Treatment satisfaction and clinically meaningful symptom improvement in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia: Secondary results from a 6-month, randomized, double-blind study comparing finasteride plus tadalafil with finasteride plus placebo.

OBJECTIVES: To report the secondary analyses of treatment satisfaction and clinically meaningful improvements in a randomized study comparing coadministration of tadalafil 5 mg with finasteride 5 mg versus finasteride alone in men with prostatic enlargement secondary to benign prostatic hyperplasia. METHODS: An international, randomized, double-blind, parallel study was carried out in men aged ≥45 years who were 5-alpha reductase inhibitor naïve, and had an International Prostate Symptom Score ≥13 and prostate volume ≥30 mL; 350 men received placebo/finasteride and 345 received tadalafil/finasteride over 26 weeks. Treatment satisfaction was assessed per protocol using the Treatment Satisfaction Scale-Benign Prostatic Hyperplasia. Responder cut-offs, analyzed post-hoc were total International Prostate Symptom Score improvement ≥3 points or ≥25% from randomization. RESULTS: Baseline patient characteristics were generally comparable between responders and non-responders. The proportion of patients with an International Prostate Symptom Score improvement ≥3 points with tadalafil/finasteride and placebo/finasteride, respectively, at week 4 was 57.0% and 47.9% (OR 1.45, 95% confidence interval 1.07-1.97), at week 12 was 68.8% and 60.7% (OR 1.48, 95% confidence interval 1.07-2.05) and at week 26 was 71.4% and 70.2% (OR 1.14, 95% confidence interval 0.81-1.61); for IPSS change ≥25%, the corresponding proportions were 44.8% and 32.9% (OR 1.66, 95% confidence interval 1.21-2.28), 55.5% and 51.9% (OR 1.18, 95% confidence interval 0.87-1.62), and 62.0% and 58.3% (OR 1.23, 95% confidence interval 0.89-1.70). Treatment satisfaction at week 26 was significantly greater with tadalafil/finasteride versus placebo/finasteride for total treatment satisfaction scale score (P=0.031) and satisfaction with efficacy subscore (P = 0.025); scores were not significantly different between treatments for satisfaction with dosing or side-effects (both P ≥ 0.371). CONCLUSIONS: Tadalafil/finasteride results in significantly more patients achieving early clinical meaningful improvements in symptoms, and in greater treatment satisfaction versus placebo/finasteride.

An open-label, multicenter, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in Chinese men naïve to phosphodiesterase 5 inhibitor therapy.

The study was to compare treatment preference, efficacy, and tolerability of sildenafil citrate (sildenafil) and tadalafil for treating erectile dysfunction (ED) in Chinese men naοve to phosphodiesterase 5 (PDE5) inhibitor therapies. This multicenter, randomized, open-label, crossover study evaluated whether Chinese men with ED preferred 20-mg tadalafil or 100-mg sildenafil. After a 4 weeks baseline assessment, 383 eligible patients were randomized to sequential 20-mg tadalafil per 100-mg sildenafil or vice versa for 8 weeks respectively and then chose which treatment they preferred to take during the 8 weeks extension. Primary efficacy was measured by Question 1 of the PDE5 Inhibitor Treatment Preference Questionnaire (PITPQ). Secondary efficacy was analyzed by PITPQ Question 2, the International Index of Erectile Function (IIEF) erectile function (EF) domain, sexual encounter profile (SEP) Questions 2 and 3, and the Drug Attributes Questionnaire. Three hundred and fifty men (91%) completed the randomized treatment phase. Two hundred and forty-two per 350 (69.1%) patients preferred 20-mg tadalafil, and 108/350 (30.9%) preferred 100-mg sildenafil (P < 0.001) as their treatment in the 8 weeks extension. Ninety-two per 242 (38%) patients strongly preferred tadalafil and 37/108 (34.3%) strongly the preferred sildenafil. The SEP2 (penetration), SEP3 (successful intercourse), and IIEF-EF domain scores were improved in both tadalafil and sildenafil treatment groups. For patients who preferred tadalafil, getting an erection long after taking the medication was the most reported reason for tadalafil preference. The only treatment-emergent adverse event reported by > 2% of men was headache. After tadalafil and sildenafil treatments, more Chinese men with ED naοve to PDE5 inhibitor preferred tadalafil. Both sildenafil and tadalafil treatments were effective and safe.

Sexual function in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia: results of a 6-month, randomized, double-blind, placebo-controlled study of tadalafil coadministered with finasteride.

