Analysis of Adherence, Persistence, and Surgery Among Endometriosis Patients Treated with Leuprolide Acetate Plus Norethindrone Acetate Add-Back Therapy.

BACKGROUND: Endometriosis affects over 10 million women in the United States. Depot leuprolide acetate (LA), a gonadotropin-releasing hormone agonist, has been used extensively for the treatment of women with endometriosis but is associated with hypoestrogenic symptoms and bone mineral density loss. The concomitant use of add-back therapies, specifically norethindrone acetate (NETA), can alleviate these adverse effects. OBJECTIVE: To compare adherence to and persistence with LA treatment and time to endometriosis-related surgery among women treated with NETA and women treated with LA plus other add-back therapies or LA only. METHODS: This retrospective analysis was conducted using Truven Health MarketScan Commercial Claims and Encounters Database. Women with a diagnosis of endometriosis (ICD-9-CM code 617.xx) who initiated LA (index date) in 2005-2011 were selected for inclusion. Additional requirements were 12 months of continuous enrollment pre- and post-index and no evidence of endometriosis-related surgeries pre-index or up to 30 days post-index; no pre-index use of estrogen or noncontraceptive hormones; and no diagnoses of uterine fibroids, malignant neoplasms, infertility, or pregnancy. Patients were characterized as using NETA; other add-back therapies (estrogens, progestins, or estrogen-progestin combinations); or no add-back therapy. Adherence to and persistence with LA were measured over the 6 months following the index date using outpatient medical and pharmacy claims. Patients were considered adherent if their proportion of days covered was greater than or equal to 0.80. Persistence was operationalized as time to discontinuation, defined as a continuous gap of > 60 days without LA on hand. Time to endometriosis-related surgery (laparotomy, laparoscopy, excision/ablation/fulguration, oophorectomy, and hysterectomy) was measured over the 12 months following the index date. Surgeries were identified from inpatient and outpatient medical claims using procedure codes. Outcomes were compared among cohorts using multivariable logistic and Cox proportional hazards regression models controlling for demographics and baseline clinical characteristics. RESULTS: The final sample included 3,114 women, with a mean age of 36.9 years. The majority of women used LA only with no add-back therapy (n = 1,963, 63.0%), while 15.1% (n = 470) used NETA, and 21.9% (N = 681) used other add-back therapies. During the 6-month follow-up, more patients in the LA plus NETA cohort were adherent to LA therapy compared with LA only (47.2% vs. 31.5%, P < 0.001), and fewer patients discontinued (37.9% vs. 59.6%, P < 0.001). Additionally, fewer patients underwent endometriosis-related surgery in the 12 months after LA initiation in the LA plus NETA cohort (12.6% vs. 16.9%, P = 0.021). In multivariable models, women who initiated LA plus NETA or LA plus other add-back therapies had a higher likelihood of being adherent to LA than LA only patients (OR = 1.91, 95% CI = 1.55-2.36 and OR = 1.95, 95% CI = 1.63-2.34) and lower likelihood of LA discontinuation (HR = 0.54, 95% CI = 0.46-0.63 and HR = 0.59, 95% CI = 0.52-0.68). NETA patients had a lower surgery rate in the 12-month post-index period compared with other add-back patients (HR = 0.68, 95% CI = 0.50-0.93) or LA only patients (HR = 0.69, 95% CI = 0.52-0.92). CONCLUSIONS: For women with endometriosis, treatment with LA and concomitant add-back therapies was associated with better adherence to and persistence with LA over the 6 months following initiation, compared with treatment with LA only. The increased adherence and persistence to LA may translate into decreased need for surgical intervention, although fewer endometriosis-related surgeries were only observed in the 12 months following LA initiation for patients using concomitant NETA add-back therapy. These results support an increased and earlier use of NETA add-back therapy among women who initiate LA. DISCLOSURES: This study was funded by AbbVie, which also markets the endometriosis drugs Lupron and Lupaneta Pack. AbbVie participated in the study design, research, data collection, analysis and interpretation, writing, review, and approval of this publication. Soliman and Castelli-Haley are employees of AbbVie and may own AbbVie stock or stock options. Bonafede and Farr are employees of Truven Health Analytics, which received a research contract to conduct this study with and on behalf of AbbVie. Winkel is a clinical professor in the Department of Obstetrics and Gynecology at Georgetown University in Washington, DC, and has served in a consulting role on research to AbbVie for this project. An earlier version of the current research was presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 20th Annual International Meeting; Philadelphia, PA; May 2015. All authors participated in data analysis and interpretation and contributed to the development of the manuscript.

Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: a before and after study.

OBJECTIVE: To assess the proportion of patients satisfied with their treatment before and after a systematic change from norethindrone acetate to dienogest as the first-line progestin for symptomatic endometriosis. DESIGN: Before and after study. SETTING: Academic department. PATIENT(S): The last 90 new consecutive endometriosis patients in whom norethindrone acetate was used, and the first 90 new consecutive endometriosis patients in whom dienogest was used. INTERVENTION(S): Norethindrone acetate at the oral dose of 2.5 mg once a day until June 6, 2013, then dienogest at the oral dose of 2 mg once a day thereafter. MAIN OUTCOME MEASURE(S): Degree of satisfaction with treatment after 6 months of progestin therapy and assessment of any variations in pain symptoms, psychological status, sexual function, or health-related quality of life associated with the introduction of dienogest. RESULT(S): The proportion of satisfied plus very satisfied women after 6 months of treatment was 71% in the "before" period (norethindrone acetate) and 72% in the "after" period (dienogest). The implementation of dienogest was not associated with statistically significant ameliorations in overall pain relief, psychological status, sexual functioning, or health-related quality of life. Treatment was well tolerated by 58% of norethindrone acetate users compared with 80% of dienogest users. After dienogest implementation, the absolute risk reduction in the occurrence of any side effect was 13.9% (95% confidence interval, 0.8%-28.6%). CONCLUSION(S): Considering the large difference in the cost of the two drugs, dienogest should be suggested selectively in women who do not tolerate norethindrone acetate.

Continuous Norethisterone Acetate versus Cyclical Drospirenone 3 mg/Ethinyl Estradiol 20 µg for the Management of Primary Dysmenorrhea in Young Adult Women.

STUDY OBJECTIVE: To evaluate the efficacy of continuous norethisterone acetate (NET-A), 5 mg (group N) vs cyclical combined oral contraceptive pill (COC) consisting of drospirenone 3 mg/ethinyl estradiol 20 µg pills (group P) in treating dysmenorrhea in young adult women. DESIGN, SETTING, AND PARTICIPANTS: This prospective, open-label, nonrandomized study included 38 Jordanian patients: 20 patients in group N and 18 patients in group P. INTERVENTIONS: Continuous NET-A 5 mg daily or cyclical COC. MAIN OUTCOME MEASURES: Pain scores, adverse effects, analgesic use, school absence, and cost. RESULTS: Thirty-eight patients used NET-A or COC for 6 months. All participants had almost the same starting levels of visual analogue scale (VAS) scores. Both drugs were similar in suppressing dysmenorrhea at the 3-month follow-up visit; VAS score mean (±SD) in group N and P were 1.30 ± 1.22 and 1.28 ± 0.83 (P = .22), respectively, and after 6 months, with mean VAS scores (±SD) of 1.30 ± 1.22 and 1.28 ± 0.83, respectively (P = .95). The cost of the treatment in the N group was much less than in the P group. Participants in the N group were less likely to use pain killers: 20% and 44% in the N and P groups, respectively (P = .006) in the first month and only 5% and 17% (P = .019) in the N and P groups, respectively, at the 3-month follow-up, and none of them used any analgesics at the 6-month follow-up. CONCLUSION: A continuous NET-A regimen is a well tolerated, effective, and inexpensive option for dysmenorrhea treatment and was as good as COC.

The effectiveness of community based distribution of injectable contraceptives using community health extension workers in Gombe State, Northern Nigeria.

