Low-dose levonorgestrel and ethinyl estradiol patch and pill: a randomized controlled trial.

OBJECTIVE: To compare a new low-dose levonorgestrel and ethinyl estradiol contraceptive patch (Patch) with a combination oral contraceptive (Pill; 100 micrograms levonorgestrel, 20 micrograms ethinyl estradiol) regarding efficacy, safety, compliance, and unscheduled uterine bleeding. METHODS: Women (17-40 years; body mass index 16-60) were randomized in a 3:1 ratio to one of two groups: Patch only (13 cycles) or Pill (six cycles) followed by Patch (seven cycles). Investigators evaluated adverse events during cycles 2, 4, 6, 9, and 13. Participants recorded drug administration and uterine bleeding on daily diary cards. Compliance was assessed by measuring levonorgestrel and ethinyl estradiol plasma levels. Pearl Index (pregnancies per 100 woman-years) was calculated to evaluate efficacy. RESULTS: Participants (N=1,504) were randomized to Patch (n=1,129) or Pill (n=375). Approximately 30% were obese, more than 40% were racial or ethnic minorities, and more than 55% were new users of hormonal contraceptives. Laboratory-verified noncompliance (undetectable plasma drug levels) was 11% of Patch and 12.6% of Pill users at cycle 6. Pearl Indices (95% confidence intervals) for the intention-to-treat population (cycles 1-6) were 4.45 (2.34-6.57) for Patch and 4.02 (0.50-7.53) for Pill; excluding laboratory-verified noncompliant participants, Pearl Indices were 2.82 (0.98-4.67) for Patch and 3.80 (0.08-7.52) for Pill (differences not statistically significant). Incidence of unscheduled bleeding and incidence and severity of adverse events were similar for both contraceptives (no statistically significant difference). CONCLUSIONS: Efficacy and safety of the new contraceptive Patch are comparable to those of a Pill. Laboratory-verified noncompliance and bleeding profile are similar between the two treatments. The Patch was well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01181479. LEVEL OF EVIDENCE: I.

Ovarian activity in obese and nonobese women treated with three transdermal contraceptive patches delivering three different doses of ethinyl estradiol and levonorgestrel.

BACKGROUND: The effect of obesity on ovarian follicular suppression in women using low-estrogen dose contraceptive patches has not been determined. STUDY DESIGN: A Phase II, parallel-group, multicenter, three-cycle study evaluated three patches containing different ethinyl estradiol (EE) and levonorgestrel (LNG) doses. Serum levels of EE, LNG, sex hormone-binding globulin and progesterone were compared in 41 obese [body mass index (BMI) ≥30] and 75 nonobese (BMI <30) women. RESULTS: Suppression of ovulation during the luteal phase was dose dependent, with the highest dose (AG200-15) preventing progesterone increases in all women (cycles 2-3). In the follicular phase, the lowest-dose patch had the highest rate of increased progesterone in nonobese subjects. Progesterone levels ≥3.0 ng/mL in the follicular phase were more common in obese than nonobese women. CONCLUSIONS: AG200-15 suppresses ovulation in obese and nonobese women. All three patches found increased progesterone in the follicular phase, albeit more in obese versus nonobese women.

Therapeutically equivalent pharmacokinetic profile across three application sites for AG200-15, a novel low-estrogen dose contraceptive patch.