INTRODUCTION: Tadalafil (TAD) 5 mg coadministered with finasteride (FIN) 5 mg significantly improves lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) and prostatic enlargement. However, its effects on erectile/sexual function have yet to be fully described. AIM: Assess the effects of TAD/FIN coadministration (compared with placebo [PBO]/FIN) on erectile and sexual function in sexually active men with LUTS and prostatic enlargement secondary to BPH with or without baseline comorbid erectile dysfunction (ED). METHODS: A randomized, double-blind, PBO-controlled study of 695 men (610 sexually active; 450 with baseline ED; 404 sexually active with baseline ED) conducted at 70 sites in 13 countries. TAD 5 mg or PBO once daily coadministered with FIN 5 mg once daily for 26 weeks. MAIN OUTCOME MEASURES: International Index of Erectile Function (IIEF) domain and single-item scores; proportions of patients who demonstrated minimal clinically important differences (MCIDs) in IIEF-Erectile Function domain scores (IIEF-EF; MCID defined as ≥4-point improvement); and sexual dysfunction adverse events (AEs). RESULTS: Compared with PBO/FIN, TAD/FIN resulted in improvements for all IIEF domain and single-item scores assessed among patients with baseline ED (P ≤ 0.002 for all measures) and among patients without baseline ED (P ≤ 0.041 for all measures). Compared with PBO/FIN, significantly larger percentages of sexually active men with baseline ED treated with TAD/FIN achieved an IIEF-EF MCID after 4, 12, and 26 weeks of therapy (P < 0.001 for odds ratio comparisons between TAD/FIN and PBO/FIN at all 3 three postbaseline timepoints). The incidence of sexual AEs was low: five TAD/FIN patients and seven PBO/FIN patients reported sexual AEs, including ED, decreased/lost libido, and ejaculation disorders. CONCLUSIONS: TAD/FIN coadministration for the treatment of men with LUTS and prostatic enlargement secondary to BPH concurrently leads to statistically significant improvements in erectile/sexual function and is well-tolerated, regardless of the presence/absence of ED at treatment initiation.

Decision tree analyses of key patient characteristics in Middle Eastern/North African and Latin American men treated with long-acting and short-acting PDE5 inhibitors for erectile dysfunction.

BACKGROUND: Phosphodiesterase type 5 (PDE5) inhibitors have discontinuation rates as high as 60% in men with erectile dysfunction. Treatment satisfaction has been significantly associated with treatment continuation. Understanding key characteristics in terms of treatment preference, relationship, and lifestyle issues could provide direction on how to improve compliance with PDE5 inhibitor treatment globally. OBJECTIVE: The objective was to identify subgroups of interest in the pooled database of two observational studies conducted in Latin America (LA) and Middle East/North Africa (MENA) exploring patient characteristics and prescription of either a long- or short-acting PDE5 inhibitor at baseline. METHODS: Two identical prospective, non-interventional, observational, studies in MENA (N = 493) and LA (N = 511) treated men with an 'on demand' (pro re nata, PRN) PDE5 inhibitor (sildenafil, tadalafil, vardenafil, or lodenafil) during 6 months. In this post-hoc meta-analysis of two observational studies with equal design, pooled data were analyzed to determine patient characteristics and PDE5 inhibitor prescribed/used most likely to be associated with patient expectations, satisfaction, self-esteem, and patient-partner relationships. Decision tree analyses, with and without weighting, were used to identify and describe key features. RESULTS: In each analysis of patient expectations, patient-partner relationship, and self-esteem, we describe the two major subgroups at baseline for each decision tree. Analyses of patient expectations and sexual self-esteem revealed that patients prescribed long-acting PDE5 inhibitors (59%) highlighted the importance of treatment effect duration, second to partner satisfaction with treatment, while patients prescribed short-acting PDE5 inhibitors (32%) placed less importance on treatment effect duration but considerable importance on treatment effect lasting until intercourse completion. Further insights regarding patients, partner relationship characteristics, and treatment expectations were identified. CONCLUSION: Our analyses have described key characteristics, such as self- and partner perceptions, sexual attitudes, and treatment expectations in relation to the patients' country and prescribed treatment, which might guide treatment decisions in MENA and LA men with ED.

Back pain in patients with severe osteoporosis on teriparatide or antiresorptives: a prospective observational study in a multiethnic population.

