 8; Norplant n = 14). Normal menses returned in almost all subjects within 3 months after removal of the implants. Implanon was inserted in a mean time of 0.61 min and Norplant in 3.90 min (p < 0.001). Similarly, the mean time required to remove the implant was significantly shorter for Implanon than for Norplant (2.18 min vs 11.25 min, p < 0.001). The maximum time required for removal of the implant was 10 min for the Implanon group and 60 min for the Norplant group. In both groups, blood pressure and hemoglobin were not affected, whereas body weight tended to increase. It can be concluded that both contraceptive systems demonstrated excellent contraceptive efficacy and were well tolerated. Compared with Norplant, there was less frequent bleeding with Implanon, whereas the incidence of infrequent bleeding and amenorrhea was higher. Implanon was significantly quicker to insert and to remove than was the multiple capsule system.

PIP: This study compares the contraceptive efficacy and bleeding patterns of a single-rod (Implanon) and a six-capsule (Norplant) contraceptive implant for 2 years, with an optional extension of up to 4 years, among 200 healthy female volunteers in China. Women were administered with Implanon for 341.6 woman-years and Norplant for 329.1 woman-years. No pregnancies occurred during the study, demonstrating excellent contraceptive efficacy. The median number of bleeding/spotting (B/S) days with Implanon decreased from 33.5 in the first period to 19.0-21.5 days in the last year. With Norplant, the median number of B/S days decreased from 34.5 to 18.9-23.0 days. There was less frequent bleeding with Implanon than with Norplant. The most common adverse effects were related to disturbed bleeding patterns, which were also the main reasons for discontinuation (Implanon, n = 8; Norplant, n = 14). Normal menses returned in almost all subjects within 3 months after removal of the implants. Lastly, Implanon required less time for insertion and removal as compared to Norplant.

Efficacy and continuation rates of Norplant in Pakistan.

A total of 265 women who had the Norplant system inserted were followed for 5 years. The present study is based on 11,435 women-months of use, describing the continuation rates and efficacy of Norplant among these women. The 5-year cumulative continuation rate was 45.7 per 100 continuing users. The continuation rates were age-dependent. The women > or = 35 years of age consistently maintained higher continuation rates at all time intervals as compared with those of younger women. During 5 years of follow-up, five women became pregnant. Three pregnancies occurred in year 2, one in year 3, and one in year 5. The 5-year cumulative pregnancy rate was 2.5 per 100 continuing users. The weight of the user did not influence the pregnancy rate. The continuation rates, as well as the pregnancy rates, are comparable to those reported from other countries in the region.

PIP: This article documents a 5-year follow-up of Norplant acceptors. The study was based on the medical records of 265 women who obtained Norplant from the Family Planning Association of Pakistan clinics in Lahore and Karachi during 1988-89 to examine the efficacy and continuation rates of Norplant in Pakistan. The studied sample participated in the introductory trial that were followed up for 5 years. Results revealed that the cumulative continuation rate during the 5-year period was 45.7 per 100 continuing users. The continuation rates were age-dependent, wherein women aged 35 years or older consistently maintained higher continuation rates at all time intervals as compared with younger women. During the 5-year follow-up, 5 women became pregnant (3 in year 2, 1 in year 3, and 1 in year 5). Furthermore, the 5-year cumulative pregnancy rate was 2.5 per 100 continuing users. The user¿s weight did not influence the pregnancy rate. Lastly, the continuation rates, as well as the pregnancy rates, were comparable to those reported from other countries in the region.

Oral contraception: current use and attitudes.

Oral contraception (OC) has been available for almost four decades. During this time, changes in contraceptive use in general and OC in particular have occurred. Knowledge and attitudes about OC may not always reflect trends in use. Contraceptive use data from 1965-1995 show that OC continue to be the method chosen consistently by more than one-quarter of women contraceptors. Probably even more women would use the pill if they had more accurate information regarding the higher failure rates with barrier methods (especially the condom), if misperceptions about OC safety were put to rest, and if greater awareness of the noncontraceptive health benefits of OC could be achieved. Increased education and awareness of women as well as their healthcare providers has the potential to positively affect future contraceptive use.

