Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: Phase 3 clinical trial results.

OBJECTIVE: To assess the contraceptive efficacy, safety, and tolerability of a contraceptive transdermal delivery system, (TDS; TWIRLAⓇ) containing levonorgestrel (LNG) and ethinyl estradiol (EE). STUDY DESIGN: This single-arm, open-label, multicenter, 1-year (13 cycle), phase 3 study enrolled sexually active women ≥18 years old at risk for pregnancy irrespective of body mass index (BMI). Women used patches in 28-day cycles (3 consecutive administrations of 7-day patches followed by 7 days off-treatment/patch-free week). We assessed contraceptive efficacy by the Pearl Index (PI) in women 18 to 35 years, excluding cycles without intercourse or when other contraceptive methods were used. RESULTS: The study enrolled 2032 demographically diverse women in the US, of which 35.3% had a BMI ≥30 kg/m2. In the primary efficacy analysis, the PI (95% confidence interval) was 5.8 (4.5-7.2) pregnancies per 100 woman-years. PIs trended higher as BMI increased; the PI was 4.3 (2.9-5.8) in women with BMI <30 kg/m2 and 8.6 (5.8-11.5) in women with BMI ≥30 kg/m2. Hormone-related treatment-emergent adverse events included nausea (4.1%) and headache (3.6%); 11% of women discontinued due to adverse events. Four women (all with BMIs ≥30 kg/m2) reported thromboembolic events considered related to treatment. CONCLUSIONS: The low-dose LNG/EE TDS was effective in preventing pregnancy in a population of women representative of US demographics. Efficacy was reduced in women with BMI ≥30 kg/m2. The TDS safety and tolerability profile was consistent with other similar dose combined hormonal contraceptives. Results of this phase 3 study supported the US Food and Drug Administration approval of TWIRLAⓇ for prevention of pregnancy in women with BMI <30 kg/m2. IMPLICATIONS: TDS (120 µg/day levonorgestrel and 30 µg/day ethinyl estradiol) is an effective, low-dose transdermal contraceptive patch with favorable tolerability profile approved for prevention of pregnancy in women with BMI <30 kg/m2. TDS has reduced effectiveness in women with BMI ≥30 kg/m2.

Adhesion Evaluation of AG200-15: An Investigational Transdermal Contraceptive Delivery System.

INTRODUCTION: AG200-15, an investigational transdermal contraceptive delivery system or patch, is designed to be a low-dose, non-daily, combined hormonal contraceptive option for women. In this phase 1 study, the in vivo adhesion of the AG200-15 patch was compared to Xulane®, the only contraceptive patch available in the USA. METHODS: This phase 1, randomized, open-label, single-dose, two-treatment, two-period crossover adhesion study compared the 7-day adhesion of the AG200-15 and Xulane contraceptive patches. Eighty-three women, ages 18 to 35 years old, with body mass index (BMI) ≥ 19 kg/m2 and < 35 kg/m2, and weight ≥ 48 kg and < 90 kg were enrolled. Trained study site personnel used a five-point scale to assess patch adhesion daily. A score of 0 reflected at least 90% adhesion; while a score of 4 represented complete detachment of the patch. The primary objective was to compare the adhesion properties of the two patches; AG200-15 would be considered statistically non-inferior to Xulane if the upper 95% confidence limit (CL) of the mean difference in adhesion scores was below + 0.15. RESULTS: The overall mean (standard deviation) scores for AG200-15 (N = 78) and Xulane (N = 77) were 0.14 (0.28) and 0.39 (0.40), respectively (lower scores on the adhesion scale indicate better adhesion). The study demonstrated a difference in mean adhesion scores of - 0.24, meeting the prespecified non-inferiority criterion by demonstrating a one-sided upper CL of - 0.16. Thus, the in vivo adhesion of AG200-15 was shown to be non-inferior to that of Xulane. Most subjects experienced no skin irritation at the application site for either patch and no serious adverse event was reported in the study. CONCLUSION: The in vivo adhesion of AG200-15 is non-inferior to that of Xulane on the basis of the prespecified criterion of the upper bound of the one-sided 95% CL for the mean adhesion score difference being below + 0.15. Both patches were generally well tolerated. FUNDING: Agile Therapeutics, Inc.

Management Strategies and Outcomes for Hyponatremia in Cirrhosis in the Hyponatremia Registry.