This study reports on findings of a pilot of community-based distribution (CBD) of injectable contraceptives in two local government areas (LGAs) of Gombe State, Nigeria. From August 2009 to January 2010, the project enrolled, trained and equipped community health extension workers (CHEWs) to distribute condoms, oral and injectable contraceptives in communities. The project mobilized communities and stakeholders to promote Family Planning (FP) services in the selected communities. Using anonymised unlinked routine service data, the mean couple years of protection (CYP) achieved through CBD was compared to that achieved in FP clinics. The CBD mean CYP for injectables- depo medroxy-progesterone acetate (DMPA) and norethisterone enantate was higher (27.72 & 18.16 respectively) than the facility CYP (7.21 & 5.08 respectively) (p < 0.05) with no injection related complications. The CBD's mean CYP for all methods was also found to be four times higher (11.65) than that generated in health facilities (2.86) (p < 0.05). This suggests that the CBD of injectable contraceptives is feasible and effective, even in a setting like northern Nigeria that has sensitivities about FP.

Digitized assessment of mammographic breast density--effects of continuous combined hormone therapy, tibolone and black cohosh compared to placebo.

OBJECTIVES: To determine the effects of continuous combined hormone therapy, tibolone, black cohosh, and placebo on digitized mammographic breast density in postmenopausal women. STUDY DESIGN: A prospective, double-blind, placebo-controlled study of 154 postmenopausal women randomized to estradiol 2 mg/norethisterone acetate 1 mg (E2/NETA), tibolone 2.5 mg or placebo and a prospective, open, uncontrolled drug safety study, of which 65 postmenopausal women were treated with black cohosh. Mammograms, at baseline and after six months of treatment, were previously classified according to visual quantification scales. MAIN OUTCOME MEASURES: Reanalysis of assessable mammograms by digitized quantification of breast density. RESULTS: Treatment groups were comparable at baseline. During treatment, both E2/NETA and tibolone significantly increased breast density (mean increase 14.3%, p<0.001 and 2.3%, p<0.001, respectively), while black cohosh and placebo did not. Twenty-four out of the 43 women on E2/NETA had an increase in density exceeding 10% and 6 women had an increase of 30% or more. In the tibolone group, only one woman had an increase in density of more than 10%. The difference in increase in breast density between E2/NETA on the one hand and tibolone, black cohosh and placebo on the other was highly significant (p<0.0001). CONCLUSIONS: Digitized mammographic breast density is a highly sensitive method confirming significant increase in density by standard E2/NETA treatment and to a lesser extent by tibolone, whereas black cohosh does not influence mammographic breast density during six months treatment. Digitized assessment also yields data on individual variation and small increases left undetectable by visual classification.

Letrozole combined with norethisterone acetate compared with norethisterone acetate alone in the treatment of pain symptoms caused by endometriosis.

BACKGROUND: The available data on effectiveness of aromatase inhibitors in treating pain symptoms related to endometriosis is limited. We compared the efficacy and tolerability of the aromatase inhibitor letrozole combined with norethisterone acetate versus norethisterone acetate alone in treating pain symptoms. METHODS: This prospective, open-label, non-randomized trial included 82 women with pain symptoms caused by rectovaginal endometriosis. Patients received either a combination of letrozole and norethisterone acetate (group L) or norethisterone acetate alone (group N) for 6 months. Changes in pain symptoms during treatment and in the 12 months of follow-up were evaluated. Side effects of each treatment protocol were recorded. RESULTS: Intensity of chronic pelvic pain and deep dyspareunia significantly decreased during treatment (P < 0.001 versus baseline by 3 months) in both study groups. At both 3- and 6-month assessment, the intensity of chronic pelvic pain (P < 0.001, P = 0.002, respectively) and deep dyspareunia (P < 0.001, P = 0.005, respectively) was significantly lower in group L than group N. At completion of treatment, 63.4% of women in group N were satisfied with treatment compared with 56.1% in group L (P = 0.49). Pain symptoms recurred after the completion of treatment; at 6-month follow-up no difference was observed in the intensity of pain symptoms between the groups. Adverse effects were more frequent in group L than in group N (P = 0.02). CONCLUSIONS: The combination drug regimen was more effective in reducing pain and deep dyspareunia than norethisterone acetate; however, letrozole caused a higher incidence of adverse effects, cost more and did not improve patients' satisfaction or influence recurrence of pain.

