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In two 12-week trials buy generic kamagra 100mg on-line impotence 101, risperidone long-acting injection was not found statistically significantly different than risperidone oral tablets in mean change in the PANSS total score or 37 discount 50mg kamagra free shipping erectile dysfunction treatment after prostatectomy, 263 secondary outcome measures order 100 mg kamagra fast delivery erectile dysfunction premature ejaculation treatment. One was a small study of inpatients in Taiwan 100 mg kamagra overnight delivery impotence following prostate surgery, and both studies required patients to be stabilized on oral risperidone prior to the study. The mean dose of oral risperidone prior to study was 3. The dose equivalency was defined as 25 mg every 2 weeks ≤ 4 mg daily oral risperidone; 37. Pain at the injection site was assessed on a 10-point visual analog scale. In the second study, dosing of oral risperidone was stabilized at 2, 4, or 6 mg daily during a run-in period. After randomization to the oral risperidone group, 27% received 2 mg daily, 39% received 4 mg daily, and 34% received 6 mg daily. Among patients randomized to the long-acting injection, 28% received 25 mg every 2 weeks, 39% received 50 mg, and 33% received 75 mg. In both studies, serum prolactin levels were elevated at baseline and decreased at 12 weeks in the risperidone long-acting injection groups (the between-group differences were statistically significant). In a 12-month open-label trial, olanzapine oral tablets were compared with risperidone long-acting injection with no statistically significant differences found between treatments at 13 53 weeks or 12 months based on mean change in PANSS or response rates. Extrapyramidal symptoms were reported in 25% with risperidone and 15% with olanzapine (P<0. In a 12-week placebo-controlled trial, patients randomized to long-acting injection risperidone at all doses had significantly greater improvements from baseline on the PANSS and 235 the CGI. An assessment of the subgroup of patients from this trial who were enrolled as 296 inpatients indicated similar results. Using the SF-36 tool to assess quality of life, the risperidone groups were shown to have greater improvement compared with placebo on 5 of 8 234 items. Short-acting injectables: aripiprazole, olanzapine, ziprasidone Acute agitation The effectiveness of aripiprazole and olanzapine injections in treatment of acute agitation over the first 24 hours in patients with schizophrenia or schizoaffective disorder was compared with 297-300 haloperidol and placebo in 2 trials of each drug. Two were fair-quality dose-ranging studies 299 of intramuscular olanzapine (2. The other 2 300 297 were studies of intramuscular olanzapine 10 mg or intramuscular aripiprazole 9. All of these studies were conducted in multiple countries and were designed to compare the atypical antipsychotic drug to placebo, with comparisons to haloperidol made in secondary analyses. Patients were similar across these trials, with baseline Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) scores of 14-15 or greater, but data were not sufficient to compare other baseline features. Atypical antipsychotic drugs Page 64 of 230 Final Report Update 3 Drug Effectiveness Review Project The studies found both atypical antipsychotic drugs and haloperidol to be superior to placebo based on the mean improvement in the PANSS-EC at 2 hours, with the exception of the 1 mg dose of aripiprazole. A subgroup analysis of those with schizophrenia (excluding those 297 with schizoaffective disorder) found similar results. Data suggest that both drugs may result in statistically significantly greater reductions in PANSS-EC compared with haloperidol and time points before 2 hours. However, these results should be interpreted with caution because these are not clearly stated pre-planned analyses and because the doses of haloperidol (6. Transition to oral therapy One study each of olanzapine and ziprasidone compared with haloperidol examined the 302, 303 transition from injectable to oral dosing over 4 to 7 days. Intramuscular olanzapine 10 mg / oral 5-20 mg daily and intramuscular haloperidol 7. The ziprasidone study found ziprasidone superior to haloperidol in the reduction of 302 the agitation component of the BPRS (P<0. During the oral dosing phase (up to day 7) the differences were not statistically significant. Tolerability and adverse events Atypical antipsychotic drugs have differing adverse event profiles, both in short- and long-term. Adverse events that may lead to mortality or serious morbidity are discussed across disease populations in the section titled