Norethisterone 200mg/1ml solution for injection ampoules

Correct and consistent use of contraception decreases the risk of unintended pregnancy; yet, outdated policies or practices can delay initiation or hinder continuation of contraceptive methods. To promote the quality of, and access to, family planning services, WHO created a series of evidence-based guidance documents for family planning, known as WHO's Four Cornerstones of Family Planning Guidance (Fig. 1). The Medical eligibility criteria for contraceptive use (MEC), first published in 1996,1 provides guidance on the safety of various contraceptive methods in users with specific health conditions or characteristics (i.e. who can use a contraceptive method safely). The Selected practice recommendations for contraceptive use (SPR) is the second cornerstone,2 outlining how to safely and effectively use contraceptive methods. These two documents can serve as a reference for policymakers and program managers as they develop their own national family planning policies in the context of local needs, values, and resources. The two other cornerstone documents—the Decision making tool for family planning clients and providers3 and Family planning: a global handbook for providers4—provide guidance to healthcare providers for applying these recommendations in practice. Between 2013 and 2014, WHO convened a Guideline Development Group (GDG) to review and update the MEC and SPR in line with current evidence. As a result of these meetings, the fifth edition of the MEC was published in 2015,5 and the third edition of the SPR will be released on December 14, 2016. The purpose of the present report is to describe the methods used to develop the SPR recommendations, research gaps identified during the guideline development process, and future directions for the dissemination and implementation of the SPR among policymakers and family planning program managers worldwide. Inconsistencies in recommendations on how to use contraceptive methods could contribute to the disparity in contraceptive failure rates reported between “perfect” and “typical” use.2, 6 In 2001, WHO convened the first scientific Working Group—with 33 participants from 16 countries—to address controversies or inconsistencies in recommendations to maximize the effective provision and management of contraception and to minimize and/or manage adverse effects that could contribute to discontinuation. The first edition of the SPR2 included recommendations made in response to 23 specific questions on contraceptive use, including when to initiate a contraceptive method, how to be reasonably certain that a woman is not pregnant before initiation, the role of necessary examinations or tests before initiation, recommended follow-up, how to maintain correct and consistent use, and how to address abnormal bleeding from contraceptive use. The Working Group based their recommendations on the best available evidence generated from systematic reviews, with consideration of the level and applicability of the evidence (i.e. direct or indirect), and relied on expert consensus when evidence was lacking. To manage the continuously evolving body of medical evidence, WHO and its collaborators launched the Continuous Identification of Research Evidence system in 2002 as an ongoing mechanism to identify, evaluate, synthesize, and peer review new evidence pertinent to the four cornerstone documents.7 Using the Continuous Identification of Research Evidence system, WHO and its partners identified novel and relevant evidence resulting in the creation of the second edition of the SPR in 2004,8 an interim guidance in 2008,9 and the latest edition in 2016. In addition to maintaining up-to-date recommendations for the contraceptive methods in the guidance, WHO strives to include guidance for new contraceptive methods as they became available (Table 1). When can a woman start COCs? What can a woman do if she misses COCs? What can a woman do if she vomits and/or has severe diarrhea while using COCs or POPs? When can a woman start CICs? When can a woman have repeat CIC injections? When can a woman start POPs? What can a woman do if she misses POPs? What can a woman do if she vomits after taking ECPs? When can a woman start POIs (DMPA or NET-EN)? When can a woman have repeat POIs (DMPA or NET-EN)? What can be done if a woman has menstrual abnormalities when using a POI (DMPA or NET-EN)? When can a woman start using an implant? What can be done if a woman experiences menstrual abnormalities when using implants? When can a copper-bearing IUD be inserted? What can be done if a woman experiences menstrual abnormalities when using a copper-bearing IUD? What should be done if a woman using a copper-bearing IUD is diagnosed with pelvic inflammatory disease? What should be done if a woman using a copper-bearing IUD is found to be pregnant? Should prophylactic antibiotics be provided for copper-bearing IUD insertion? What can a Standard Days Method user do if she has menstrual cycles outside the 26–32 d range? What examinations or tests should be done routinely before providing a method of contraception? How many pill packs (combined or POPs) should be given at initial and return visits? What follow-up is appropriate for COC, POP, implant, and IUD users? How can a provider be reasonably sure that a woman is not pregnant? When can a woman have repeat POIs (DMPA or NET-EN)? When can a woman have a copper-bearing