INTRODUCTION: We evaluated reduced back pain in a multiethnic population treated with teriparatide and/or antiresorptives in real-life clinical settings over 12 months. METHODS: This prospective observational study comprised 562 men and postmenopausal women (mean age 68.8 years) receiving either teriparatide (n = 230), antiresorptives (raloxifene or bisphosphonates; n = 322), or both (n = 10) for severe osteoporosis. The primary endpoint was the relative risk of new/worsening back pain at six months. RESULTS: At baseline, a higher proportion of teriparatide-treated than antiresorptive-treated patients had severe back pain (30.9% vs. 17.7%), extreme pain/discomfort (25.3% vs. 16.8%), extreme anxiety/depression (16.6% vs. 7.8%) and were confined to bed (10.0% vs. 5.3%). Teriparatide-treated patients had higher visual analog scale (VAS) scores for pain (5.8 ± 2.42 vs. 5.1 ± 2.58) and lower mean European Quality of Life-5 Dimensions (EQ-5D) scores (37.7 ± 29.15 vs. 45.5 ± 31.42) than antiresorptive-treated patients. The incidence of new/worsening back pain at six months for patients on teriparatide and antiresorptives was 9.8% and 10.3% (relative risk 0.99, 95% confidence interval 0.80-1.23), respectively. The incidence of severe back pain at 12 months was 1.3% and 1.6% in the teriparatide and antiresorptive treatment groups, respectively. Teriparatide-treated patients had lower mean VAS (2.71 ± 2.21 vs. 3.30 ± 2.37) and EQ­5D (46.1 ± 33.18 vs. 55.4 ± 32.65) scores at 12 months. More teriparatide-treated patients felt better (82.7% vs. 71.0%) and were very satisfied with treatment (49.4% vs. 36.8%) compared to antiresorptive-treated patients. CONCLUSION: Patients treated with either teriparatide or antiresorptives had similar risk of new/worsening back pain at six months.

Tadalafil in the management of lower urinary tract symptoms: a review of the literature and current practices in Russia.

INTRODUCTION: Strong epidemiologic evidence supports correlation between lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH) and erectile dysfunction (ED). The link has biologic plausibility given phosphodiesterase type 5 (PDE5) expression in pelvic structures. PDE5 inhibitors target pathophysiologic processes implicated in LUTS/BPH. MATERIAL AND METHODS: This review highlights the efficacy and safety of the daily use of a PDE5 inhibitor tadalafil in LUTS/BPH, with a focus on LUTS/BPH medical management in Russia. RESULTS: Alpha-blockers and phytotherapy are major components of the current LUTS/BPH therapy in Russia. Russian regulatory authorities granted approval for once-daily tadalafil for treatment of LUTS/BPH in January 2012. In a pivotal study, tadalafil 5 mg once-daily significantly improved International Prostate Symptom Score (IPSS) over 12 weeks vs. placebo (P = .004) regardless of baseline ED severity. IPSS improvement was maintained at 12 weeks. Integrated analysis of randomized studies showed that tadalafil 5 mg once-daily resulted in significant symptom improvements across a range of men with LUTS/BPH. Relief of LUTS due to tadalafil was independent of improvement in ED; improvements in IPSS and erectile function were only weakly correlated (r = -0.229). Another pooled analysis found similar improvement in LUTS/BPH between men with or without ED, with non-significant P values for treatment-by-ED-status interactions for total IPSS ( P = .73). Non-registration studies of tadalafil and alpha-blocker co-therapy in LUTS/BPH suggest an additive effect, but co-therapy is not recommended in current tadalafil prescribing instructions. CONCLUSIONS: Tadalafil results in symptom improvements across a range of men with LUTS/BPH and represents a new treatment option for patients in Russia with LUTS/BPH.

PDE5 inhibitor treatment persistence and adherence in Brazilian men: post-hoc analyses from a 6-month, prospective, observational study.

PURPOSE: Characterize persistence and adherence to phosphodiesterase type - 5 inhibitor (PDE5I) on-demand therapy over 6 months among Brazilian men in an observational, non-interventional study of Latin American men naïve to PDE5Is with erectile dysfunction (ED). MATERIALS AND METHODS: Men were prescribed PDE5Is per routine clinical practice. Persistence was defined as using ≥ 1 dose during the previous 4 - weeks, and adherence as following dosing instructions for the most recent dose, assessed using the Persistence and Adherence Questionnaire. Other measures included the Self - Esteem and Relationship (SEAR) Questionnaire, and International Index of Erectile Function (IIEF). Multivariate logistic regression was used to identify factors associated with persistence/adherence. RESULTS: 104 Brazilian men were enrolled; mean age by treatment was 53 to 59 years, and most presented with moderate ED (61.7%). The prescribed PDE5I was sildenafil citrate for 50 (48.1%), tadalafil for 36 (34.6%), vardenafil for 15 (14.4%), and lodenafil for 3 patients (2.9%). Overall treatment persistence was 69.2% and adherence was 70.2%; both were numerically higher with tadalafil (75.0%) versus sildenafil or vardenafil (range 60.0% to 68.0%). Potential associations of persistence and/or adherence were observed with education level, ED etiology, employment status, and coronary artery disease. Improvements in all IIEF domain scores, and both SEAR domain scores were observed for all treatments. Study limitations included the observational design, brief duration, dependence on patient self - reporting, and limited sample size. CONCLUSION: Approximately two-thirds of PDE5I-naive, Brazilian men with ED were treatment persistent and adherent after 6 months. Further study is warranted to improve long-term outcomes of ED treatment.

