Injectable contraception: updates and innovation.

PURPOSE OF REVIEW: Injectable contraception is a highly effective form of birth control that is globally popular. Recent research has focused on ways to make injectables such as depot medroxyprogesterone acetate (DMPA) more accessible and to improve the side-effect profile of injectables. This review will focus on new directions and approaches to the use of injectable contraception. RECENT FINDINGS: Research in the area of injectable contraception has focused on improving access for women through home or self-injection, and also task-shifting and community-based distribution in low-resource areas. Specific to DMPA, studies have focused on lowering the overall dose of medication while maintaining efficacy, and improving drug-delivery systems. More research into the association between DMPA and HIV is needed, and also the effects of administration of DMPA at the time of medication abortion. SUMMARY: Injectable contraceptives are an important part of the global method mix of highly effective birth control. Improving the accessibility and side effect profile of commodities such as DMPA will make injectables even more valuable for women seeking effective contraception.

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.

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.

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.

Co-administration of vismodegib with rosiglitazone or combined oral contraceptive in patients with locally advanced or metastatic solid tumors: a pharmacokinetic assessment of drug-drug interaction potential.

PURPOSE: Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug-drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib's teratogenic potential warranted a DDI study with oral contraceptives (OCs). METHODS: This single-arm, open-label study included two cohorts of patients with locally advanced or metastatic solid malignancies [Cohort 1: rosiglitazone 4 mg (selective CYP2C8 probe); Cohort 2: OC (norethindrone 1 mg/ethinyl estradiol 35 µg; CYP3A4 substrate)]. On Day 1, patients received rosiglitazone or OC. On Days 2-7, patients received vismodegib 150 mg/day. On Day 8, patients received vismodegib plus rosiglitazone or OC. The effect of vismodegib on rosiglitazone and OC pharmacokinetic parameters (primary objective) was evaluated through pharmacokinetic sampling over a 24-h period (Days 1 and 8). RESULTS: The mean ± SD vismodegib steady-state plasma concentration (Day 8, N = 51) was 20.6 ± 9.72 µM (range 7.93-62.4 µM). Rosiglitazone AUC(0-inf) and C(max) were similar with concomitant vismodegib [≤8% change in geometric mean ratios (GMRs); N = 24]. Concomitant vismodegib with OC did not affect ethinyl estradiol AUC(0-inf) and C(max) (≤5% change in GMRs; N = 27); norethindrone C(max) and AUC(0-inf) GMRs were higher (12 and 23%, respectively) with concomitant vismodegib. CONCLUSIONS: This DDI study in patients with cancer demonstrated that systemic exposure of rosiglitazone (a CYP2C8 substrate) or OC (ethinyl estradiol/norethindrone) is not altered with concomitant vismodegib. Overall, there appears to be a low potential for DDIs when vismodegib is co-administered with other medications.

A study of the use of Primolut N tablet as a contraceptive in the Kumasi metropolis of Ghana.

This study investigated the use of Primolut N tablet which contains norethisterone 5mg popularly called N-tablet by users as a pre-coital contraceptive by women in the Kumasi metropolis of Ghana. Clients who called at any of the twenty (20) selected Pharmacies in residential areas within the Kumasi metropolis demanding the drug, with or without valid prescriptions were interviewed using a guide. Of the two hundred and twenty (220) users interviewed, 94% demanded the drug for contraception and 6% for menstrual disorders. Sixty one percent of those demanding it for contraception were between the ages 20-25 years. Respondents preferred the use of norethisterone tablets as a contraceptive to other methods because it worked for them and they also found it easy and convenient taking a tablet just before coitus than taking daily oral contraceptive pills. Norethisterone is being used as a pre-coital contraceptive, though the efficacy, safety and reliability of the drug for that purpose is unknown. Until these are known, women must be discouraged from using the drug.

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.

Cyclic and individualized administration of gonadotropin-releasing hormone agonists plus progestogens: an alternative protocol for contraception.

Twenty-one women presenting with different diseases, with absolute or relative contraindications to hormonal contraception or the use of intrauterine devices, received 300-600 micrograms/day buserelin intranasally from the 1st to the 21st day, and 5 mg/day norethisterone acetate orally from the 16th to the 23rd day of the cycle for a total of 245 cycles. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol and testosterone were determined on days 3-5 and 13-15 of the cycle, while progesterone determinations and ovarian sonography were performed during the second half of the cycle. According to progesterone values, 92.7% of the treatment cycles were anovulatory, while in one cycle pregnancy was detected (0.4%). Values of serum LH, FSH and estradiol were low, and in most of the cycles ovarian follicular development was limited to follicles < or = 11 mm. In 21 treatment cycles (9%), statistically significant increases in FSH (p < 0.0001) and LH (p < 0.02), as well as ovarian proliferation to preovulatory follicles or luteinized follicles, were found. It appears that in spite of the high cost of medication and monitoring of patients, this regimen could be useful as an alternative in cases where other forms of contraception are contraindicated or have failed.