Aim: Treatment practices and effectiveness in cirrhotic patients with hyponatremia (HN) in the HN Registry were assessed. Methods: Characteristics, treatments, and outcomes were compared between patients with HN at admission and during hospitalization. For HN at admission, serum sodium concentration [Na] response was analyzed until correction to > 130 mmol/L, switch to secondary therapy, or discharge or death with sodium ≤ 130 mmol/L. Results: Patients with HN at admission had a lower [Na] and shorter length of stay (LOS) than those who developed HN (P < 0.001). Most common initial treatments were isotonic saline (NS, 36%), fluid restriction (FR, 33%), and no specific therapy (NST, 20%). Baseline [Na] was higher in patients treated with NST, FR, or NS versus hypertonic saline (HS) and tolvaptan (Tol) (P < 0.05). Treatment success occurred in 39%, 39%, 52%, 78%, and 81% of patients with NST, FR, NS, HS, and Tol, respectively. Relapse occurred in 55% after correction and was associated with increased LOS (9 versus 6 days, P < 0.001). 34% admitted with HN were discharged with HN corrected. Conclusions: Treatment approaches for HN were variable and frequently ineffective. Success was greatest with HS and Tol. Relapse of HN is associated with increased LOS.

Current Management of Hyponatremia in Acute Heart Failure: A Report From the Hyponatremia Registry for Patients With Euvolemic and Hypervolemic Hyponatremia (HN Registry).

BACKGROUND: Hyponatremia (HN) occurs commonly in patients with acute heart failure and confers a worse prognosis. Current HN treatment varies widely, with no consensus. This study recorded treatment practices currently used for patients hospitalized with acute heart failure and HN. METHODS AND RESULTS: Data were collected prospectively from 146 US sites on patients hospitalized with acute heart failure and HN (serum sodium concentration [Na+] ≤130 mEq/L) present at admission or developing in the hospital. Baseline variables, HN treatment, and laboratory values were recorded. Of 762 patients, median [Na+] was 126 mEq/L (interquartile range, 7) at baseline and increased to 130 mEq/L at discharge. Fluid restriction was the most commonly prescribed therapy (44%), followed by no specific HN treatment beyond therapy for congestion (23%), isotonic saline (5%), tolvaptan (4%), and hypertonic saline (2%). Median rate of change in [Na+] varied by treatment (0.5 [interquartile range, 1.0] to 2.3 [8.0] mEq/L/d) and median treatment duration ranged from 1 (interquartile range, 1) to 6 (5) days. Fluid restriction and no specific HN treatment resulted in similar changes in [Na+], and were least effective in correcting HN. Few patients (19%) had [Na+] ≥135 mEq/L at discharge. CONCLUSIONS: The most commonly used treatment approaches for HN (fluid restriction and no specific treatment) in acute heart failure increased [Na+] minimally, and most patients remained hyponatremic at discharge.

Tolvaptan use in cancer patients with hyponatremia due to the syndrome of inappropriate antidiuretic hormone: a post hoc analysis of the SALT-1 and SALT-2 trials.

Hyponatremia is a common electrolyte disorder in cancer patients and has been associated with poor prognosis. A frequent cause of cancer-related hyponatremia is the syndrome of inappropriate antidiuretic hormone (SIADH). This study was a post hoc subgroup analysis of the SALT-1 (Study of Ascending Levels of Tolvaptan in Hyponatremia) and SALT-2 clinical trials. Hyponatremic subjects with SIADH and cancer received the oral selective vasopressin V2-receptor antagonist tolvaptan (n = 12) or matching placebo (n = 16) once-daily for 30 days. The initial tolvaptan dose (15 mg) was titrated over 4 days to 30 or 60 mg per day, as needed, according to serum sodium level and tolerability. Baseline serum sodium levels in the SIADH/cancer cohort of the SALT trials was 130 and 128 mEq/L for tolvaptan and placebo, respectively. Mean change from baseline in average daily serum sodium AUC for tolvaptan relative to placebo was 5.0 versus -0.3 mEq/L (P < 0.0001) at day 4, and 6.9 versus 1.0 mEq/L (P < 0.0001) at day 30; the observed treatment effects were similar to those in the overall SIADH population (i.e., with and without cancer) at both time points. Serum sodium normalization was observed in 6/12 and 0/13 subjects at day 4 and 7/8 and 2/6 subjects at day 30 in the tolvaptan and placebo groups, respectively (P < 0.05 for both). Common treatment-emergent AEs for tolvaptan were consistent with previously reported results. In this post hoc study of the SALT trial population, oral tolvaptan was an effective and safe therapy for the treatment of hyponatremia in subjects with SIADH and cancer.

The occurrence of hyponatremia and its importance as a prognostic factor in a cross-section of cancer patients.