PIP: During the four decades that oral contraceptives (OCs) have been available to US women, important changes have occurred in their use patterns. The mass media, health care providers, and health insurance companies all have shaped these patterns. The media continue to emphasize the health risks of OC use, despite the fact that changes in the steroid content of OCs and identification of patient risk factors have eliminated or minimized many adverse outcomes. Educational efforts by health care providers on the noncontraceptive benefits of OC use have been inadequate to counteract media-promoted public misperceptions. Inaccurate information may lead women to select a method that lacks the appropriate degree of effectiveness and a consequent increased risk of unintended pregnancy. Two measures of socioeconomic status--income and education--exert a major influence on the choice of a contraceptive method by US women. Low-income women with a high school education or less are more likely to use female sterilization and less likely to use OCs than women with more education and income. Future contraceptive trends in the US will depend on factors such as the changing age distribution of women, revised upper age limits for OC use, the effects of delayed childbearing and sterilization, the impact of new methods, the availability of abortion, and concerns about HIV infection and other sexually transmitted diseases.

Contraceptive introduction reconsidered: a new methodology for policy and program development.

Although new contraceptive technology has the potential for providing women with expanded options for fertility control, the historical record of international family planning shows that, in practice, introduction of new methods has not always broadened reproductive choice. Using the example of introduction of intrauterine devices into the Indian family planning program in the 1960s, we show that an exclusive focus on the technology itself is problematic and argue that methodologies are needed that relate introduction of new methods to user needs and program capacities. We summarize key findings from the Indonesian experience with Norplant introduction. Although an effort was made to address problems with previous approaches, major deficiencies in both the technical and interpersonal dimensions of care arose when the implants were made broadly available within the program. We subsequently present a methodology for contraceptive introduction developed by the World Health Organization. This methodology emphasizes the social and institutional context in which technology is used and suggests a participatory and research-based approach to program and policy development. We illustrate results from this new approach in its implementation in Vietnam and suggest areas for further evaluation.

The pharmacodynamics and efficacy of Implanon. An overview of the data.

Implanon is a long-acting reversible contraceptive method, consisting of a single rod that is applied subdermally. Ovulation inhibition was determined by serum progesterone (P) levels and ultrasound scanning (USS) of the ovaries. Ovarian function was further assessed by serum estradiol (E2) levels. The effects of Implanon on serum gonadotropin levels (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) and on cervical mucus were also investigated, by means of Insler scores and sperm penetration tests. The effect of the endometrium was assessed by endometrial biopsies and USS. The Pearl index was calculated over 13 studies performed according to Good Clinical Practice (GCP), including 1716 women using Implanon. Return of ovulation after implant removal was determined by P levels and USS of the ovaries. The contraceptive efficacy of Implanon was high, with zero pregnancies during 53,530 cycles (4103 woman-years), resulting in a Pearl index of 0.0 (95% confidence interval, 0.00-0.09). This was achieved by inhibition of ovulation, which was reflected by suppressed P levels, as the primary mode of action. Ovulation was inhibited, but otherwise ovarian activity was still present (follicle growth, E2 synthesis). The FSH serum concentrations were only slightly lower than preinsertion levels and LH surges were prevented. The viscosity of the cervical mucus was increased. The endometrium was thin but not atrophic; it showed primarily inactive or weak proliferation. Return of ovulation after removal of Implanon was rapid.

Acceptance, efficacy, and side effects of Norplant implants in four counties in north China.

This report attempts to present a comprehensive analysis of the acceptability, side effects, and efficacy of Norplant as used in rural areas, based on a field experiment conducted in four counties in Hebei and Shandong Provinces, China. The initial acceptance of Norplant was relatively high but waned after the first year in three of the four counties. Compared with clinical trials, the current study shows a lower prevalence but similar patterns of side effects. The pregnancy rate during the first two years of use is similar to that found in large-scale clinical trials conducted in China, but discontinuation due to other reasons is lower. A three-level logistic regression analysis shows significant variation in the probability of discontinuation due to side effects across counties. It also indicates an increase in the conditional probability of discontinuation with the duration of use. Whereas introducing Norplant and achieving a very low failure rate and high continuation rate in rural areas is feasible under diverse socioeconomic conditions, the results vary significantly across different areas. Particular attention should be paid to the local factors that may affect results.