PDE5 Inhibitor Treatment Persistence and Adherence in Brazilian Men: Post-hoc Analyses from a 6-Month, Prospective, Observational Study

Purpose Characterize persistence and adherence to phosphodiesterase type - 5 inhibitor (PDE5I) on-demand therapy over 6 months among Brazilian men in an observational, non-interventional study of Latin American men naïve to PDE5Is with erectile dysfunction (ED). Materials and Methods Men were prescribed PDE5Is per routine clinical practice. Persistence was defined as using ≥ 1 dose during the previous 4 - weeks, and adherence as following dosing instructions for the most recent dose, assessed using the Persistence and Adherence Questionnaire. Other measures included the Self - Esteem and Relationship (SEAR) Questionnaire, and International Index of Erectile Function (IIEF). Multivariate logistic regression was used to identify factors associated with persistence/adherence. Results 104 Brazilian men were enrolled; mean age by treatment was 53 to 59 years, and most presented with moderate ED (61.7%). The prescribed PDE5I was sildenafil citrate for 50 (48.1%), tadalafil for 36 (34.6%), vardenafil for 15 (14.4%), and lodenafil for 3 patients (2.9%). Overall treatment persistence was 69.2% and adherence was 70.2%; both were numerically higher with tadalafil (75.0%) versus sildenafil or vardenafil (range 60.0% to 68.0%). Potential associations of persistence and/or adherence were observed with education level, ED etiology, employment status, and coronary artery disease. Improvements in all IIEF domain scores, and both SEAR domain scores were observed for all treatments. Study limitations included the observational design, brief duration, dependence on patient self - reporting, and limited sample size. Conclusion Approximately two-thirds of PDE5I-naive, Brazilian men with ED were treatment persistent and adherent after 6 months. Further study is warranted to improve long-term outcomes of ED treatment. .

The Efficacy and Safety of Tadalafil 5 mg Once Daily in Korean Men with Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: An Integrated Analysis.

PURPOSE: This post hoc integrated analysis assessed the efficacy and safety of tadalafil 5 mg once daily in a large Korean population with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH-LUTS). MATERIALS AND METHODS: Individual Korean participant data were integrated from three 12-week, randomized, double-blind, placebo-controlled studies in Asian men with BPH-LUTS, wherein 177 Korean men received placebo and 177 received tadalafil 5 mg once daily. The primary objective was to compare the change from baseline to week 12 in total International Prostate Symptom Score (IPSS) after treatment with tadalafil versus placebo. RESULTS: A significantly greater improvement (p<0.001) in total IPSS from baseline to week 12 was observed for tadalafil compared to placebo (least squares mean: tadalafil=-5.97; placebo=-3.94 ). Total IPSS at weeks 4 and 12, IPSS voiding and storage subscores at weeks 4, 8, and 12, and IPSS quality of life index at weeks 8 and 12 were also significantly improved (p<0.05) for tadalafil compared to placebo. There was significant improvement (p<0.001) in the patient global Impression of improvement responses and numerical improvement in the clinician global impression of improvement responses with tadalafil compared to placebo. There were no significant treatment differences for peak urine flow rate or postvoid residual volume. Few participants had treatment-emergent adverse events and there were no unexpected safety findings. CONCLUSIONS: This integrated analysis of three randomized, placebo-controlled Asian studies confirmed tadalafil 5 mg once daily as an efficacious and well-tolerated treatment for Korean men with BPH-LUTS.

Efficacy and safety of the coadministration of tadalafil once daily with finasteride for 6 months in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia.