Serious Harms. In this section, adverse events that relate to the tolerability of the drugs are discussed for the population of patients with schizophrenia. The adverse events reported here are the overall rate of withdrawal from studies due to adverse events, extrapyramidal symptoms, sexual side effects, weight gain, serum lipids, and metabolic syndrome. Discontinuations from studies due to adverse events Adverse events that are intolerable lead to discontinuation from studies, although some may take longer to result in discontinuation. Such discontinuations take into account the patient’s evaluation of the degree to which the adverse event is tolerable. The CATIE trials included these discontinuations as a secondary outcome measure and found statistically significant differences among the drugs. In CATIE Phase 1, discontinuations due to adverse events were highest among patients taking olanzapine (primarily due to weight gain or other metabolic effects, 18%) and lowest among those taking risperidone (10%; P=0. Time to discontinuation for adverse events did not differ among the groups. In Phases 1B, 2T, and 2E, differences were not seen between groups for rate of discontinuations or time to discontinuation due to adverse events (intolerability). Data from discontinuation rates from 64 head-to-head trials were used in a mixed- treatment comparisons analysis (also known as a network meta-analysis; Table 10). This analysis used direct and indirect comparisons based on the head-to-head trials and found that clozapine resulted in discontinuation due to adverse events statistically significantly more often than olanzapine, immediate-release quetiapine, or risperidone. This analysis controlled for between study heterogeneity and dose level within study (low, medium, or high) by using the fixed- Atypical antipsychotic drugs Page 65 of 230 Final Report Update 3 Drug Effectiveness Review Project effects model. It did not control for within study heterogeneity for those studies where there were more than 2 drug arms. As noted previously, dose comparisons have been an issue in this set of studies, with early studies using doses that are not considered clinically optimal now. For example, early studies of risperidone often used doses well above those used today and clozapine and olanzapine studies used doses below those used today. In stratified sensitivity analysis (studies of greater than 6 months in duration) the findings were no longer statistically significant, although the point estimates were in the same direction was the overall analysis. This is most likely due to the lower number of studies in each stratified analysis. There are fewer data available for the newer drugs, particularly iloperidone, asenapine, and paliperidone long-acting injection. Hence, results for these drugs should be interpreted with caution. Atypical antipsychotic drugs Page 66 of 230 Final Report Update 3 Drug Effectiveness Review Project a Table 10. Mixed-treatment effects model: Rates of discontinuation due to adverse events Aripiprazole Asenapine Clozapine Iloperidone Olanzapine Quetiapine Paliperidone Risperidone Ziprasidone 0. Atypical antipsychotic drugs Page 67 of 230 Final Report Update 3 Drug Effectiveness Review Project Because the 3 of 4 short-term trials of iloperidone were published in an abbreviated fashion and because the lower-dose studies did not indicate superiority over placebo in efficacy, there was very limited data available to evaluate comparative harms with iloperidone. A pooled analysis of 3 unpublished 6-week studies indicated that the proportion of patients discontinuing due to adverse events was highest in the risperidone group (6. Similar results were found in a study including 94 ziprasidone: iloperidone (5%, 24 mg daily), ziprasidone (8%, 160 mg daily), and placebo (8%), and in a pooled analysis of 3 longer-term trials (3. Extrapyramidal symptoms 60 In CATIE Phase 1, differences were not found between olanzapine, immediate-release quetiapine, risperidone, or ziprasidone in the incidence of extrapyramidal symptoms identified as an adverse event, or akathisia or movement disorders based on rating scales. Similarly, 77 64 differences were not found between drugs in the subsequent CATIE Phase 1B, Phase 2E, or 78 Phase 2T, or in another trial with multiple drugs (aripiprazole, olanzapine, immediate-release 62 quetiapine, risperidone, and ziprasidone). In a more detailed analysis of only treatment- emergent extrapyramidal symptoms among patients in CATIE, differences in incidence or severity between the atypical antipsychotic drugs were not found based on rating scales for 304 parkinsonism, dystonia, akathisia, or tardive