A cost-benefit analysis of four hormonal contraceptive methods.

This paper presents the results of a cost-benefit analysis conducted for pregnancy prevention treatment with four hormonal methods of contraception using a managed-care viewpoint. The therapies analyzed are medroxy-progesterone acetate injection (Depo-Provera), levonorgestrel subdermal implants (Norplant), progestogenonly oral tablets (Nor-QD), and combination progestogen/estrogen oral tablets (Ortho-Novum 7/7/7). Cost and benefits associated with the use of therapies are identified and analyzed based on the cost per patient-day of effective pregnancy prevention. The analysis demonstrates that all four methods have a positive net benefit, with Depo-Provera having the highest net benefit. This information can provide decision makers within a pharmacy and therapeutics committee of a managed-care organization the framework on which to base formulary decisions.

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.

Two-stage sampling in pharmaceutical applications.

In the pharmaceutical industry, some tests for quality assurance before, during and after the manufacture of a drug product involve a two-stage sampling technique. We propose statistical testing procedures in a two-stage sampling problem with large within-class sample sizes. We also derive a two-stage sampling plan by minimizing the expected squared volume (or the generalized variance) of the confidence region related to the test. We present two examples to illustrate the proposed methods.

[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.

Assessment of a new low-dose once-a-month injectable contraceptive.

Norethisterone (NET) in combination with mestranol (ME), in a macrocrystalline aqueous suspension that provides sustained release of steroids, was assessed as a once-a-month injectable contraceptive in ten healthy women of reproductive age. The ovarian function was studied before and after the intramuscular administration of 12mg NET plus 1.2mg ME, delivered as crystals of 150 micron average size. Serial blood samples were taken throughout the injection intervals in all women to measure serum progesterone (P), estradiol (E2), and NET. The NET/ME preparation effectively inhibited ovulation in 23 out of the 25 injection intervals studied. The administration of this formulation induced in some women a small degree of follicular maturation not followed by luteal activity. The endometrial bleeding patterns after each injection showed a bleeding-free period of two to three weeks. The overall data demonstrate that the parenteral administration of a macrocrystalline steroid preparation of NET/ME can bring about a sustained release contraceptive system at a substantially lower dose than those currently employed in once-a-month injectable contraception.

Influence of psychosocial factors on adolescent compliance with oral contraceptives.

This paper prospectively tests the influence of a variety of sociomedical and psychosocial factors on compliance with oral contraceptives among adolescent females from a population at high risk for pregnancy. Fifty-six females aged 14-19 yr from a lower socioeconomic background received a battery of pretest measurements and were then given Ortho-Novum 1/35 combined with riboflavin during an initial visit and 1-, 2-, and 4-month follow-ups. Compliance was measured at each follow-up using a Guttman scale consisting of: (1) avoidance of pregnancy, (2) appointment adherence, (3) pill count, and (4) urinary fluorescence for riboflavin. Six factors were found to be significantly associated with noncompliance: (1) multiple sexual partners, (2) appointment being made by the adolescent, (3) low evaluation of personal health, (4) feelings of hopelessness, (5) worry about becoming pregnant, and (6) previous abortion. These findings suggest that certain indicators of sexual activity and social psychological status may help predict noncompliance in some adolescent females.

A comparative study of standard-dose and low-dose oral contraceptives in rural Bangladesh.

Fieldworkers in a rural area of Bangladesh distributed two kinds of oral contraceptives to women accepting this method; 286 women received a standard-dose oral contraceptive and 366 women one mile away were given a low-dose pill of the same formulation. Continuation rates at 12 months were 86% for the standard-dose and 75% for the low-dose pill. Worker performance accounted for some of the difference, but the results suggest that the lower-dose pill is less acceptable in rural Bangladesh than the standard-dose pill of the same formulation.

PIP: A study was undertaken in rural Bangladesh to compare continuation rates of standard-dose Norinyl in 286 acceptors, and continuation rates of low-dose pill of the same formulation, Brevicon, in 357 acceptors. Acceptors of Norinyl were generally younger and better educated, while socioeconomic characteristics of both groups were similar. The cumulative continuation rate was significantly higher for Norinyl acceptors from 6 months on. Main reason for discontinuation was pregnancy. Continuation rates for both types of pill, however, appeared to be high; this fact suggests that either pill could be acceptable, and that differences in continuation rates were not caused by differences in age and education, but by differences in the performance of the field workers who were gathering data.