PURPOSE: Medical treatment for men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia is 5α-reductase inhibitor monotherapy or coadministration with an α-blocker. We assessed the effects of tadalafil 5 mg coadministered with finasteride 5 mg during 26 weeks on lower urinary tract symptoms and sexual symptoms. MATERIALS AND METHODS: In an international, randomized, double-blind, parallel study of men 45 years old or older who were 5α-reductase inhibitor naïve and had an I-PSS (International Prostate Symptom Score) of 13 or greater and prostate volume 30 ml or greater, 350 were treated with placebo/finasteride and 345 received tadalafil/finasteride for 26 weeks. Changes in lower urinary tract symptoms secondary to benign prostatic hyperplasia were assessed with the I-PSS, erectile dysfunction improvements were assessed with the IIEF-EF (International Index of Erectile Function-Erectile Function) in sexually active men and safety was assessed by evaluating adverse events. RESULTS: Least squares mean changes from baseline in I-PSS after 4, 12 and 26 weeks of tadalafil/finasteride coadministration were -4.0, -5.2 and -5.5, respectively. Corresponding values for placebo/finasteride coadministration were -2.3, -3.8 and -4.5 (p ≤ 0.022 at all visits favoring tadalafil/finasteride coadministration). I-PSS subscores (storage and voiding) and quality of life index were also numerically improved with tadalafil/finasteride coadministration. Least squares mean changes from baseline in IIEF-EF with tadalafil/finasteride coadministration were 3.7 after 4 weeks, and 4.7 after 12 and 26 weeks. Corresponding values for placebo/finasteride coadministration were -1.1, 0.6 and -0.0 (p <0.001 at all visits favoring tadalafil/finasteride coadministration). Tadalafil/finasteride coadministration was well tolerated and most adverse events were mild/moderate. CONCLUSIONS: The coadministration of tadalafil/finasteride provides early improvement in lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement. Tadalafil/finasteride coadministration also improves erectile function in men who have comorbid erectile dysfunction.

A 6 month, prospective, observational study of PDE5 inhibitor treatment persistence and adherence in Latin American men with erectile dysfunction.

OBJECTIVES: To assess persistence/adherence rates of phosphodiesterase type-5 inhibitor (PDE5I) on-demand dosing in Latin American men with erectile dysfunction (ED), and explore patient characteristics and treatment factors that may be predictive for PDE5I persistence and adherence. METHODS: Men from Brazil, Mexico, and Venezuela with ED who were naïve to PDE5Is were prescribed sildenafil, tadalafil, vardenafil, or lodenafil on-demand dosing and asked to provide information about PDE5I use at baseline and at 1, 3, and 6 months. Patients were persistent if they used ≥1 dose during the 4 week period prior to each evaluation. Patients were adherent if they complied with dosing instructions during most recent dose. Main outcome measures included Persistence and Adherence Questionnaire (PAQ), Partner Relationship Questionnaire (PRQ), Self-Esteem and Relationship (SEAR) Questionnaire, and International Index of Erectile Function (IIEF). Multivariate logistic regression was used to identify factors associated with persistence and adherence. RESULTS: A total of 511 men were enrolled; most had mild to moderate ED (77.1%); 317 patients (62.0%) were prescribed tadalafil, 116 (22.7%) sildenafil, 75 (14.7%) vardenafil, and 3 (0.6%) lodenafil (not further analyzed). A total of 340 patients (66.5%) were 'persistent' at 6 months; 345 (67.5%) were 'adherent'. Persistence and adherence were associated with age, education level, and ED duration. Reasons for non-persistence included medication cost and lack of efficacy. Study limitations included its design, brief observation period, its bias observed toward tadalafil selection; its dependence on patient self-reporting, limited number of factors that were analyzed for persistence/adherence association, its small number of participating patients and Latin American countries, and inherent differences in PDE5I preference and medical practices. CONCLUSION: Approximately two-thirds of PDE5I-naïve, Latin American men with ED were persistent and adherent after 6 months of therapy. Factors like education level, ED severity, and ED duration were associated with persistence and adherence; additional study is warranted to investigate the predictive value of these factors.

Urinary Tract Symptoms (LUTS) Secondary to Benign Prostatic Hyperplasia (BPH) and LUTS/BPH with Erectile Dysfunction in Asian Men: A Systematic Review Focusing on Tadalafil.

This review assesses lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) with or without erectile dysfunction (ED) and related therapies focusing on tadalafil. A literature search was obtained and reviewed for the epidemiology, treatment therapies, pathophysiology, and efficacy and safety of phosphodiesterase type 5 inhibitor (PDE5i) tadalafil in patients with LUTS/BPH. Approximately 42% of men aged 51 to 60 years have BPH. Approximately 90% of men aged 45 to 80 years have LUTS. Occurrence of LUTS increases with age for almost all racial/ethnic groups (range, 32% to 56%) with prevalence of LUTS highest among Hispanic men, then Blacks, Caucasians, and Asians. There is an independent relationship with LUTS/BPH and ED, with approximately 70% of men with LUTS/BPH having ED with severity of one disease often correlating with the other. The European Urological Association guidelines include the use of the PDE5i tadalafil. Tadalafil is the only therapy recommended for treatment of co-existing BPH and ED, while other therapies have unwanted ED side effects. The mode of action of tadalafil may involve different areas of the lower urinary tract such as smooth muscle cell relaxation in the bladder neck, prostate, and urethra, but there may also be resulting modulation of the afferent nerve activity. Tadalafil (5 mg) in Asian men with LUTS/BPH, similar to global studies, is efficacious and safe. Tadalafil (5 mg) improves co-existing LUTS/BPH and ED, independently. Men with LUTS/BPH likely also have ED. Asian men with LUTS/BPH have similar incidence rates, co-existing ED, comorbid diseases, and risks as non-Asian men. Tadalafil can improve co-existing LUTS/BPH and ED.