BACKGROUND: Hyponatremia is prognostic of higher mortality in some cancers but has not been well studied in others. We used a longitudinal design to determine the incidence and prognostic importance of euvolemic and hypervolemic hyponatremia in patients following diagnosis with lymphoma, breast (BC), colorectal (CRC), small cell lung (SCLC), or non-small cell lung cancer (NSCLC). METHODS: Medical record and tumor registry data from two large integrated delivery networks were combined for patients diagnosed with lymphoma, BC, CRC, or lung cancers (2002-2010) who had ≥1 administration of radiation/chemotherapy within 6 months of diagnosis and no evidence of hypovolemic hyponatremia. Hyponatremia incidence was measured per 1000 person-years (PY). Cox proportional hazard models assessed the prognostic value of hyponatremia as a time-varying covariate on overall survival (OS) and progression-free survival (PFS). RESULTS: Hyponatremia incidence (%, rate) was 76 % each, 1193 and 2311 per 1000 PY, among NSCLC and SCLC patients, respectively; 37 %, 169 in BC; 64 %, 637 in CRC, and 60 %, 395 in lymphoma. Hyponatremia was negatively associated with OS in BC (HR 3.7; P = <.01), CRC (HR 2.4; P < .01), lung cancer (HR 2.4; P < .01), and lymphoma (HR 4.5; P < .01). Hyponatremia was marginally associated with shorter PFS (HR 1.3, P = .07) across cancer types. CONCLUSIONS: The incidence of hyponatremia is higher than previously reported in lung cancer, is high in lymphoma, BC, and CRC and is a negative prognostic indicator for survival. Hyponatremia incidence in malignancy may be underestimated. The effects of hyponatremia correction on survival in cancer patients require further study.

Diagnosing and Treating the Syndrome of Inappropriate Antidiuretic Hormone Secretion.

BACKGROUND: The syndrome of inappropriate antidiuretic hormone secretion is the most common cause of hyponatremia in clinical practice, but current management of hyponatremia and outcomes in patients with syndrome of inappropriate antidiuretic hormone secretion are not well understood. The objective of the Hyponatremia Registry was to assess the current state of management of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion in diverse hospital settings, specifically which diagnostic and treatment modalities are currently used and how rapidly and reliably they result in an increase in serum sodium concentration ([Na(+)]). A secondary objective was to determine whether treatment choices and outcomes differ across the United States and the European Union. METHODS: The Hyponatremia Registry recorded selected diagnostic measures and use, efficacy, and outcomes of therapy for euvolemic hyponatremia diagnosed clinically as syndrome of inappropriate antidiuretic hormone secretion in 1524 adult patients with [Na(+)] ≤130 mEq/L (1034 from 146 US sites and 490 from 79 EU sites). A subgroup of patients with more rigorously defined syndrome of inappropriate antidiuretic hormone secretion via measurement of relevant laboratory parameters was also analyzed. RESULTS: The most common monotherapy treatments for hyponatremia in syndrome of inappropriate antidiuretic hormone secretion were fluid restriction (48%), isotonic (27%) or hypertonic (6%) saline, and tolvaptan (13%); 11% received no active agent. The mean rate of [Na(+)] change (mEq/L/d) was greater for all active therapies than no active treatment. Hypertonic saline and tolvaptan produced the greatest mean rate of [Na(+)] change (interquartile range, both 3.0 [6.0] mEq/L/d) compared with lower interquartile range rates of [Na(+)] change for isotonic saline (1.5 [3.0] mEq/L/d) and fluid restriction (1.0 [2.3] mEq/L/d). The general pattern of responses was similar in both the US and EU cohorts. At discharge, [Na(+)] was <135 mEq/L in 75% of patients and ≤130 mEq/L in 43% of patients. Overly rapid correction occurred in 10.2% of patients. CONCLUSIONS: Current treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion often uses therapies with limited efficacy; the most commonly chosen monotherapy treatments, fluid restriction and isotonic saline, failed to increase the serum [Na(+)] by ≥5 mEq/L in 55% and 64% of monotherapy treatment episodes, respectively. Appropriate laboratory tests to diagnose syndrome of inappropriate antidiuretic hormone secretion were obtained in <50% of patients; success rates in correcting hyponatremia were significantly higher when such tests were obtained. Few outcome differences were found between the United States and the European Union. A notable exception was hospital length of stay; use of tolvaptan was associated with significantly shorter length of stay in the European Union but not in the United States. Despite the availability of effective therapies, most patients with syndrome of inappropriate antidiuretic hormone secretion were discharged from the hospital still hyponatremic.

