An Actual Use Study of Tamsulosin in Men with Bothersome Urinary Symptoms in a Simulated Over-the-Counter Setting.

INTRODUCTION: We assessed the ability of men with bothersome urinary symptoms to use an over-the-counter tamsulosin (0.4 mg) product concordant with the information in the proposed drug facts label in a simulated over-the-counter setting. METHODS: Eligibility for this 24-week study was determined by a phone interview. Men who reported not using (nonprescription users) or using (prescription users) a prescription medicine for benign prostatic hyperplasia at screening/baseline reviewed the proposed over-the-counter tamsulosin product. They could then choose to purchase this product and enter the actual use phase. The primary objective was to assess the proportion of nonprescription users compliant with "stop use" directions (performance threshold upper bound of 95% CI 10% or less). Secondary objectives included assessing the proportion of nonRx users compliant with other prespecified instructions on the proposed drug facts label and evaluating adverse events. Analyses were based on outcomes mitigated by a panel of urologists. RESULTS: Of the 4,508 men screened 3,929 were eligible for product review and 1,117 entered the home use phase. Overall 1,074 men (nonprescription users 924, prescription users 150) purchased and used tamsulosin. Mean±SD age was 62.6±10.7 and 66.5±8.8 years, respectively. The primary end point was met, as only 2 of 924 nonprescription users (0.2%, 95% CI 0.0-0.8) reported a "stop use" condition within the first 12 weeks and did not appropriately stop use or initiate contact with a doctor. No unexpected safety concerns were observed. CONCLUSIONS: Results indicate that self-directed use by men interested in using an over-the-counter tamsulosin product was in line with the drug facts label instructions implemented in this study and no unexpected safety concerns were identified.

Over-the-Counter Tamsulosin for Men with Urinary Symptoms: A Simulated Self-Selection Study.

INTRODUCTION: We determined whether consumers who self-select to use tamsulosin for urinary symptoms can make appropriate decisions without health care provider guidance in a simulated over-the-counter setting. METHODS: In a simulated retail setting eligible participants (18 years old or older) reviewed a mock-up of Flomax® over-the-counter packaging and determined whether it was right for them to use tamsulosin capsules (0.4 mg). Per an a priori mitigation procedure 3 urologists reviewed self-reported data, dipstick urinalysis results and AUA-SI (American Urological Association symptom index) scores of men who self-selected tamsulosin as appropriate to use despite information on the drug facts label instructing otherwise. Seemingly incorrect decisions were revised to "appropriate" if deemed well-informed and medically acceptable by 2 or 3 urologists. RESULTS: Overall 619 men and 38 women (mean age 60.9 and 51.6 years, respectively) were enrolled. Of the 470 (75.9%) men who self-selected to use tamsulosin 82 (17.4%) had low health literacy per the REALM (Rapid Estimate of Adult Literacy in Medicine) test and 365 (77.7%) reported seeing a physician at least once a year. Mean AUA-SI total score was 16.5 and 380 (80.9%) men reported urinary symptoms for 1 year or more. The proportions of men who made appropriate self-selection decisions in unmitigated and mitigated analyses were 92.8% (95% CI 90.0-94.9) and 97.9% (95% CI 96.1-99.0), respectively, and findings were similar regardless of health literacy level. Overall 36 of the 38 women (94.7%) made an appropriate decision not to use tamsulosin. CONCLUSIONS: These findings support the potential use of over-the-counter tamsulosin for male urinary symptoms.

Tamsulosin dispensation patterns in the United States: a real-world, longitudinal, population claims database analysis.

BACKGROUND: Tamsulosin remains the single most popular uroselective alpha adrenoceptor antagonist approved for the treatment of lower urinary tract symptoms (LUTS) attributable to benign prostatic hyperplasia (BPH). Over the last 3 decades, the utilization of tamsulosin has extended to conditions beyond its original indication. To identify potential changes to prescribing patterns and the extent of tamsulosin use for conditions beyond its original indication, we evaluated tamsulosin dispensing patterns in the United States using a large, multi-payer claims database. METHODS: We conducted a retrospective analysis using IMS PharMetrics Plus™. Patients with a tamsulosin dispensation/BPH diagnosis code (index dates), identified during a 12-month selection period (October 2012-September 2013), were included if continuously enrolled in a health plan during the 18-month analysis period (12 months pre-index-6 months post-index). Patient and provider characteristics were evaluated using descriptive statistics and were contrasted with previously reported data from the literature. RESULTS: Of 133,977 patients dispensed tamsulosin during the analysis period, 72,583 (54.2%) were new users [59,197 (81.6%) men; 13,386 (18.4%) women]. Tamsulosin was newly initiated in men and women mostly by primary care physicians (PCPs; 31.6%) and emergency medicine physicians (21.6%). During the analysis period, 35,071 (59.2%) male new tamsulosin users did not receive a BPH diagnosis code during the analysis period. Of 199,468 men with a BPH diagnosis code, 143,444 (71.9%) were newly diagnosed, mostly [70,412 (49.1%)] by urologists. Few men received hypotension diagnosis: 252 (0.4%) new tamsulosin users within 1 month of starting tamsulosin and 640 (0.4%) within 1 month of a new BPH diagnosis. CONCLUSIONS: Tamsulosin was prescribed in patients without a recorded diagnosis of BPH and in women. Physicians were comfortable prescribing tamsulosin in the presence of comorbidity and polypharmacy, and PCPs and emergency medicine physicians were the primary prescribers. These results have important implications for future retrospective research for tamsulosin.