A randomized, double-blind, placebo-controlled, parallel study to assess the efficacy and safety of once-a-day tadalafil in men with erectile dysfunction who are naïve to PDE5 inhibitors.

INTRODUCTION: The majority of subjects included in previous tadalafil once-a-day clinical trials were non-naïve to previous phosphodiesterase 5 (PDE5) inhibitors on demand. A study on PDE5 inhibitor naïve subjects was therefore warranted. AIM: To evaluate the efficacy and safety of once-a-day tadalafil in PDE5 inhibitor-naïve men with erectile dysfunction (ED). MAIN OUTCOMES MEASURES: Primary efficacy end points were changes from baseline to end point in the International Index of Erectile Function (IIEF) Erectile Function (EF) domain score and the per-subject proportion of "yes" responses to sexual encounter profile (SEP) question 2 (SEP2) and question 3 (SEP3). METHODS: PDE5 inhibitor-naïve men with ED (N=217) were randomized in a 1:2 ratio to receive placebo or tadalafil 5 mg once a day for 12 weeks. Enrollment began in January 2009 and the last subject completed in January 2010. RESULTS: At end point, least square mean change from baseline IIEF-EF domain score (7.3 vs. 3.4), SEP2 (23.8% vs. 12.2%) and SEP3 (39.5% vs. 21.5%), was significantly larger for tadalafil vs. placebo (all P<0.001). The most common adverse events (AEs) in tadalafil-treated subjects were back pain, nasopharyngitis, dyspepsia, headache, and myalgia. Four subjects (2.7%) in the tadalafil group and one subject (1.4%) in the placebo group discontinued because of AEs. CONCLUSIONS: In PDE5 inhibitor-naïve men, tadalafil once a day significantly improved EF compared with placebo. Safety results were consistent with previous tadalafil once-a-day clinical trials.

Optimizing treatment outcomes with phosphodiesterase type 5 inhibitors for erectile dysfunction: opening windows to enhanced sexual function and overall health.

PURPOSE: Phosphodiesterase type 5 (PDE5) inhibitors have proved to be efficacious, safe, and well tolerated, in clinical trials and practice, for men with erectile dysfunction (ED). However, many patients are not satisfied with treatment and discontinue it prematurely. This review discusses evidence-based strategies that nurse practitioners (NPs) can use to improve diagnosis of ED, optimize patient outcomes, and identify opportunities to detect other potentially serious comorbid conditions. DATA SOURCES: This article was based on a previously published review, which involved a PubMed-MEDLINE search of the clinical literature from January 1, 1998 (year of sildenafil's approval in many markets), through August 30, 2008 (date of search). CONCLUSIONS: Strategies to optimize responses to PDE5 therapy are summarized by the mnemonic "EPOCH": Evaluating and educating to ensure realistic expectations of therapy; Prescribing a treatment individualized to the couple's needs and preferences; Optimizing drug dose/regimen and revisiting key educational messages at follow-up visits; Controlling comorbidities via lifestyle counseling, medications, and/or referrals; and Helping patients and their partners to seek other forms of therapy if they have decided not to use a PDE5 inhibitor. IMPLICATIONS FOR PRACTICE: The "EPOCH" mnemonic may remind NPs of steps to optimize treatment outcomes with PDE5 inhibitors.

Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, I: analysis of cases.

BACKGROUND: An advance in the treatment of schizophrenia is the development of long-acting intramuscular formulations of antipsychotics, such as olanzapine long-acting injection (LAI). During clinical trials, a post-injection syndrome characterized by signs of delirium and/or excessive sedation was identified in a small percentage of patients following injection with olanzapine LAI. METHODS: Safety data from all completed and ongoing trials of olanzapine LAI were reviewed for possible cases of this post-injection syndrome. Descriptive analyses were conducted to characterize incidence, clinical presentation, and outcome. Regression analyses were conducted to assess possible risk factors. RESULTS: Based on approximately 45,000 olanzapine LAI injections given to 2054 patients in clinical trials through 14 October 2008, post-injection delirium/sedation syndrome occurred in approximately 0.07% of injections or 1.4% of patients (30 cases in 29 patients). Symptomatology was consistent with olanzapine overdose (e.g., sedation, confusion, slurred speech, altered gait, or unconsciousness). However, no clinically significant decreases in vital signs were observed. Symptom onset ranged from immediate to 3 to 5 hours post injection, with a median onset time of 25 minutes post injection. All patients recovered within 1.5 to 72 hours, and the majority continued to receive further olanzapine LAI injections following the event. No clear risk factors were identified. CONCLUSIONS: Post-injection delirium/sedation syndrome can be readily identified based on symptom presentation, progression, and temporal relationship to the injection, and is consistent with olanzapine overdose following probable accidental intravascular injection of a portion of the olanzapine LAI dose. Although there is no specific antidote for olanzapine overdose, patients can be treated symptomatically as needed. Special precautions include use of proper injection technique and a post-injection observation period. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, II: investigations of mechanism.