Patterns of treatment and correction of hyponatremia in intensive care unit patients.

PURPOSE: The goal of this study was to examine the real-world patterns of care and interventions among intensive care unit (ICU) patients with hypervolemic and euvolemic hyponatremia using a large clinical database. MATERIALS AND METHODS: The Phillips eICU Research Institute database was used to investigate hyponatremia treatment patterns and trends, mortality, and ICU and hospital length of stay. Demographics, clinical characteristics, and outcome variables were compared in patients corrected for hyponatremia using both a more strict and a less strict definition. RESULTS: At admission, 35%, 55%, and 10% of patients had mild, moderate, and severe hyponatremia, respectively. At the end of an ICU stay, the percentage of patients who did not have corrected serum sodium concentration was 48% (using a more strict definition) and 24% (using a less strict definition). Using either definition of correction, patients with serum sodium correction had lower mortality and longer survival than did patients without corrected serum sodium concentration. CONCLUSIONS: A significant proportion of hyponatremia is not corrected during an ICU stay. Critically ill patients with hyponatremia who have their serum sodium corrected have lower mortality and longer survival, highlighting the need for more attention to hyponatremia and its correction in critically ill patients.

Current treatment practice and outcomes. Report of the hyponatremia registry.

Current management practices for hyponatremia (HN) are incompletely understood. The HN Registry has recorded diagnostic measures, utilization, efficacy, and outcomes of therapy for eu- or hypervolemic HN. To better understand current practices, we analyzed data from 3087 adjudicated adult patients in the registry with serum sodium concentration of 130 mEq/l or less from 225 sites in the United States and European Union. Common initial monotherapy treatments were fluid restriction (35%), administration of isotonic (15%) or hypertonic saline (2%), and tolvaptan (5%); 17% received no active agent. Median (interquartile range) mEq/l serum sodium increases during the first day were as follows: no treatment, 1.0 (0.0-4.0); fluid restriction, 2.0 (0.0-4.0); isotonic saline, 3.0 (0.0-5.0); hypertonic saline, 5.0 (1.0-9.0); and tolvaptan, 4.0 (2.0-9.0). Adjusting for initial serum sodium concentration with logistic regression, the relative likelihoods for correction by 5 mEq/l or more (referent, fluid restriction) were 1.60 for hypertonic saline and 2.55 for tolvaptan. At discharge, serum sodium concentration was under 135 mEq/l in 78% of patients and 130 mEq/l or less in 49%. Overly rapid correction occurred in 7.9%. Thus, initial HN treatment often uses maneuvers of limited efficacy. Despite an association with poor outcomes and availability of effective therapy, most patients with HN are discharged from hospital still hyponatremic. Studies to assess short- and long-term benefits of correction of HN with effective therapies are needed.

Hyponatremia in cirrhosis and end-stage liver disease: treatment with the vasopressin V2-receptor antagonist tolvaptan.

Hyponatremia is common in patients with cirrhosis and portal hypertension, and is characterized by excessive renal retention of water relative to sodium due to reduced solute-free water clearance. The primary cause is increased release of arginine vasopressin. Hyponatremia is associated with increased mortality in cirrhotic patients, those with end-stage liver disease (ESLD) on transplant waiting lists, and, in some studies, posttransplantation patients. Clinical evidence suggests that adding serum sodium to model for ESLD (MELD) scoring identifies patients in greatest need of liver transplantation by improving waiting list mortality prediction. Hyponatremia is also associated with numerous complications in liver disease patients, including severe ascites, hepatic encephalopathy, infectious complications, renal impairment, increased severity of liver disease in cirrhosis, and increased hospital stay and neurologic/infectious complications posttransplant. Vasopressin receptor antagonists, which act to increase free water excretion (aquaresis) and thereby increase serum sodium concentration, have been evaluated in patients with hypervolemic hyponatremia (including cirrhosis and heart failure) and euvolemic hyponatremia (SIADH). Tolvaptan, a selective vasopressin V(2)-receptor antagonist, is the only oral agent in this class approved for raising sodium levels in hypervolemic and euvolemic hyponatremia. The SALT trials showed that tolvaptan treatment rapidly and effectively resolved hyponatremia in these settings, including cirrhosis, and it has been shown that this agent can be safely and effectively used in long-term treatment. Fluid restriction should be avoided during the first 24 h of treatment to prevent overly rapid correction of hyponatremia, and tolvaptan should not be used in patients who cannot sense/respond to thirst, anuric patients, hypovolemic patients, and/or those requiring urgent intervention to raise serum sodium acutely.