Characteristics of men with untreated LUTS interested in over-the-counter tamsulosin.

INTRODUCTION: Treatment for lower urinary tract symptoms (LUTS) is often delayed, as it is considered a natural progression of aging. We described baseline demographic and clinical characteristics of men currently not using prescription medications for benign prostatic hyperplasia (BPH) but interested in self-directed use of over-the-counter (OTC) tamsulosin and who had participated in OTC tamsulosin-simulated studies. MATERIALS AND METHODS: Pooled baseline data from four OTC tamsulosin-simulated studies were analyzed for men who were currently not using BPH prescription medication and who believed that OTC tamsulosin was appropriate for use or were interested in purchasing it. Data from the OTC-simulated studies for men using BPH prescription medication and from the BPH registry, which included men diagnosed with BPH, were used for comparison. RESULTS: Overall, 3285 non-prescription-using men (mean age +/- standard deviation [SD], 60.6 +/- 11.6 years) were included. Average American Urological Association Symptom Index (AUA-SI) total score was 17.6; 25.5% reported urinary symptoms for > 5 years. Overall, 46.7% of these men had > 1 visit/year with their physicians. Baseline characteristics of prescription users from the OTC-simulated studies (n = 364; mean age ± SD, 68.3 +/- 9.1 years; mean AUA-SI score, 18.5) and of men from the BPH registry (n = 5042; 64.8 +/- 10 years; 11.6) were similar to those of non-prescription users. CONCLUSIONS: Non-prescription users had long term moderate-to-severe male LUTS, yet remained untreated; self-management may be a viable alternative strategy for this population. Disease characteristics of men not using BPH prescription medication and interested in using OTC tamsulosin were similar to those using BPH medication or diagnosed with BPH.

Is Dipstick Urinalysis Screening Beneficial in Men with Lower Urinary Tract Symptoms?

INTRODUCTION: Dipstick urinalysis is a widely used screening tool in the evaluation of men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). As limited data support the use of dipstick urinalysis, we have used data from three recently published studies to assess clinical outcomes in those who had dipstick urinalysis findings for blood, glucose, and/or leukocytes. METHODS: We analyzed data from three observational studies involving men interested in using over-the-counter tamsulosin: a self-selection study (SSS) and two actual-use studies of 8-week (AUS8) and 24-week (AUS24) durations. Subgroup analyses focused on pooled data from participants not using α-blockers or other prescription medication for LUTS suggestive of BPH (nonRx users) and who had urine dipstick findings. Data from participants using α-blockers (AUS8) or any prescription BPH medications (SSS and AUS24) are presented as reference. RESULTS: Overall, 2488 nonRx users underwent dipstick urinalysis and 680 (27.3%) had positive findings including traces of blood (332; 13.3%), glucose (259; 10.4%), and/or leukocytes (245; 9.8%). Among users of prescription medicines, 21.6% (37/171) in SSS, 27.4% (23/84) in AUS8, and 31.1% (47/151) in AUS24 had urine dipstick findings. The 200 dipstick-positive nonRx users in SSS underwent per protocol urological assessment: 26 (13.0%) had a newly diagnosed condition causing/contributing to urinary symptoms of which 2.9% were identified as medically important conditions. Among nonRx users with or without a dipstick finding, medically important conditions reported included prostate cancer (1.0% vs. 1.0%, respectively) and urolithiasis (1.0% vs. 0.3%, respectively). The proportion of men with dipstick urinalysis findings was similar between men who regularly visited their physician and those who did not. CONCLUSION: Dipstick urinalysis did not markedly increase the detection of undiagnosed medically important conditions that cause/contribute to urinary symptoms, suggesting that this test may not be a very effective screening tool for men with LUTS. FUNDING: Boehringer Ingelheim Pharmaceuticals, Inc.

Management of Male Lower Urinary Tract Symptoms in a Simulated, Over-the-Counter Setting: An Exploratory Study of Tamsulosin.