dyskinesia. The use of antiparkinsonism medications was greater with risperidone and lower with immediate-release quetiapine (P=0. In a 52-week trial of olanzapine, immediate-release quetiapine, and risperidone in patients with early psychosis (median duration of illness 6. This study did find statistically significantly more patients taking olanzapine requiring anticholinergic medication for extrapyramidal symptoms compared with immediate- release quetiapine (4% compared with 11%; P=0. Data or analysis for comparison on immediate-release quetiapine and risperidone were not reported. A study of patients with acute schizophrenia, conducted in the inpatient setting over 3 weeks, found no statistically significant difference in symptom scores among aripiprazole, haloperidol, olanzapine, immediate-release 62 quetiapine, risperidone, or ziprasidone. This study reported that 30% of patients taking risperidone and 10% taking immediate-release quetiapine or ziprasidone required anticholinergic medication for extrapyramidal symptoms, while no patient taking aripiprazole or olanzapine did. In head-to-head trials comparing only 2 drugs, differences were not found between 55, 76, 83 olanzapine and immediate-release quetiapine in 3 studies, clozapine and olanzapine in 5 28, 68, 82, 104, 305 38, 65, 99 studies, or olanzapine and aripiprazole in 2 studies. In most cases, some proportion of patients entering the trials had pre-existing extrapyramidal symptoms, such that measures were actually improvements from baseline. Very few trials were specific about measuring new-onset extrapyramidal symptoms as a treatment-emergent adverse event. For all other comparisons made in head-to-head trials, at least some differences were found. Of 10 studies of olanzapine and risperidone (2223 patients total) reporting extrapyramidal 41, 47, 50, 52, 53, 59, symptom adverse event data, 8 found no significant differences between the drugs 82, 306 while 2 (586 patients total) found risperidone to have higher rates or worsening symptoms Atypical antipsychotic drugs Page 68 of 230 Final Report Update 3 Drug Effectiveness Review Project of extrapyramidal symptoms on measures reflecting akathisia, dyskinesia, dystonia, 80, 307 pseudoparkinsonism, and overall extrapyramidal symptoms. Mean doses of risperidone 5 and 7 mg were compared with olanzapine 13 and 17 mg of olanzapine, respectively. Across these studies, size and quality ratings were similar. One good-quality, short-term trial (N=377) was statistically powered to determine a difference in extrapyramidal adverse event reports and found no significant differences between the groups on this measure or on Extrapyramidal 41 Symptom Rating Scale (ESRS) scores or use of anticholinergic medications. In this trial the mean dose of olanzapine was below midrange, while the mean dose of risperidone was near the 23 midpoint (5 mg). The other good-quality trial found treatment-emergent and worsening pre- existing extrapyramidal symptoms in 28. Dosing in this study also had olanzapine slightly below midrange and risperidone within midrange. A 13-week study of risperidone long-acting injection compared with olanzapine found statistically significantly higher rates of extrapyramidal symptoms with risperidone (25% 53 compared with 15%; P<0. Rates of discontinuation due to these adverse events were not different between the groups. In a retrospective study of pharmacy records, new users of haloperidol, olanzapine, and risperidone were identified. Prescriptions for antiparkinson drugs taken during the first 90 days of atypical antipsychotic use were analyzed using a Cox proportional hazards model adjusting 308 for potential confounders. The analysis compared olanzapine and risperidone to haloperidol. Both drugs resulted in a lower risk for starting antiparkinson drugs even after considering prior antipsychotics and antiparkinson drug use. Although the reduction in risk was numerically greater with olanzapine, direct analysis was not conducted and the confidence intervals overlapped. Yet differences were not found on 6 other measures of extrapyramidal symptoms and higher rates of use of anticholinergic medications with higher doses of risperidone were found in another 29, 82 study. The strength of the evidence on extrapyramidal symptoms in comparisons of clozapine and risperidone was severely hampered by the dose inequities – usually higher doses 310 of risperidone (> 6 mg daily) and lower doses of clozapine than typically used. In 1 study the difference in use of anticholinergic medications at the higher but not the lower dose of risperidone supported the dose-response relationship between extrapyramidal symptoms and risperidone.