BACKGROUND: AG200-15 Agile Patch (AP) is a novel 7-day contraceptive patch providing ethinyl estradiol (EE) exposure comparable to low-dose combination oral contraceptives. This study determined whether application of the AP to three different anatomical sites (lower abdomen, buttock and upper torso) influences the pharmacokinetic profile of EE and levonorgestrel (LNG). STUDY DESIGN: In this open-label, three-period, crossover study, 24 subjects were randomized to one of six treatment sequences; each included application of patch to abdomen, buttock and upper torso, with the AP worn on one site for 7 days. After a 7-day washout, a new patch was applied to the next anatomical site. Multiple blood samples were collected up to 240 h after patch application. RESULTS: For plasma EE levels, median time to maximum drug concentration (Tmax, 24-48 h) and mean maximum concentration (Cmax, 47.9-61.5 pg/mL) were similar among application sites. Compared with lower abdomen, EE exposure was higher (16%-30%) at buttock and upper torso (15%-22%). For plasma LNG levels, median Tmax (72-120 h) and mean Cmax (1436-1589 pg/mL) were similar across application sites. Compared with lower abdomen, LNG exposure was higher at buttock (1%-7%) and upper torso (16%-17%). No serious adverse events (AEs) or AE-related discontinuations occurred. The most common treatment-emergent AEs were nausea, application site pruritus and headache, with frequencies comparable across anatomical sites. CONCLUSIONS: Absorption from the abdomen was slightly lower versus other sites; however, exposure to EE and LNG for all sites was therapeutically equivalent. The AP was well tolerated at all three anatomical sites.

Pharmacokinetics and adhesion of the Agile transdermal contraceptive patch (AG200-15) during daily exposure to external conditions of heat, humidity and exercise.

BACKGROUND: This study compares the pharmacokinetic profile, adhesion and safety of the AG200-15 Agile Patch (AP), a novel contraceptive patch releasing low-dose ethinyl estradiol (EE) and levonorgestrel (LNG), during wear under external conditions of heat, humidity and exercise versus normal activities. STUDY DESIGN: This open-label, three-period, five-treatment, crossover study randomized 24 healthy women to one of six external condition sequences. Each sequence included one normal wear and two external conditions periods. Participants wore the AP for 7 days under normal conditions or conditions of daily sauna, treadmill, whirlpool or cool water immersion, with a 7-day washout between treatments. Blood samples were collected for pharmacokinetic evaluations. RESULTS: Twenty-four subjects completed the study. For EE, the mean maximum concentration level (Cmax), area under the plasma concentration-time curve from time 0 to 168 h (AUC(0-168)) and area under the plasma concentration-time curve from time 0 to infinity (AUC(0-inf)) were higher during normal conditions compared with all external conditions (geometric means ratio range: 80%-93%), except cool water. Mean steady-state concentrations (C(ss)) of EE were highest under normal conditions, followed by cool water, sauna, whirlpool and treadmill. The LNG mean C(max), AUC(0-168), AUC(0-inf) and C(ss) were higher under normal wear versus all other conditions (geometric means ratios: 75%-82%), with the exception of AUC(0-168), AUC(0-inf) and C(ss) for cold water. Median times to maximum concentration (Tmax) for EE and LNG were comparable across conditions. Patch adhesion was excellent under all conditions. Adverse events were mild, with none serious or leading to discontinuation. CONCLUSIONS: Although slightly lower mean drug concentration levels were observed for whirlpool, treadmill and sauna, drug concentrations under all conditions were well within therapeutic ranges established for the AP during normal wear and within ranges reported for low-dose combination oral contraceptives. Patch adhesion was excellent; the AP was safe and well tolerated under all conditions.

Ethinyl estradiol and levonorgestrel pharmacokinetics with a low-dose transdermal contraceptive delivery system, AG200-15: a randomized controlled trial.