BACKGROUND: Lower urinary tract symptoms (LUTS) attributed to benign prostatic hyperplasia (BPH) are common in men, considerably affecting quality of life. AIMS: The self-directed use of over-the-counter (OTC) tamsulosin (0.4 mg) and potential safety risks were evaluated in an open-label, uncontrolled, exploratory, 8-week OTC-simulated study. METHODS: Men (≥ 18 years) were recruited via mass advertising about bothersome LUTS. In a working retail environment, respondents reviewed the product and decided whether it was appropriate for them to use (self-selection phase). After purchasing the product, participants' ability to use it as directed by the proposed drug facts label (DFL) was assessed (home-use phase). RESULTS: Of 1446 eligible men, 679 completed the self-selection phase, and 73.9% (502/679) self-selected to use tamsulosin correctly according to the DFL. Of 369 participants who purchased tamsulosin and entered the home-use phase, 321 took one or more doses of tamsulosin and participated in at least one telephone interview. In total, 85.4% (274/321) of participants adhered to the 'Stop Use' and 'Directions' instructions in the DFL. Overall, 139 (39.6%) participants experienced one or more adverse events (AEs); 65 (18.5%) were deemed drug-related, including dizziness (11 [3.1%]), ejaculation disorder (6 [1.7%]), and semen volume decrease (6 [1.7%]). No unexpected AEs were reported. CONCLUSIONS: Of the men interested in self-managing their LUTS, a majority had moderate-to-severe LUTS of long duration. Most men were able to appropriately self-select and use tamsulosin in concordance with DFL instructions and directions. No unexpected AEs were reported during self-directed use. With further label refinement, an over-the-counter tamsulosin option might be feasible. TRIAL REGISTRATION: ClinicalTrials.gov NCT01726270.

Feasibility of an Alternative Option for the Management of Male Lower Urinary Tract Symptoms.

PURPOSE: We determine if men with self-reported lower urinary tract symptoms can make a correct decision to use an over-the-counter alpha-1 blocker. Furthermore, we assess the frequency of medically significant conditions presenting with urinary symptoms in these consumers. MATERIALS AND METHODS: Subjects reviewed a mock-up of an over-the-counter product for male lower urinary tract symptoms (part 1). Subjects who selected the product underwent urine dipstick testing and male subjects completed the AUA Symptom Index (part 2). Urological assessment was conducted in women; in men younger than 45 years; men 45 years old or older who reported "Do Not Use" symptoms listed on the over-the-counter label; who had glucose, leukocytes and/or blood in their urine; or had an AUA-SI score of 20 or greater. RESULTS: Of the 1,967 subjects enrolled 1,953 completed part 1 (men/women 1,697/256), 1,311 (1,294/17) entered part 2 and 1,289 (1,274/15) were evaluated. Frequently reported baseline medical conditions were hypertension (45.8%/46.7%) and dyslipidemia (36.4%/60.0%). Lower urinary tract symptoms were present for more than 3 years in 47.6% of men and 40% of women. Mean AUA-SI score was 18.9. Urine dipstick results were positive in 20.9% of men. Overall 729 men and 12 women underwent urological assessment, and 517 (70.9%) men had urologist confirmed lower urinary tract symptoms while 200 (27.4%) did not. Newly diagnosed medically significant conditions causing/contributing to lower urinary tract symptoms were identified in 21 (2.9%) men and 2 (16.7%) women. CONCLUSIONS: Most men correctly selected the over-the-counter product for the management of lower urinary tract symptoms/benign prostatic hyperplasia, while most women correctly deselected to use the product. Since few men had undiagnosed medically significant conditions causing/contributing to urinary symptoms, the risk of harm due to incorrect selection was low.

Pharmacokinetic interactions between buprenorphine/naloxone and tipranavir/ritonavir in HIV-negative subjects chronically receiving buprenorphine/naloxone.