This larger decrease in A1c occurred in the glibenclamide group across strata defined by sex kamagra 100mg for sale effexor xr impotence, race kamagra 100mg with visa erectile dysfunction treatment vacuum constriction devices, age kamagra 100 mg visa impotence diabetes, baseline A1c kamagra 100mg without a prescription impotence sentence, or entry metformin dose. Comorbidities and other population characteristics Patients with impaired renal function were examined in several studies. Agrawal and 112 colleagues examined patients with renal impairment (creatinine clearance 30-80 mL/min) and found that rosiglitazone had similar effects on A1c in patients with and without renal 236 impairment. In a retrospective chart review of patients on dialysis with end stage renal disease, rosiglitazone was associated with weight gain and a decrease in hematocrit at 3-month follow-up compared with pioglitazone. Data for pioglitazone, however, were not presented, limiting conclusions that can be drawn. In a fair-quality study pooling 2 randomized controlled trials that compared rosiglitazone 118 plus metformin combined therapy with metformin monotherapy, Jones and colleagues 2 2 2 examined subgroups with body mass index < 25 kg/m , 25-30 kg/m , and >30 kg/m. They noted greater improvement in A1c with rosiglitazone 4 or 8 mg daily plus metformin than with metformin monotherapy (P=0. Weight gain 2 was noted in the obese group (body mass index > 30 kg/m ) receiving metformin plus rosiglitazone (2. Weight change was not reported for the other body mass index subgroups. Patients with diagnosed coronary artery disease were examined in 3 studies which were described above in Key Question 2, as these were the only studies that reported cardiovascular 103 outcomes. Wang and colleagues examined 70 Chinese with coronary artery disease and type 2 diabetes and noted significant improvement in A1c with rosiglitazone with change in weight similar to the to no-treatment control group. The primary and composite endpoint of coronary events (including death) was significantly decreased in the rosiglitazone group (P value reported 158 as both <0. Wang and colleagues also examined Chinese persons with metabolic syndrome and found that fasting plasma glucose did not improve significantly in either the rosiglitazone or the placebo group (A1c was not presented). At 6-month follow-up there were no significant differences in glycemic control or lipid concentrations between the 2 groups. The rate of restenosis and the stenosis diameter were less in the rosiglitazone group (between-group P=0. Thirty-one postmenopausal women were examined in a poor-quality, placebo-controlled 101 trial of rosiglitazone 4 mg daily. Results were similar to other placebo-controlled trials and no adverse events were reported. No studies explicitly examined populations with a history of hypoglycemic episodes. Nor were studies identified that examined the effect of concomitant medications on the comparative effectiveness of pioglitazone and rosiglitazone. Most studies permitted the use of a variety of antihypertensive, cardiac, and cholesterol-lowering medications among participants. Subgroup or Thiazolidinediones Page 79 of 193 Final Report Update 1 Drug Effectiveness Review Project other stratified analyses were not performed to allow examination of drug-drug interactions with the thiazolidinediones. In the updated report, we identified new data on the use of thiazolidinediones in persons with comorbidities, particularly with cardiovascular disease. Since the publication of the large 60 PROACTIVE study (discussed above) which compared pioglitazone with placebo, several additional subgroup analyses have been published, including of subjects with prior myocardial 79 80 infarction or stroke. In the subgroup of patients with a previous myocardial infarction at 79 baseline (N=2445) pioglitazone had a significant beneficial effect on fatal and nonfatal myocardial infarction (28% risk reduction, P=0. There were no significant differences between groups for cardiovascular death or nonfatal myocardial infarction, or stroke, although event rates in the pioglitazone group were consistently lower than with placebo. Rates of heart failure requiring hospitalization or fatal heart failure were not significantly different between the pioglitazone and placebo groups, but heart failure occurred in a greater proportion of patients in the myocardial infarction subgroup (11. In another prespecified subgroup analysis of the PROACTIVE trial, pioglitazone was 80 examined in subjects with (N=984) and without (N=4254) a prior stroke. In subjects with prior stroke, there was a trend towards benefit with pioglitazone