BACKGROUND: Olanzapine long-acting injection (LAI) is a salt-based depot antipsychotic combining olanzapine and pamoic acid. The slow intramuscular dissolution of this practically insoluble salt produces an extended release of olanzapine lasting up to 4 weeks. However, in a small number of injections (< 0.1%), patients experienced symptoms suggestive of olanzapine overdose, a phenomenon that has been termed "post-injection delirium/sedation syndrome" (PDSS). The authors conducted a series of parallel investigations into the possible reasons PDSS events occur. METHODS: Healthcare providers involved in the PDSS cases were queried for clinical information around the events. Plasma samples from patients experiencing PDSS were collected when possible (12/30 cases) and olanzapine concentrations compared with the known pharmacokinetic profile for olanzapine LAI. Product batches and used vials from the PDSS cases were evaluated for compliance with established manufacturing standards and/or possible user error. Because this depot formulation depends upon slow dissolution at the intramuscular injection site, in-vitro experiments were conducted to assess solubility of olanzapine pamoate in various media. RESULTS: Injection administrators reported no unusual occurrences during the injection. No anomalies were found with the product batches or the remaining suspension in the used vials. Olanzapine concentrations during PDSS events were higher than the expected 5-73 ng/mL range, with concentrations exceeding 100 ng/mL and in some cases reaching >600 ng/mL during the first hours after injection but then returning to the expected therapeutic range within 24 to 72 hours. Solubility and dissolution rate of olanzapine pamoate were also found to be substantially greater in plasma than in other media such as those approximating the environment in muscle tissue. CONCLUSIONS: Manufacturing irregularities, improper drug reconstitution, and inappropriate dosing were ruled out as possible causes of PDSS. In-vitro solubility and in-vivo pharmacokinetic investigations suggest that PDSS is related to exposure of the injected product to a substantial volume of blood. This exposure is most likely the result of unintended partial intravascular injection or blood vessel injury during the injection (occurring even with proper injection technique) with subsequent seepage of the medication into the vasculature, which would produce higher than intended olanzapine concentrations and symptoms consistent with PDSS. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

Characteristics and mortality among hospitalized patients treated with intramuscular antipsychotics: analysis of a United States hospital database.

Mortality rates across matched cohorts of hospitalized patients treated with IM olanzapine, haloperidol, and/or ziprasidone in a hospital database were compared. Using propensity score matching, matched cohorts of IM olanzapine- (N=2,984) and IM haloperidol-treated patients (N=2,984) and IM olanzapine- (N=2,876) and IM ziprasidone-treated patients (N=2,876) were obtained. The study outcome was in-hospital death within 2 days of administering IM antipsychotic. Incidence of death was not statistically different between olanzapine-ziprasidone cohorts (OR=1.21, 95% CI 0.92-1.59). The olanzapine cohort demonstrated a significantly lower death incidence than the haloperidol cohort (OR=0.73, 95% CI 0.57-0.93; p=.011). The results suggest that patients treated with IM olanzapine do not have a significantly greater risk of death than patients treated with IM haloperidol or IM ziprasidone.

Case reports of postmarketing adverse event experiences with olanzapine intramuscular treatment in patients with agitation.