BACKGROUND: This study evaluated the ethinyl estradiol (EE) and levonorgestrel (LNG) pharmacokinetic profiles of AG200-15, a transdermal contraceptive delivery system, compared with a combination oral contraceptive (COC) containing EE 35 mcg and norgestimate 250 mcg. STUDY DESIGN: A Phase 1, open-label, single-center study in 36 healthy women was conducted over three cycles with a randomized crossover design. After a run-in cycle of 21 days on and 7 days off with AG200-15, participants were randomized to receive one of two treatments: a 21/7-day cycle of AG200-15 either followed or preceded by one cycle of the COC. This trial is registered on ClinicalTrials.gov under the identifier NCT01243580. RESULTS: During the third week of AG200-15 use, mean (±standard deviation) maximum serum concentration (C(max)), area under the curve(0-168 h) and steady-state concentration (C(ss48-168 h)) for EE were 51.3 ± 17.3 pg/mL, 6.26 ± 2.46 ng h/mL and 35.7 ± 14.5 pg/mL, respectively; for LNG, the corresponding values were 2400 ± 1140 pg/mL, 317 ± 159 ng h/mL and 1847 ± 930 pg/mL, respectively. The AG200-15 EE C(max) was approximately 60% lower and the EE C(ss) was 15%-20% lower than those obtained with the COC. The calculated daily dose of AG200-15 was equivalent to a 30-mcg EE COC. The most common adverse events (AEs; >10%) in the AG200-15 group were headache, nausea and application-site irritation. All drug-related AEs were mild, and no serious AEs were reported. CONCLUSIONS: EE and LNG daily exposure during AG200-15 treatment was within the range reported for a low-dose COC. The daily EE dose with AG 200-15 was equivalent to a 30-mcg COC and was safe and well tolerated.

Pharmacokinetics, tolerability and cycle control of three transdermal contraceptive delivery systems containing different doses of ethinylestradiol and levonorgestrel.

BACKGROUND: The only available contraceptive patch, Ortho Evra®, delivers a relatively high dose of estrogen. MATERIALS AND METHODS: Three transdermal contraceptive delivery systems (TCDS) containing low doses of ethinylestradiol (EE) and levonorgestrel (LNG) were evaluated in two open-label randomized trials. In a phase 1, two-period, cross-over trial, AG200-12.5 and AG200LE were compared with a 150 µg LNG/30 µg EE oral contraceptive (OC) (Levlen®) in 39 women. In a phase 2, parallel-group, multicenter, three-cycle study, AG200LE, AG200-12.5 and a higher-dose formulation, AG200-15, were evaluated in 123 women. RESULTS: In Study 1, mean steady-state plasma concentrations (Css, pg/mL) for the TCDS were 17 pg/mL to 26 pg/mL for EE and 1117 pg/mL to 1505 pg/mL for LNG (for AG200LE and AG200-12.5 respectively). Maximum concentration (Cmax) and Css for both analytes were significantly lower than for Levlen. In both studies, the Css levels for EE and LNG in all groups were within the ranges reported for low-dose OCs. Cycle control for AG200-15, assessed by breakthrough bleeding and spotting episodes as well as number of days of unscheduled bleeding and/or spotting, was similar to that reported for low-dose OCs. Most adverse events were considered mild to moderate in intensity. The incidence of patches falling off was <2%. CONCLUSIONS: All three patches exhibited excellent safety and wearability profiles while maintaining plasma drug levels required for ovulation suppression and adequate cycle control. A slight increase in the EE dose in AG200-15 still places this TCDS within the range of low-dose OCs, with EE exposure much lower than reported for Ortho Evra. AG200-15 was selected for further testing in phase 3 studies.

Menorrhagia Impact Questionnaire: assessing the influence of heavy menstrual bleeding on quality of life.