for the primary composite endpoint (all-cause death, nonfatal myocardial infarction, acute coronary syndrome, and cardiac interventions, stroke, amputation above the ankle, or revascularization) (hazard ratio 0. Also in the group with prior stroke, pioglitazone reduced fatal or nonfatal stroke (hazard ratio 0. In the subgroup without prior stroke, pioglitazone did not reduce the risk of first stroke. Several other smaller recent trials also examined comorbidity subgroups with pioglitazone. In a small, open-label study in subjects with overt diabetic nephropathy (mean creatinine 2. A small, placebo- controlled pioglitazone monotherapy study in persons newly diagnosed with type 2 diabetes and 237 coronary heart disease found was no significant difference between groups in change in A1c. In a small randomized controlled trial (N=47) patients with impaired glucose tolerance or type 2 diabetes in addition to nonalcoholic steatohepatitis received either pioglitazone 45 mg 82 daily or placebo, in addition to a weight loss intervention. Glycemic control improved with pioglitazone compared with placebo (P<0. Liver aminotransferase levels normalized with pioglitazone, and plasma aspartate and alanine aminotransferase levels, along with hepatic fat content, all decreased with pioglitazone compared with placebo (P<0. Histologic changes in the liver also improved significantly with pioglitazone. In this fair-quality trial, patients were not stratified with respect to type 2 diabetes or impaired glucose tolerance status. In another small study, patients with acute coronary syndrome received pioglitazone or 93 no additional treatment starting 2 weeks after percutaneous, bare metal stent placement. Determined from quantitative angiography at 6 months, the late luminal loss was less in the pioglitazone group than in the control group (P=0. Major cardiac events (myocardial infarction or revascularization of the target lesion) were significantly decreased in the pioglitazone group at 6 months compared with the control group (7. Several studies in the updated report examined rosiglitazone with comorbidities. In a very small (N=16), poor-quality randomized controlled trial, subjects with coronary stent implantation were randomized to rosiglitazone 4-8 mg daily or placebo for 6 months. Rosiglitazone did not 108 reduce in-stent restenosis. There were no differences in cardiac events between the groups. Lautamaki and colleagues noted a decrease in A1c compared with placebo in a study of combination therapy in patients with coronary artery disease (P<0. Thiazolidinediones Page 81 of 193 Final Report Update 1 Drug Effectiveness Review Project Table 19. Studies exam ining subgroups based ondem ograph icch aracteristics orcom orbidities B aseline A uth or, C oncurrent M eanage A 1c(SD) Y ear C ountry Study R ace/ h ypoglycem ic Inclusioncriteria (SD) W eigh t(SD) A 1c A dverse events Q uality Setting design eth nicity treatm ent Exclusioncriteria G ender orB M I (SD) outcom es and tolerability Pioglitaz one Hispanic,>18y,D M 2, uncontrolled hyperglycemiawith 8patients(5. Patientsmusthavehad atrialof dietand lifestyleinterventions beforestudyenrollment A1cat1-year E x clusioncriteria: TanM 2004 follow-up Incidenceof significantfunctional (glimepiride 55. E x clusion criteria:Significant renalorhepatic impairment, hypertension,anemia, abnormalbloodcell countsorhypertension; Thiazolidinediones Page 86 of 193 Final Report Update 1 Drug Effectiveness Review Project B aseline A uth or, C oncurrent M eanage A 1c(SD) Y ear C ountry Study R ace/ h ypoglycem ic Inclusioncriteria (SD) W eigh t(SD) A 1c A dverse events Q uality Setting design eth nicity treatm ent Exclusioncriteria G ender orB M I (SD) outcom es and tolerability severeangina, coronaryinsufficiency, heartfailure,E K G evidenceof left ventricularhypertrophy; patientsrequiring insulinorwhohad takeninvestigational drugswithin30daysof screening. Aged50to73,witha diagnosisof coronary arterydisease(>50% stenosisasprovenon angiography)and establishedD M 2 ChangeinA1c E x clusioncriteria: reported AcuteM I during the graphically W eightgain:NSD W ang G. Thiazolidinediones Page 87 of 193 Final Report Update 1 Drug Effectiveness Review Project B aseline A uth or, C oncurrent M eanage A 1c(SD) Y ear C ountry Study R ace/ h ypoglycem ic Inclusioncriteria (SD) W eigh t(SD) A 1c A dverse events Q uality Setting design eth nicity treatm ent Exclusioncriteria G ender orB M I (SD) outcom es and tolerability Presenceof metabolic syndromeandmeetat leastof thefollowing 3 criteria:waist circumferenceof >90 cm inmenand>80cm inwomen,serum TG > 150mg/dl,HD L <40 mg/dlinmenand<50 mg/dlinwomen,IF G 110-125mg/dl,BP >130/85mm