IUD inserted? When can a woman have a LNG IUD inserted? What can a woman do if she misses COCs? What can a woman do if she misses POPs? What can be done if a woman has menstrual abnormalities when using POIs (DMPA or NET-EN)? In 2007, WHO's Director General established the Guidelines Review Committee to ensure that WHO guidelines achieve a high methodological quality and are in accordance with the requirements described in the WHO handbook for guideline development.10 One of the first steps in the updated process was to create groups with different roles to undertake the revision. A Secretariat, comprising personnel within WHO headquarters, oversaw the guideline development process. The Secretariat provided administrative support, coordinated the process for guideline development, and selected participants for the GDG, Evidence Secretariat, and external review group. The GDG consisted of technical experts in the contraceptive field, with geographical representation from all WHO regions. The GDG determined the scope and content of the guidelines; developed population, intervention, comparator and outcome (PICO) questions to guide systematic reviews; and formulated recommendations based on the available evidence. Experts in evidence synthesis formed the Evidence Secretariat and conducted the systematic reviews, following the predetermined PICO question format. A guideline methodologist with expertise in assessing the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was also part of the Evidence Secretariat. Finally, the external review group provided feedback on the draft guidelines from a real-world perspective. The GRADE system offers a process for rating the quality of evidence from systematic reviews.11 The GRADE approach considers the study design (i.e. randomized trial or observational study), risk of bias, inconsistency across studies, indirectness, data imprecision, and publication bias to categorize evidence as high, moderate, low, or very low quality. In addition to the GRADE rating, consideration of the values and preferences of contraceptive users, the balance of benefits and harms of contraceptive use, and the resource implications associated with providing contraceptive services also weighed into the determination of the strength of a particular guideline recommendation. For the third edition of the SPR, the GDG reviewed 19 topics related to five new contraceptive methods (Table 2): the two-rod levonorgestrel implant (Sino-implant (II)), subcutaneously-administered depot medroxyprogesterone acetate, combined transdermal contraceptive patch, combined contraceptive vaginal ring, and ulipristal acetate for emergency contraception. Additionally, the GDG considered guidance regarding the initiation of regular contraception after emergency contraceptive use. The GDG evaluated direct evidence from 15 systematic reviews and extrapolated indirect evidence from pharmacologically similar contraceptive methods in the absence of direct evidence. In addition to the GRADE evidence profiles, the GDG explicitly considered the values and preferences of choice, ease of use, adverse effects, efficacy, and the importance of balancing the benefits of preventing unintended pregnancy with potential harms of contraceptive method use. The GDG designated a “strong” recommendation as one that could be adopted as policy in most situations, whereas a “conditional” recommendation would require substantial debate and involvement of various stakeholders before universal implementation in all or most settings.10 The goal of WHO and its partners is to use the best available evidence to develop SPR guidance; however, many recommendations are based on limited or indirect evidence. For example, limited information exists on optimal follow-up schedules after contraceptive method initiation, and further investigations on the impact of follow-up on contraceptive continuation can refine existing recommendations. Additionally, certain recommendations are based on indirect evidence from similar contraceptive methods in the absence of direct evidence. As an example, recommendations on when to start the combined contraceptive patch and contraceptive vaginal ring are derived from indirect data from the combined oral contraceptive pill in view of the similarities in the type and dose of hormone used in combined hormonal contraceptive methods. Although these recommendations are likely to be scientifically valid, evidence review highlights the relative lack of available data for newer contraceptive methods. Knowledge gaps for future research in contraceptive management are identified with every update of the SPR.2, 8, 9, 12, 13 Prior SPR editions highlight gaps or key unresolved issues for each of the contraceptive methods, such as “Does starting each pill pack on a specific day of the week increase consistent, correct and continued use of combined oral contraceptive pills?”, “How quickly is protection reliably established by injections of DMPA [depot medroxyprogesterone acetate] and NET-EN [norethisterone enantate]?”, and “What are the mechanisms underlying progestogen-only injectable-associated bleeding abnormalities and how can they best be treated?”