A cost-effectiveness evaluation of two continuous-combined hormone therapies for the management of moderate-to-severe vasomotor symptoms.

OBJECTIVES: After the release of the results of the Women's Health Initiative, an emerging consensus suggests that continuous-combined hormone therapy (CCHT) should be limited to short-term management of moderate-to-severe vasomotor symptoms. This, in turn, raises the important question of the economic value, if any, of short-term CCHT for this indication. We conducted a cost-effectiveness analysis comparing a 1-year treatment course with 1 mg of norethindrone acetate/5 microg of ethinyl estradiol (1/5 NA/EE) or 0.625 mg/day of conjugated estrogens plus 2.5 mg of medroxyprogesterone (0.625/2.5 CEE/MPA) compared with no therapy for the management of moderate-to-severe vasomotor symptoms. DESIGN: A literature-based Markov model was developed to compare these three options' cost and quality-of-life (QOL) benefits. The impact of therapy on vasomotor symptoms and breakthrough bleeding/spotting on the direct costs of care and QOL were considered. RESULTS: Compared with no therapy, CCHTs resulted in net increases in quality-adjusted life-years (QALYs) gained (0.110 for 1/5 NA/NE v 0.104 for 0.625/2.5 CEE/MPA). Net costs (v no therapy) were $167 lower for 1/5 NA/NE compared with 0.625/2.5 CEE/MPA. Cost per QALY gained (compared with no therapy) were $6,200 and $8,200, respectively. Cost-effectiveness was most favorable for individuals with more severe symptoms who were less bothered by breakthrough bleeding/spotting. CONCLUSIONS: A short-term course of CCHT for the sole purpose of managing moderate-to-severe vasomotor symptoms is cost-effective. However, 1/5 NA/NE seemed to be more cost-effective than 0.625/2.5 CEE/MPA. These findings can be used to further refine the role of CCHT and to improve formulary decisions.

Counting the costs: comparing depot medroxyprogesterone acetate and norethisterone oenanthate utilisation patterns in South Africa.

BACKGROUND: In South Africa, where health care resources are limited, it is important to ensure that drugs provision and use is rational. The Essential Drug List includes depot medroxyprogesterone acetate (DMPA) and norethisterone oenanthate (NET-EN) as injectable progestagen-only contraceptives (IPCs), and both products are extensively used. OBJECTIVES AND METHODS: Utilisation patterns of the injectable contraceptive products DMPA and NET-EN are compared in the context of current knowledge of the safety and efficacy of these agents. Utilisation patterns were analysed by means of a Pareto (ABC) analysis of IPCs issued from 4 South African provincial pharmaceutical depots over 3 financial years. A case study from rural KwaZulu-Natal, South Africa, is used to examine utilisation patterns and self-reported side effects experienced by 187 women using IPCs. RESULTS: IPCs accounted for a substantial share of total state expenditure on drugs. While more DMPA than NET-EN was issued, NET-EN distribution from 2 depots increased over the 3-year period. Since DMPA was cheaper, if all NET-EN clients in the 1999/2000 financial year (annualised) had used DMPA, the 4 depots could have saved 4.95 million South African Rands on product acquisition costs alone. The KZN case study showed slightly more NET-EN (54%) than DMPA (46%) use; no significant differences in self-reported side effects; and that younger women were more likely to use NET-EN than DMPA (p = 0.0001). CONCLUSIONS: Providing IPCs on the basis of age is not appropriate or cost effective. Rational use of these products should include consideration of the cost of prescribing one over another.