Hg or treatedhypertension. E x clusioncriteria: Patientswithacute coronaryevents,stroke orcoronary revasculariz ationwithin thepreceding 3 W ang,T months;diabetes A1cNR 2004 mellitusaccording to NR F PG:NSD (M etabolic thecriteriaof the 59. Thiazolidinediones Page 88 of 193 Final Report Update 1 Drug Effectiveness Review Project B aseline A uth or, C oncurrent M eanage A 1c(SD) Y ear C ountry Study R ace/ h ypoglycem ic Inclusioncriteria (SD) W eigh t(SD) A 1c A dverse events Q uality Setting design eth nicity treatm ent Exclusioncriteria G ender orB M I (SD) outcom es and tolerability Pioglitaz one and rosiglitaz one Comparisonof rositopio: interdialytic weightchange Rosi:3. Center D iabeteswasthe NR providedfor (Cohort causeof E SRD in 35% female pio,but study) 92. Thiazolidinediones Page 89 of 193 Final Report Update 1 Drug Effectiveness Review Project CONCLUSIONS Table 20 summarizes results of this review. Summary of the evidence by Key Question Key question Quality of evidence Conclusion Key Question 1: Good Pioglitazone compared to rosiglitazone: For persons with type 2 Prior systematic reviews: diabetes, do pioglitazone - Both drugs appear to have similar effects on and rosiglitazone differ from A1c, producing a decrease of approximately 1%, each other, from placebo, similar to the change produced with other oral and from other oral agents (including metformin, glibenclamide, or hypoglycemic agents in the glimepiride). TZDs compared to other oral hypoglycemic agents: In a prior systematic review, there were no between-group differences between thiazolidinediones and metformin (7 randomized controlled trials) or second- generation sulfonylureas (13 randomized controlled trials). Thiazolidinedione plus metformin compared with a second-generation sulfonylurea plus metformin (2 randomized controlled trials) did not show a consistent effect favoring 1 of the combinations, nor did 2 randomized controlled trials comparing thiazolidinediones with repaglinide. One trial comparing pioglitazone to acarbose favored pioglitazone for A1c reduction. Key Question 2: Insufficient Data are not sufficient to determine the For persons with type 2 comparative effectiveness of pioglitazone and diabetes, do pioglitazone rosiglitazone on microvascular or macrovascular and rosiglitazone differ from complications of diabetes as there are no head- Thiazolidinediones Page 90 of 193 Final Report Update 1 Drug Effectiveness Review Project Key question Quality of evidence Conclusion each other, from placebo, to-head data and indirect data are sparse. Key Question 3 (NOT Body of evidence is - It is not possible to conclude whether there is a UPDATED): insufficient: difference in weight change between Pio and For patients with - There are few Rosi. Key Question 4: Insufficient for the There were insufficient data to determine whether For persons with pre- comparison of pio to pioglitazone and rosiglitazone have different effects on diabetes or the metabolic rosi the incidence of diabetes among persons with either prediabetes or the metabolic syndrome. A smaller trial found a nonsignificant reduction in cases Placebo of new onset diabetes with rosiglitazone compared to placebo. Key Question 5: Body of evidence is - Data are insufficient to determine the comparative (NOT UPDATED) For insufficient effectiveness of Pio and Rosi on cardiovascular risk patients with prediabetes or - Four fair-quality factors among persons with prediabetes or the studies provided data metabolic syndrome. Key Question 6: Good to fair Adverse events occurring with pioglitazone and For persons with type 2 rosiglitazone were similar in 3 head-to-head trials. Key Question 7 (NOT Body of evidence is Hypoglycemia: UPDATED): insufficient How do thiazolidinediones - Four fair-quality Pioglitazone studies were identified - 1 fair-quality study reported significantly fewer compare to sulfonylureas in relevant to hypoglycemic events with Pio than with a serious hypoglycemic hypoglycemia and sulfonylurea (P<0. Functional status and quality of life - No evidence upon which to draw conclusions Key Question 8: Fair for demographic Demographic characteristics Are there subgroups of characteristics - The vast majority of studies were conducted in the persons with type 2 Poor for comorbidities United States or in Western Europe and examined and other Caucasian populations. Comorbidities and other characteristics hypoglycemic agents? Thiazolidinediones Page 92 of 193 Final Report Update 1 Drug Effectiveness Review Project REFERENCES 1. National Diabetes fact sheet: general information and national estimates on diabetes in the United States, 2007. Atlanta, GA: Department of Health and Human Services. Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. Delaying the Onset of Type 2 Diabetes Mellitus in Patients with Prediabetes. Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose for prevention of type 2 diabetes mellitus: the Stop-NIDDM randomised trial. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Executive Summary of the Third Report of the National Cholestrol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholestrol in Adults (Adult Treatment Panel III).