.2, 8 During the creation of the third edition of the SPR, the GDG identified the following research gaps related to the new methods: “How long after the start of the menstrual cycle can a woman initiate use of the combined hormonal vaginal ring without needing to use a backup method of contraception?”, “Does the timing of return to fertility after a DMPA subcutaneous injection differ compared with the timing following a DMPA intramuscular injection?”, and “Can Sino-implant (II) be used as an effective method of contraception for more than 4 years?”.12 Another research gap is when to start regular hormonal contraception after using ulipristal acetate for emergency contraception. New evidence suggests that taking ulipristal acetate and progestin-containing contraception in close succession could impact effectiveness of both UPA and the regular contraceptive in terms of pregnancy prevention.12 Recognition of such research gaps during the SPR revision process can serve as a framework to direct future high-quality studies that will further inform recommendations, better meet providers' needs, and improve quality of family planning services. Translating policy into practice is a challenge across all disciplines. To bridge this gap, WHO follows the core principles of dissemination, adaptation, implementation, and monitoring and evaluation after the creation and publication of a guideline.10 Dissemination should be broad and in multiple languages, including online and print publications, peer-reviewed journals, social media, and regional or scientific meetings. Adaptation takes into account specific needs of the country or region. Robust implementation consists of both active strategies (e.g. interactive workshops, educational follow-ups, clinical audits, reminders, and multifaceted interventions) and passive modalities (e.g. dissemination of guidelines in print and electronic form).14 For successful utilization, future guidelines should incorporate these effective but underutilized active techniques into detailed, stepwise implementation plans. Finally, systems to monitor and evaluate SPR use can determine its impact and provide feedback for future implementation strategies.10 In April 2016, WHO convened a Working Group to advise WHO on the preparation of an implementation guide for the MEC/SPR, which could enable users of these guides to put these principles into action. Since the inception of the SPR, WHO has received few requests to translate the SPR into other languages, indicating that the dissemination and uptake of the guidance has been limited, especially when compared with the MEC.15 The Working Group reviewed strategies for dissemination of the SPR guideline, which currently include distribution throughout WHO regional and country offices, coordination with UN partners, broadcasting via social media, and promotion of the recommendations at relevant conferences and regional meetings. Promoting the SPR and MEC together is important because of their inter-related nature; however, the Working Group advised WHO to highlight the distinct purpose of the SPR in addressing contraceptive management when disseminating both guidelines. The Working Group proposed a multipronged approach according to three strategies—(1) improving guideline usability, (2) assisting countries in adapting the guidelines within their local contexts, and (3) turning policy into practice—to structure the implementation guide. To improve the usability of the updated SPR, the document has been reformatted to be more intuitive and user-friendly. For example, the SPR is now organized by contraceptive methods rather than by clinical questions, as previous editions had been. For adaptation, the Working Group strategized ways to help countries to take ownership of the SPR, stressing the importance of integrating the guidance into current service delivery standards and protocols. Currently, only the USA,16 UK,17 and China have adapted the SPR into their national family planning recommendations. Once a country completes adaptation of the SPR guidelines, WHO could provide technical support to assist countries to put policy into practice through monitoring and evaluation. Strategies to achieve this aim include programmatic audits, formation of specialized implementation groups, and creation of a repository of implementation prototypes. Lastly, the Working Group recommended developing a research and documentation plan to inform future steps in the implementation process. For example, WHO can take a qualitative approach to formally assess a country's uptake, utilization, and adaptation of contraceptive guidelines and tools. Research is important not only in monitoring and evaluating the implementation of current guidelines, but also in generating evidence to inform future guideline recommendations. The persistent pursuit to close the research gaps identified through the SPR guideline update process is paramount to promoting quality in family planning care. WHO has a long-standing history of developing and updating its evidence-based guidance on contraceptive method use for a global audience; however, this technical organization recognizes the importance of engaging with partners in the guideline development and subsequent dissemination, adaptation and implementation processes. Many global partners—including the Implementing Best Practices Consortium, the International Federation of Gynecology and Obstetrics, the International Confederation of Midwives, country-level medical societies, and non-governmental organizations—contribute to distributing, promoting uptake, and facilitating utilization of the WHO contraceptive guidelines in individual countries. As one of