OBJECTIVE: Menorrhagia, or heavy menstrual bleeding (HMB), has a negative impact on women's quality of life (QOL). The objective was to develop, validate, and assess the performance of a disease-specific patient-reported outcome (PRO) measurement instrument for HMB (the Menorrhagia Impact Questionnaire [MIQ]). RESEARCH DESIGN AND METHODS: The MIQ was designed to measure the effect of HMB on a woman's self-assessment of menstrual blood loss (MBL), limitations in social/leisure activities, physical activities, and ability to work. Meaningfulness of these observed MBL changes were also measured. The development and psychometric validation of the MIQ was performed utilizing data from a long-term safety study of tranexamic acid (Lysteda * *Lysteda is a registered trade name of Ferring Pharmaceuticals Inc., Parsippany, NJ, USA. ), with comparison to an age-matched normal control group recruited from the general population. Performance of the MIQ was also evaluated using data from a six-cycle, randomized, double-blind, clinical study of tranexamic acid for the treatment of HMB. Correlations and sensitivity of each pertinent MIQ item to the treatment-induced changes in MBL were assessed, and the minimally important differences (MID) for the individual MIQ items were determined. RESULTS: The psychometric properties of the MIQ were fully validated. Correlations between individual MIQ items and changes in MBL were statistically significant (p < 0.001). A clear differentiation between tranexamic acid and placebo groups confirmed sensitivity of the MIQ and its ability to detect treatment-induced changes in MBL. MIDs were estimated for the individual MIQ items, with sensitivities and specificities in the 64-79% and 63-82% ranges using receiver operating characteristic (ROC) curve analyses, respectively. MIDs were found to be equal to or greater than 0.5. Statistically significant treatment differences were also observed for the proportions of subjects achieving at least 1-point improvement in MIQ scores. CONCLUSION: The MIQ contains validated constructs important to women with HMB. CLINICAL TRIAL REGISTRATION: NCT00113568 and NCT00386308 (ClinicalTrials.gov ID).

Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial.

OBJECTIVE: To assess the efficacy and safety of an oral formulation of tranexamic acid for the treatment of heavy menstrual bleeding. METHODS: Adult women with heavy menstrual bleeding (mean menstrual blood loss 80 mL or more per cycle) were enrolled in a double-blind, placebo-controlled study. After two pretreatment menstrual cycles, women were randomized to receive tranexamic acid 3.9 g/d or placebo for up to 5 days per menstrual cycle through six cycles. To meet the prespecified three-component primary efficacy end point, mean reduction in menstrual blood loss from baseline with tranexamic acid treatment needed to be 1) significantly greater than placebo, 2) greater than 50 mL, and 3) greater than a predetermined meaningful threshold (36 mL or higher). Health-related quality of life was measured using a validated patient-reported outcome instrument. RESULTS: Women who received tranexamic acid (n=115) met all three primary efficacy end points: first, a significantly greater reduction in menstrual blood loss of -69.6 mL (40.4%) compared with -12.6 mL (8.2%) in the 72 women who received placebo (P<.001); reduction of menstrual blood loss exceeding a prespecified 50 mL; and last, reduction of menstrual blood loss considered meaningful to women. Compared with women receiving placebo, women treated with tranexamic acid experienced significant improvements in limitations in social or leisure and physical activities, work inside and outside the home, and self-perceived menstrual blood loss (P<.01). The majority of adverse events were mild to moderate in severity, and the incidence of gastrointestinal adverse events was comparable with placebo. CONCLUSION: In this study, a new oral tranexamic acid treatment was well tolerated and significantly improved both menstrual blood loss and health-related quality of life in women with heavy menstrual bleeding. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00386308. LEVEL OF EVIDENCE: I.

Medical diagnoses and growth of children residing in Russian orphanages.

AIMS: Survey the health of young children residing in Russian orphanages. METHODS: Retrospective chart review of all 193 'healthy' young children (105M:88F, age range 2-72 months) residing in orphanages in Murmansk, Russia. RESULTS: Mothers of these institutionalized children had complex histories including chronic health problems (38%), use of tobacco (41%), alcohol (39%) and illicit drugs (7%). Frequent diagnoses of the children included rickets (21%), foetal alcohol syndrome (10%), anemia (6%), developmental delay (11% mild, 25% moderate, 28% severe), behavioural problems (60%) and 'perinatal encephalopathy' (46%<1 year of age). At orphanage entry, growth delays were common (underweight 34%, short stature 25%, microcephaly 34%). During orphanage residence, height z scores further decreased (p=0.01), but head circumference improved (p<0.0001, paired t-tests). Head circumferences increased significantly in 62% of microcephalic children. Smaller children (z score<-2) at entry exhibited more rapid growth (z score/month) for weight (+0.24 vs. -0.12, p=0.04), height (+0.81 vs. -0.65, p=0.0001), and head circumference (+1.02 vs. -0.10, p=0.0004). Growth correlated with child developmental status. CONCLUSIONS: Young institutionalized children in Murmansk have complex medical status, social histories and frequent growth and developmental delays. Anthropometric measurements-particularly head circumference-improved during orphanage residence in children who entered with more severe growth delays.