PIP: Field research conducted in 24 rural townships in four counties (Zunhua and Leting in Hebei Province and Boshan and Yiyuan in Shandong Province) in China identified potential local-level obstacles to widespread use of Norplant contraceptive implants. A total of 1556 women received the implants between June 1992 and June 1993. In 1992, Norplant represented 20% of total contraceptive use in the study area; however, in 1993, this statistic dropped to 10% in 3 of the 4 counties. About 49% of Norplant acceptors experienced at least 1 side effect in the first 6 months, primarily menstrual disorders, headache, vertigo, and nausea. The gross discontinuation rate due to menstrual disorder was 1% at 6 months, 3% at 12 months, and 8% at 24 months; the overall discontinuation rates were 2%, 4%, and 10%, respectively. There were only 3 pregnancies due to method failure in the 24-month study period. Despite the high acceptability and effectiveness of this method, family planning workers complained that the required acceptor screening, insertion, follow-up visits, counseling, and treatment of side effects associated with Norplant increased their work loads. The decline in the method's popularity from 1992 to 1993 is presumed due to local program-related factors such as decreased implementation of an informed choice policy, unavailability of daily Norplant insertion services, the slow response of family planning workers to requests for treatment of side effects or capsule removal, and the improved availability of alternative contraceptive choices. However, demand for Norplant remained stable in Yiyuan County, where there was widespread resistance to sterilization and a willingness on the part of family planning workers to accept the increased work load associated with this method.

A multicenter comparative study on the efficacy, safety, and acceptability of the contraceptive subdermal implants Norplant and Norplant-II.

In order to assess efficacy, safety, and acceptability of the contraceptive subdermal implants Norplant and Norplant-II in Mexican women, a comparative phase III clinical trial was undertaken in eight clinics across the country. The study involved 1052 women who were followed-up trimonthly for three years. Cumulative pregnancy rates were 0.29% and 0.34% for Norplant and Norplant-II implants, respectively. Similar overall cumulative discontinuation rates were observed at three years: 50.38% for Norplant capsules, and 50.44% for Norplant-II rods. The main method-related reason for termination was endometrial bleeding irregularity which led to discontinuation rates of 11.94% and 11.62% for Norplant and Norplant-II contraceptive systems, respectively. In 15,279 woman-months of experience accumulated with Norplant implants and 14,092 with Norplant-II implants, there were few adverse events reported. No difference was found between the two groups in either difficulty for implants placement and removal or women's discomfort, even though the time required for insertion and removal of Norplant capsules was longer than for Norplant-II rods. It is concluded that during the first three years of use, both implants systems are equally effective, safe, and acceptable.

Clinical performance of a new two-rod levonorgestrel contraceptive implant: a three-year randomized study with Norplant implants as controls.

In a randomized three-year clinical trial at seven clinics, the performance of levonorgestrel rod (LNG ROD) implants used by 600 women was compared with that of soft tubing NORPLANT implants used by 598 women. No pregnancies occurred in either group of women and, accordingly, body weight did not affect the efficacy of either type of implant. There were neither statistically significant nor important differences in termination rates for any reason over the three years. Complaint and illness rates during use of either of the two implant types were statistically indistinguishable and were attributable to the same set of conditions. Seventy-one per 100 of the women using each implant regimen continued to the three-year point, for an average annual continuation rate of 89 per 100. Removals of LNG ROD implants were accomplished in about half the time required for removal of Norplant capsule implants (p < 0.001).

Levonorgestrel concentrations during use of levonorgestrel rod (LNG ROD) implants.

In a three-year randomized trial that included 398 women, blood samples were collected for the purpose of assaying levonorgestrel concentrations in women using a new two-rod contraceptive implant system or an earlier implant formulation, Norplant-2 implants. Sample collection was at 1, 3, 6, 9, and 12 months after placement and semiannually thereafter through three years. Resulting assays and analyses showed that levonorgestrel concentrations of each implant formulation decreased significantly with time after placement, with increasing body weight, and with ponderal index. In the third year, several measures indicated that concentrations of the contraceptive drug were higher in women using the LNG ROD implants than in users of the original formulation. No pregnancies occurred among women in either group in the three years. This study provides evidence that the minimum levonorgestrel concentration needed to protect against pregnancy is below 200 pg/ml, and possibly is below 175 pg/ml.