the four cornerstones of family planning guidance, the SPR plays a vital part in advancing the quality of, and access to, family planning on a global scale. The present report has reviewed the history of the SPR and its evolution as both new evidence and novel contraceptive methods became available. Additionally, the revision process uncovered evidence gaps, highlighting the significant role that research has in informing this guideline's recommendations and continual updates. In view of the relative underuse of the SPR as compared with the MEC, the recent update of the SPR has underscored the need and importance of applying effective and efficient approaches to promote its dissemination and implementation. Findings from high-quality research studies will further strengthen the recommendations to ultimately promote the provision of quality family planning care worldwide. The authors have no conflicts of interest. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

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Young women in sub-Saharan Africa are disproportionally affected by HIV infection and unintended pregnancies. However, hormonal contraceptive (HC) use may influence HIV risk through changes in genital tract microbiota and inflammatory cytokines. To investigate this, 130 HIV negative adolescent females aged 15-19 years were enrolled into a substudy of UChoose, an open-label randomized crossover study (NCT02404038), comparing acceptability and contraceptive product preference as a proxy for HIV prevention delivery methods. Participants were randomized to injectable norethisterone enanthate (Net-En), combined oral contraceptives (COC) or etonorgesterol/ethinyl estradiol combined contraceptive vaginal ring (CCVR) for 16 weeks, then crossed over to another HC for 16 weeks. Cervicovaginal samples were collected at baseline, crossover and exit for characterization of the microbiota and measurement of cytokine levels; primary endpoints were cervical T cell activation, vaginal microbial diversity and cytokine concentrations. Adolescents randomized to COCs had lower vaginal microbial diversity and relative abundance of HIV risk-associated taxa compared to Net-En or CCVR. Cervicovaginal inflammatory cytokine concentrations were significantly higher in adolescents randomized to CCVR compared to COC and Net-En. This suggests that COC use may induce an optimal vaginal ecosystem by decreasing bacterial diversity and inflammatory taxa, while CCVR use is associated with genital inflammation.

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An oral fixed-dose combination of relugolix/estradiol/norethisterone (also known as norethindrone) acetate [Myfembree® (USA); Ryeqo® (EU)] (hereafter referred to as relugolix combination therapy) has been approved in the USA for the management of moderate to severe pain associated with endometriosis in premenopausal women and in the EU for the symptomatic treatment of endometriosis in adult women of reproductive age with a history of previous medical or surgical treatment for their endometriosis. The gonadotropin-releasing hormone (GnRH) receptor antagonist relugolix decreases estradiol and progesterone levels, while the addition of estradiol/norethisterone acetate mitigates hypoestrogenic effects including bone mineral density (BMD) loss and vasomotor symptoms. In two pivotal phase III trials, relugolix combination therapy significantly improved dysmenorrhoea and non-menstrual pelvic pain in premenopausal women with moderate to severe endometriosis. The combination also reduced overall pelvic pain and dyspareunia, reduced analgesic and opioid use, and improved health-related quality of life. The efficacy of relugolix combination therapy was sustained over the longer term (up to 2 years). Relugolix combination therapy was generally well tolerated and BMD loss over time was minimal. With the convenience of a once daily oral dosing regimen, relugolix combination therapy is a valuable addition to the options currently available for the management of endometriosis-associated pain. Endometriosis is a disease where tissue similar to the lining of the uterus grows outside the uterus and may reach other organs. This causes chronic pain as a result of increased inflammation and scar tissue. Women with endometriosis may experience painful menstrual periods, pelvic pain between periods, pain during sex, painful bowel movements and painful urination. Recently, a fixed-dose tablet comprising relugolix, estradiol and norethisterone (also known as norethindrone) acetate [Myfembree® (USA); Ryeqo® (EU)] (hereafter referred to as relugolix combination therapy) has been approved to treat endometriosis-associated pain. The treatment works by decreasing levels of ovarian hormones (estrogen and progesterone). In clinical trials, relugolix combination therapy improved period pain and pain between periods in women with moderate to severe pain associated with endometriosis. The treatment also improved other symptoms (overall pelvic pain and pain during sex), reduced the need for pain medications and improved health-related quality of life. Relugolix combination therapy was generally well tolerated and caused minimal bone loss, which is known to occur with some hormone therapies. With the convenience of a once daily oral pill, relugolix combination therapy is a valuable addition to the options currently available for women with endometriosis-associated pain.