HIV-infected patients with opioid dependence often require opioid replacement therapy. Pharmacokinetic interactions between HIV therapy and opioid dependence treatment medications can occur. HIV-seronegative subjects stabilized on at least 3 weeks of buprenorphine/naloxone (BUP/NLX) therapy sequentially underwent baseline and steady-state pharmacokinetic evaluation of open-label, twice daily tipranavir 500 mg co-administered with ritonavir 200 mg (TPV/r). Twelve subjects were enrolled and 10 completed the study. Prior to starting TPV/r, the geometric mean BUP AUC(0-24h) and C(max) were 43.9 ng h/mL and 5.61 ng/mL, respectively. After achieving steady-state with TPV/r (> or = 7 days), these values were similar at 43.7 ng h/mL and 4.84 ng/mL, respectively. Similar analyses for norBUP, the primary metabolite of BUP, demonstrated a reduction in geometric mean for AUC(0-24h) [68.7-14.7 ng h/mL; ratio=0.21 (90% CI 0.19-0.25)] and C(max) [4.75-0.94 ng/mL; ratio=0.20 (90% CI 0.17-0.23)]. The last measurable NLX concentration (C(last)) in the concentration-time profile, never measured in previous BUP/NLX interaction studies with antiretroviral medications, was decreased by 20%. Despite these pharmacokinetic effects on BUP metabolites and NLX, no clinical opioid withdrawal symptoms were noted. TPV steady-state AUC(0-12h) and C(max) decreased 19% and 25%, respectively, and C(min) was relatively unchanged when compared to historical control subjects receiving TPV/r alone. No dosage modification of BUP/NLX is required when co-administered with TPV/r. Though mechanistically unclear, it is likely that decreased plasma RTV levels while on BUP/NLX contributed substantially to the decrease in TPV levels. BUP/NLX and TPV/r should therefore be used cautiously to avoid decreased efficacy of TPV in patients taking these agents concomitantly.

Pharmacokinetic assessment of nevirapine and metabolites in human immunodeficiency virus type 1-infected patients with hepatic fibrosis.

Nevirapine is a nonnucleoside reverse transcriptase inhibitor used as part of combination therapy for human immunodeficiency virus (HIV) infection. Nevirapine may be prescribed for patients with hepatic fibrosis and cirrhosis. Significant autoinduction of cytochrome P450 3A4 and 2B6 following multiple dosing prompted an assessment of the metabolic profiles in patients with liver disease receiving chronic nevirapine therapy. HIV-infected patients with hepatic fibrosis who were receiving a stable antiretroviral regimen containing nevirapine for > or = 6 weeks had liver biopsy specimens assessed by Ishak histologic scoring and were grouped by severity (group 1, Ishak scores of 1 and 2; group 2, Ishak scores of 3 and 4; group 3, Ishak scores of 5 and 6). Steady-state trough nevirapine levels were determined for all patients, and additional measurements were obtained at 1, 2, and 4 h following nevirapine dosing for a subset of patients. The pharmacokinetics of nevirapine and its five metabolites were characterized, and a comparison of the results for the different Ishak groups was performed. Among 51 patients with hepatic fibrosis, the majority of whom were coinfected with hepatitis C virus or hepatitis B virus, differences between the maximum and the minimum observed plasma concentrations demonstrated a statistically significant flattening of the systemic exposure curves with progression from Ishak group 1 to Ishak group 2 or 3, suggesting a decrease in systemic clearance with the progression of liver disease. However, there were no significant differences in the trough and the maximum nevirapine concentrations between the Ishak groups. The metabolite profiles were also comparable across the Ishak groups. In HIV-infected patients who were chronically treated with nevirapine and who had various degrees of hepatic fibrosis, including cirrhosis, trough plasma nevirapine concentrations were not significantly increased, and thus, no dose adjustment is warranted.

Steady-state disposition of the nonpeptidic protease inhibitor tipranavir when coadministered with ritonavir.

The pharmacokinetic and metabolite profiles of the antiretroviral agent tipranavir (TPV), administered with ritonavir (RTV), in nine healthy male volunteers were characterized. Subjects received 500-mg TPV capsules with 200-mg RTV capsules twice daily for 6 days. They then received a single oral dose of 551 mg of TPV containing 90 microCi of [(14)C]TPV with 200 mg of RTV on day 7, followed by twice-daily doses of unlabeled 500-mg TPV with 200 mg of RTV for up to 20 days. Blood, urine, and feces were collected for mass balance and metabolite profiling. Metabolite profiling and identification was performed using a flow scintillation analyzer in conjunction with liquid chromatography-tandem mass spectrometry. The median recovery of radioactivity was 87.1%, with 82.3% of the total recovered radioactivity excreted in the feces and less than 5% recovered from urine. Most radioactivity was excreted within 24 to 96 h after the dose of [(14)C]TPV. Radioactivity in blood was associated primarily with plasma rather than red blood cells. Unchanged TPV accounted for 98.4 to 99.7% of plasma radioactivity. Similarly, the most common form of radioactivity excreted in feces was unchanged TPV, accounting for a mean of 79.9% of fecal radioactivity. The most abundant metabolite in feces was a hydroxyl metabolite, H-1, which accounted for 4.9% of fecal radioactivity. TPV glucuronide metabolite H-3 was the most abundant of the drug-related components in urine, corresponding to 11% of urine radioactivity. In conclusion, after the coadministration of TPV and RTV, unchanged TPV represented the primary form of circulating and excreted TPV and the primary extraction route was via the feces.