[A clinical assessment of a 3 month replacement therapy effectiveness with low norethisterone acetate (Activelle) in postmenopausal women]. / Ocena kliniczna trzymiesiecznej terapii substytucyjnej przy zastosowaniu niskich dawek estradiolu i octanu norethisteronu w postaci leku Activelle u kobiet po menopauzie.

AIM: The clinical evaluation of Activelle formula in treatment of climacteric symptoms in postmenopausal women. MATERIAL AND METHODS: Formula Activelle (oral 1 mg 17 beta-estradiol combined with 0.5 mg norethisterone acetate) was applied daily in 100 post-menopausal women during 3 months. The control group consisted of 20 women. Initially and at the 3rd month body mass, body mass index, systolic and diastolic blood pressure, AspAT and AIAT levels as well as total cholesterol, triglycerides, FSH and 17 beta-estradiol levels were measured. Green scale was used to assess the severity of menopausal symptoms. RESULTS: Mean FSH levels decreased and mean estradiol level increased in plasma significantly in women who were given Activelle formula. Only vasomotoric group of symptoms in Green scale was reduced after 3 month therapy in women who had activelle administered. No significant change was found in regard to other parameters. CONCLUSION: Formula Activelle seems to be efficient in removal of vasomotoric menopausal symptoms after 3 month of therapy. The administration of Activelle formula enables to reach the serum estradiol level which is sufficient in prophylaxis of osteoporosis.

Economic impact of tibolone compared with continuous-combined hormone replacement therapy. In the management of postmenopausal women with climacteric symptoms in the UK.

OBJECTIVE: To estimate the economic impact of using tibolone 2.5 mg compared with 17 beta-estradiol 2 mg/norethisterone acetate 1 mg (E2/NETA) in postmenopausal women with climacteric symptoms. DESIGN AND SETTING: This was a modelling study performed from the perspective of the UK's National Health Service (NHS). METHODS: The clinical outcomes from a previously reported trial were used as the clinical basis for the analysis, which showed that 48 weeks' treatment with tibolone and E2/NETA significantly alleviated the climacteric symptoms experienced by postmenopausal women. These data were combined with resource utilisation estimates derived from a panel of 10 GPs and 3 gynaecologists, enabling us to construct a Markov model depicting changes in the health status of postmenopausal women. The model was used to estimate the expected NHS costs and consequences after 48 weeks' treatment with tibolone and E2/NETA. MAIN OUTCOME MEASURES AND RESULTS: The mean expected direct healthcare cost of using tibolone and E2/NETA to manage postmenopausal women for 48 weeks was estimated to be 260 Pounds and 239 Pounds (1997/1998 prices) per patient, respectively. Starting hormone replacement therapy (HRT) with tibolone instead of E2/NETA was equally effective in alleviating climacteric symptoms (65.9 and 62.2%, respectively; p = 0.516) over 48 weeks and significantly reduced the incidence of vaginal bleeding by 36% (p < 0.0001) and breast tenderness by 57% (p < 0.0001) for a mean additional cost of 21 Pounds (ranging between -3 Pounds and 42 Pounds) per patient. The acquisition cost of HRT was the primary cost driver for tibolone-treated patients, whereas the cost of managing adverse events was the primary cost driver for E2/NETA-treated patients. CONCLUSIONS: The true cost of prescribing tibolone and E2/NETA is impacted on by a broad range of resources, not only drug acquisition costs. Although the acquisition cost of tibolone is higher than that of E2/NETA, the difference in the expected NHS cost of the first year of treatment between the 2 HRTs is negligible. This is because of the higher incidence of adverse events among E2/NETA-treated patients, which also results in a higher continuation rate among tibolone-treated patients. Factors such as patient preferences should also be taken into consideration so that treatment choices are not decided solely on the basis of acquisition costs.

Animal toxicity studies performed for risk assessment of the once-a-month injectable contraceptive Mesigyna.