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Abnormal uterine bleeding (AUB) is an acute/chronic variation in the normal menstrual cycle that affects adolescents, women of reproductive age and perimenopausal women. AUB affects approximately 3-30% of reproductive-aged women worldwide, and reduces their quality of life and productivity whilst increasing the overall healthcare burden. Its management requires thorough medical evaluation and individualized treatment. Depending on the severity and cause of AUB, its treatment ranges from lifestyle modifications and hormonal therapies to more invasive procedures or surgery. Although hormonal therapy is the preferred first-line measure in AUB, the available pharmacological options have various adverse effects. There exists a need for safer and more efficient treatment regimens with high patient compliance to effectively treat AUB. Norethisterone, also known as norethindrone, is a widely used synthetic analogue of progestogen. Controlled release formulations of norethisterone/ norethisterone acetate help maintain constant drug levels in the blood and exert minimal side-effects; therefore, they are promising therapeutic agents for effective AUB management. The present review summarizes the epidemiology and diagnosis of AUB, with a focus on the safety, efficacy and tolerability of norethisterone/ norethisterone acetate in AUB management. We also report a case of AUB in a 40-year-old woman, who was treated with NETA tablets. The treatment resulted in favourable outcomes, and patient satisfaction.

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BACKGROUND: Norethisterone acetate (NETA), also known as norethindrone acetate is a progestogens medication that is widely used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders as abnormal uterine bleeding and endometriosis. There is a lack of detailed histological information regarding the effects of NETA on the uterine structure. So, the present study focuses on the uterine histological, histochemical and ultrastructure changes following the exposure to NETA in the albino rats. To do this aim, fourteen adult female albino rats were used. They were randomly divided into two equally groups: Control group and NETA treated group. Albino rats of control group were administered daily food, water and orally distilled water only, while rats of NETA treated group were administered daily orally 20 µg of NETA dissolved in 2 ml distilled water, food, and water. The experiment was continued for three weeks. RESULTS: The findings of the present work indicated that the use of NETA has negative effects on the endometrial epithelium (proliferation, autophagy and apoptosis), glands (necrotic, apoptotic or pseudosecretory glands) and stromal and myometrial reactions (granulocytes, connective tissue remodeling, apoptosis, myocytes hypertrophy). CONCLUSION: This work revealed that NETA has desynchronized progestogenic effect on the uterine tissues of the albino rat and thereby prevent implantation and pregnancy.

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A multicentre phase III clinical trial has been undertaken to compare norethisterone enantate (NET-EN) given by two different treatment regimens and depot-medroxyprogesterone acetate (DMPA). After 18 months of observation, preliminary findings are reported for 1,589 women who received DMPA 150mg every 90 days; 790 women who received NET-EN 200mg every 60 days; and 796 women who received NET-EN, 200mg every 60 days for 6 months, then 200mg every 84 days. The overall discontinuation rates per 100 women were similar for all three treatment groups over the 18 months observation (61.8–63.5 per 100 women). The discontinuation rates for bleeding problems and for personal reasons were also similar for all three treatment groups. However, terminations due to amenorrhoea were significantly higher among DMPA users (12.1 and 17.4 per 100 women at 12 and 18 months) as compared with both NET-EN groups (6.8–8.2 per 100 women at 12 months and 10.4–10.9 per 100 women at 18 months). The only significant difference in pregnancy rates observed between the three groups was a higher rate at 18 months among NET-EN (84 days) users (1.6 per 100 women), as compared with DMPA users (0.2 per 100 women). There was no overall significant difference between the two NET-EN groups, although between the 6 and 18 month's follow-up when the two NET-EN regimens diverged, the NET-EN (84 days) users' pregnancy rate rose significantly, wherease in the NET-EN (60 days) group the pregnancy rate did not change. There was a significantly higher weight gain in those subjects using NET-EN at 60-day intervals compared with those using it at 84-day intervals.

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