OBJECTIVE: Agitation is a medical emergency with increased risk for poor outcome. Successful treatment often requires intramuscular (IM) psychotropics. Safety data from the first 21 months of olanzapine IM, approved in the United States for the treatment of agitation associated with schizophrenia and bipolar disorder, are presented. METHOD: A Lilly-maintained safety database was searched for all spontaneous adverse events (AEs) reported in temporal association with olanzapine IM treatment. RESULTS: The estimated worldwide patient exposure to olanzapine IM from January 1, 2004, through September 30, 2005, was 539,000; 160 cases containing AEs were reported from patients with schizophrenia (30%), bipolar disorder (21%), unspecified psychosis (10%), dementia (8%), and depression (5%). Many reported concomitant treatment with benzodiazepines (39%) or other antipsychotics (54%). The most frequently reported events involved the following organ systems: central nervous (21%), cardiac (12%), respiratory (6%), vascular (6%), and psychiatric (5%). Eighty-three cases were considered serious, including 29 fatalities. In these fatalities, concomitant benzodiazepines or other antipsychotics were reported in 66% and 76% of cases, respectively. The most frequently reported events in the fatal cases involved the following organ systems: cardiovascular (41%), respiratory (21%), general (17%), and central nervous (10%). The majority of fatal cases (76%) included comorbid conditions and potentially clinically significant risk factors for AEs. CONCLUSIONS: Clinicians should use care when treating agitated patients, especially when they present with concurrent medical conditions and are treated with multiple medications, which may increase the risk of poor or even fatal outcomes. Clinicians should use caution when using olanzapine IM and parenteral benzodiazepines simultaneously.

Safety, efficacy, and pharmacokinetic overview of low-dose daily administration of tadalafil.

INTRODUCTION: Several phosphodiesterase type 5 (PDE5) inhibitors are commercially available for the treatment of erectile dysfunction (ED). Development of the first once-daily alternative dosing regimen with a PDE5 inhibitor was motivated by the behavioral complexities associated with sexual intimacy. AIM: To provide an alternative dosing option for certain men who may benefit from the removal of the temporal linkage between administration of an ED therapy and sexual intimacy or for men and their partners who anticipate at least twice-weekly sexual activity. METHODS: Pharmacokinetic predictions of tadalafil plasma concentrations were generated based upon empirical data following 20-mg, single-dose administration coupled with tadalafil usage patterns from as-needed clinical trials. To support the pharmacokinetic simulations and pharmacodynamic assumptions, clinical trials were conducted to demonstrate the efficacy and safety of once-daily, low-dose tadalafil 2.5 and 5 mg. MAIN OUTCOME MEASURES: Simulated tadalafil plasma concentrations and comparison with safety and efficacy measures from clinical trials. RESULTS: Based upon pharmacodynamic and pharmacokinetic data, once-daily doses of tadalafil 5 mg were predicted to provide therapeutic concentrations that would be maintained throughout the 24-hour dosing interval. Additionally, for a subgroup of men who anticipate at least twice-weekly sexual activity and are currently taking tadalafil 20 mg, a reduction in daily tadalafil exposure was predicted. To support the hypothesis that low-dose, once-daily tadalafil may be a safe and effective treatment alternative, clinical trials were conducted to demonstrate the safety and efficacy of once-daily tadalafil 2.5 and 5 mg. These results were similar to those of historical as-needed studies evaluating tadalafil 10 and 20 mg. CONCLUSIONS: Consistent with pharmacokinetic predictions, data from clinical trials indicate that once-daily use of low-dose tadalafil is a safe and effective treatment for men with ED.

Efficacy and safety of tadalafil once daily: considerations for the practical application of a daily dosing option.

OBJECTIVE: To provide clinically relevant information on tadalafil 2.5 or 5 mg once daily for the treatment of erectile dysfunction (ED), by reviewing safety and efficacy study findings. Findings from an integrated analysis of trials of tadalafil 10 and 20 mg as needed are presented to provide context for the daily dosing regime. RESEARCH DESIGN AND METHODS: Of the three studies that included approved once-daily doses, two were conducted in the general ED population and one in a diabetic ED population. An integrated analysis was performed using 12-week efficacy and safety data from the studies conducted in the general ED population. RESULTS: In the general ED population, the 12-week mean International Index of Erectile Function (IIEF) erectile function (EF) domain scores increased by 6.2 to an endpoint score of 19.2 and by 8.6 to 21.9 for 2.5 and 5 mg doses, respectively, versus an increase of 1.3 to 14.9 for placebo (p < 0.01). Mean successful intercourse attempts (SEP3) were 50% and 62% for tadalafil 2.5 and 5 mg once daily, respectively, versus 33% for placebo (p < 0.01). These findings were consistent with those for tadalafil as needed. In 1- and 2-year open label extensions of tadalafil 5 mg once daily, efficacy was maintained. In the diabetic ED population, 12-week mean IIEF EF scores increased by 4.8 to 18.3 and 4.5 to 17.2 with tadalafil 2.5 and 5 mg, respectively, versus an increase of 1.3 to 14.7 for placebo (p < 0.01). Mean successful intercourse attempts were more than 40% for each tadalafil dose, versus 28% for placebo (p < 0.01). The profile of treatment-emergent adverse events with tadalafil once daily was similar to that previously reported with as-needed treatment; the most common adverse events with tadalafil (dyspepsia, nasopharyngitis, headaches) were reported in