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Importance of pharmacological and physicochemical properties for tolerance of antimuscarinic drugs in the treatment of detrusor instability and detrusor hyperreflexia - Chances for improvement of therapy generic 100 mg kamagra free shipping doctor for erectile dysfunction philippines. Clinical efficacy of tolterodine with or without a simplified pelvic floor exercise regimen buy cheap kamagra 50 mg icd-9-cm code for erectile dysfunction. Does concomitant stress incontinence alter the efficacy of tolterodine in patients with overactive bladder? Prevalence purchase kamagra 50mg with amex 498a impotence, incidence and correlates of urinary incontinence in healthy kamagra 50mg free shipping erectile dysfunction groups, middle-aged women. Tolterodine for overactive bladder: time to onset of action, preferred dosage, and 9-month follow-up. Trials with an ineligible duration of study Milani, R. Comparison of flavoxate hydrochloride in daily dosages of 600 versus 1200 mg for the treatment of urgency and urge incontinence. Flavoxate hydrochloride for urinary urgency after pelvic radiotherapy: comparison of 600 mg versus 1200 mg daily dosages. The use of salivary stimulant pastilles to improve compliance in women taking oxybutynin hydrochloride for detrusor instability: A pilot study. Overactive bladder Page 71 of 73 Final Report Update 4 Drug Effectiveness Review Project Briggs, R. The effect of flavoxate on uninhibited detrusor contractions and urinary incontinence in the elderly. Overactive bladder Page 72 of 73 Final Report Update 4 Drug Effectiveness Review Project Excluded Studies Update 4 3=Wrong intervention, 4=wrong population, 6=wrong study design Exclusion Excluded studies codes Head-to-head trials Armstrong RB, Dmochowski RR, Sand PK, et al. Safety and tolerability of extended-release oxybutynin once daily in urinary 6 incontinence: combined results from two phase 4 controlled clinical trials. Horstmann M, Schaefer T, Aguilar Y, Stenzl A, Sievert KD. Neurogenic bladder treatment by doubling the recommended 4 antimuscarinic dosage. Active control trials Chapple C, Van Kerrebroeck P, Tubaro A, et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with 3 overactive bladder. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. A randomized double- blind placebo-controlled multicentre study to explore the efficacy 3 and safety of tamsulosin and tolterodine in women with overactive bladder syndrome. Effects of bladder training and/or tolterodine in female patients with overactive bladder 6 syndrome: a prospective, randomized study. Comparison of electric stimulation and oxybutynin chloride in management of overactive bladder with 6 special reference to urinary urgency: a randomized placebo- controlled trial. A meta-analysis comparing trials of antimuscarinic 6 medications funded by industry or not. Overactive bladder Page 73 of 73 Drug Class Review Agents for Overactive Bladder Final Report Update 4 Evidence Tables March 2009 Update 3 Report date: December 2005 Update 2 Report date: May 2005 Update 1 Report date: January 2004 Original Report date: February 2003 A literature scan of this topic is done periodically The purpose of this report is to make available information regarding the comparative effectiveness and safety profiles of different drugs within pharmaceutical classes. Reports are not usage guidelines, nor should they be read as an endorsement of, or recommendation for, any particular drug, use, or approach. Oregon Health & Science University does not recommend or endorse any guideline or recommendation developed by users of these reports. McDonagh, PharmD Dana Selover, MD, MPH John Santa, MD Sujata Thakurta, MPA:HA Oregon Evidence-based Practice Center Oregon Health & Science University Mark Helfand, MD, MPH, Director Copyright © 2009 by Oregon Health & Science University Portland, Oregon 97239. Final Report Update 4 Drug Effectiveness Review Project TABLE OF CONTENTS Evidence Table 1. Anticholinergic overactive bladder syndrome drugs compared with other drugs……………………………………………………………………………………………………. Anticholinergic overactive bladder syndrome drugs compared with non-drug