Fetal alcohol spectrum disorders in children residing in Russian orphanages: a phenotypic survey.

BACKGROUND: Alcohol use in Russia is among the highest in the world. Over 600,000 children reside in institutional care in Russia, most of them in baby homes and orphanages. The actual prevalence of fetal alcohol spectrum disorders (FASD) among these children is unknown. Therefore, we performed a systematic survey of phenotypic features associated with prenatal alcohol exposure among institutionalized Russian children and related these findings to their growth, development, medical, and social histories. METHODS: Phenotypic screening was conducted of all 234 baby home residents in the Murmansk region of Russia (mean age 21+12.6 months). Phenotypic expression scores were devised based on facial dysmorphology and other readily observable physical findings. Growth measurements from birth, time of placement in the baby home, and at present were analyzed. In addition, the charts of 64% of the children were randomly selected for retrospective review. Information collected included maternal, medical, developmental, and social histories. RESULTS: Thirteen percent of children had facial phenotype scores highly compatible with prenatal alcohol exposure and 45% had intermediate facial phenotype scores. These scores correlated with maternal gravidity and age. At least 40% of mothers in whom history was available ingested alcohol during pregnancy; some also used illicit drugs and tobacco. Z scores for growth measurements corresponded to phenotypic score, as did the degree of developmental delay. Children with no or mild delay had significantly lower phenotypic scores than those with moderate or severe delay (p = 0.04); more than 70% of children with high phenotypic scores were moderately or severely delayed. CONCLUSIONS: More than half of residents of the baby homes in Murmansk, Russia, have intermediate (45%) or high (13%) phenotypic expression scores suggesting prenatal exposure to alcohol. Despite good physical care, stable daily routine, availability of well-trained specialists, and access to medical care, these vulnerable children show significant growth and developmental delays compared with their institutionalized peers.

Efficacy of sertraline in the long-term treatment of obsessive-compulsive disorder.

OBJECTIVE: Obsessive-compulsive disorder (OCD) typically begins early in life and has a chronic course. Despite the need for long-term treatment, the authors found no placebo-controlled studies that have examined the relapse-prevention efficacy of maintenance therapy. METHOD: Patients who met criteria for response after 16 and 52 weeks of a single-blind trial of sertraline were randomly assigned to a 28-week double-blind trial of 50-200 mg/day of sertraline or placebo. Primary outcomes after the double-blind trial were full relapse, dropout due to relapse or insufficient response, or acute exacerbation of OCD symptoms. RESULTS: Of 649 patients at baseline, 232 completed 52 weeks of the single-blind trial and met response criteria. Among the 223 patients in the double-blind phase of the study, sertraline had significantly greater efficacy than placebo on two of three primary outcomes: dropout due to relapse or insufficient clinical response (9% versus 24%, respectively) and acute exacerbation of symptoms (12% versus 35%). Sertraline resulted in improvement in quality of life during the initial 52-week trial and continued improvement, significantly superior to placebo, during the subsequent 28-week double-blind trial. Long-term treatment with sertraline was well tolerated. Over the entire study period, less than 20% of the patients stopped treatment because of adverse events. CONCLUSIONS: Sertraline demonstrated sustained efficacy among patients responding to treatment and was generally well tolerated during the 80-week study. During the study's last 28 weeks, sertraline demonstrated greater efficacy than placebo in preventing dropout due to relapse or insufficient clinical response and acute exacerbation of OCD symptoms.