Results from toxicity studies performed for risk assessment of the combined injectable hormonal preparation Mesigyna are reviewed. Both components of Mesigyna, i.e., estradiol valerate (E2Val) and norethisterone enanthate (NET-EN), have been thoroughly investigated as individual compounds and some limited toxicity data have been obtained for the combination. Most findings which were gathered in these studies from different animal species occurred in the gonads, accessory genital and endocrine organs and can be related to the known species-specific pharmacological activity of a typical estrogen or progestin, respectively. No additional or unexpected information which might indicate a possible estrogen/progestin interaction was gained from the administration of the combined preparation to animals. Based on the results from toxicity testing, there were no objections to the long-term therapeutic use of Mesigyna for hormonal contraception. The predictive value of the effects (including the tumorigenicity) observed in the common laboratory animals with regard to human safety is critically discussed, taking the vast amount of previous experience with hormonal contraceptives into consideration. The conclusion is drawn that there is no animal model for safety assessment of sex steroids that adequately represents the human situation. Quantitative extrapolations from animal toxicity findings to humans, therefore, are not possible. Especially, the value of long-term studies and of toxicity studies on estrogen/progestin combinations is put into question. Like endocrine pharmacology studies, the toxicity studies with these steroid hormones are useful for the characterization of the possible endocrine pharmacological profile only.

PIP: Considerable research has been conducted on the 2 steroid components of the once-a-month injectable contraceptive, Mesigyna. These steroids are estradiol valerate and norethisterone enanthate. Most findings from the limited toxicity studies of the combined injectable in different animal species were limited to the gonads and accessory genital and endocrine organs. The steroids have a toxicological activity profile in each of the species, which indicate that they act as a typical steroidal estrogen or progestin. They are no different than comparable compounds as used in oral contraceptives. Other than these findings, researchers did not acquire any more or unexpected information that would suggest a possible estrogen/progestin interaction from administering the combined preparation to animals. The findings of the toxicity testing do not suggest problems with the long-term use of Mesigyna for hormonal contraception. Yet, the fundamental species differences in endocrinology, metabolism of compounds, and pharmacokinetics make it virtually impossible to quantitatively extrapolate from findings of animal toxicity studies to human, e.g., those on tumorigenicity. A critical review of in vitro and animal toxicity studies of both compounds individually and combined lead to the conclusion that no animal model for safety assessment of sex steroids exists that correctly replicates the human environment. Toxicologists with Schering AG even question the value of long-term studies and toxicity studies on estrogen/progestin combinations. Animal models can be used, however, to characterize a possible endocrine pharmacological profile of newly developed steroids. Any such animal studies need not last any longer than 6 months.

[Doctors and injectable contraception. Analysis of the logistics of prescribing in accordance with the views expressed by doctors]. / Médecins et contraception injectable. Analyse des logiques de prescription à partir des discours de médecins.

Injectable contraception (IC) using medroxyprogesterone acetate (Depoprovera) and norethisterone enanthate (Noristerat) has been discussed in numbers of publications since the Food and Drug Administration (FDA) of the USA have refused to authorize the use of Depoprovera as a contraceptive in America. This has provoked a large number of publications in the international literature. The refusal was based on the potential oncogenic risk of the molecule. The distribution of this product as a contraceptive in developing countries and its restricted authorisation in many industrialised countries including France has brought about contradictory debates about the assessment of this method (secondary effects, risks of developing cancer and teratogenesis). In 1986 we started a research using close collaboration between the health teams of Seine-Saint-Denis (which control clinics, family planning clinics and hospitals) in order to try to find some solution to this problem "for or against IC". The object of this research was to find out how acceptable this method was as compared with other contraceptive methods. The fact that many disciplines were involved (gynaecologists, sociologists, epidemiologists and pharmacologists) in this work made it possible first to find out the conditions under which IC was prescribed (by sociological analysis and discussions with doctors). And the socio-cultural features in which the doctors who prescribed this method of contraception were situated also came into play. The criteria under which ICs are prescribed are not mainly medical but are narrowly linked to socio-cultural factors and the socio-economic factors of the women for whom it is prescribed: and this is in comparison with other methods of contraception. Prescribing this substance has a degree of urgency about it.