therapy…………………………………………………………………………………………………. New overactive bladder syndrome drugs compared with placebo…………168 Evidence Table 6. Assessment of abstracts for publication bias…………………………………176 Evidence Table 8. Overactive bladder syndrome observational studies: Adverse events……. Prior versions of this report can be accessed at the DERP website. Overactive bladder 2 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Study Design Y ear Setting Eligibility criteria Exclusioncriteria Im m ediate R elease vs Im m ediate R elease (IR vs IR ) O xybutynin(O xy) vs. Tolterodine (Tol) L eung R CT W om en,age ≥18,urodynam icallyconfirm ed D iagnosisof stressincontinence,clinicallysignificantvoiding difficulty, 2002 M ulticenter diagnosisof overactivebladder(phasic detrusor U TIs,requirecatheteriz ation,uninvestigatedhem aturiaorbladdercancer, Hong K ong contractionwith anam plitude ≥15cm water, currentlyontreatm entforoveractivebladderoronanticholinergic drugs, urinaryfrequency(≥8voids/24h),urgencyor presenceof psychiatric diseaseorcognitiveim pairm ent,contraindications urgeincontinence(≥1incontinence forantim uscarinic drugs. L ee R CT M aleorfem ale,18+yrs,with overactivebladder Significantstressincontinence,anyanticholinergic drug treatm entwithin2 2002 M ulticenter definedbysym ptom sof urinaryfrequencyand wks,renalorhepatic disease,anycontraindicationtoantim uscarinic South K orea urgencywith orwithoutincontinence. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 3 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Interventions (drug,regim en, O th erinterventions/ M eth od ofO utcom e A ssessm entand Tim ing of Y ear duration) m edications A ssessm ent Im m ediate R elease vs Im m ediate R elease (IR vs IR ) O xybutynin(O xy) vs. Tolterodine (Tol) L eung Tol2m g twicedailyx 10weeks N onereported VisualAnalog Scaleof patientassessm entof severityof 2002 O x y5m g twicedailyx 10weeks sym ptom satbaseline,4and10weeks,(0= noeffect, 10= m ax severity),perceivedchangesinsym ptom s beforeandaftertreatm entassessedat4and10weeks (+5= m ax im provem ent,-5= m ax deterioration). M icturitiondiaryassessedat8wks 2002 O x y5m g twicedaily Patientassessm entof treatm entbenefitsasyes/no;with x 8wks yesfurtherdefinedaslittleorm uch. Com plianceassessedbytabletcountat8wks *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 4 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials N um berscreened/ A ge O th erpopulation A uth or, eligible/ G ender ch aracteristics N um berwith drawn/ Y ear enrolled Eth nicity (diagnosis,etc) lostto fu/analyz ed Im m ediate R elease vs Im m ediate R elease (IR vs IR ) O xybutynin(O xy) vs. Tolterodine (Tol) L eung 106enrolled(num ber Agerange43-63yrs 56% postm enopausal,m edianparity3 W ithdrawals: 2002 pergroup notstated) M edianage49. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 5 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Y ear O utcom es Im m ediate R elease vs Im m ediate R elease (IR vs IR ) O xybutynin(O xy) vs. Tolterodine (Tol) L eung D iaries 2002 Analysisof varianceshowsN S betweengroupsonanym easure,allgroupsim proved. Sym ptom s Changeinoverallseverity(from baseline) O x y:4and10weeks0. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 6 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, A dverse effects assessed? Y ear H ow assessed Im m ediate R elease vs Im m ediate R elease (IR vs IR ) O xybutynin(O xy) vs. Tolterodine (Tol) L eung X erostom iaQ uestionnaireat4and10weeks,independentreporting of othersideeffects. Sideeffectsreported: O x y49% Tol60% (N S) R eportedtobem ostlyabdom inalaches,generalm alaiseandurinaryretention L ee Spontaneouslyreportedadverseeventswerereportedandratedasseriousornonseriousandaccording to 2002 intensity,andrelationship tostudydrug. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 7 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Y ear W ith drawals due to adverse events C om m ents Im m ediate R elease vs Im m ediate R elease (IR vs IR ) O xybutynin(O xy) vs. L ee 29: 2002 Tol11(6drym outh,55%) O x y18(16drym outh,88%) *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 8 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Study Design Y ear Setting Eligibility criteria Exclusioncriteria Abram s R CT M enorwom en18+yrs,urodynam ically Clinicallysignificantstressincontinence,detrusorhyper-reflex ia,hepatic, 1998 M ulticenter confirm edbladderoveractivity,increased renalorhem atologic disorders,sym ptom atic orrecurrentU TI,bladder U K ,Irelandand frequency(8orm orem icturitions/24hrs),and outletobstruction,bladdertraining orelectrostim ulation,indwelling or Sweden urgeincontinence(1orm oreepisodes/24hrs) interm ittentcatheter and/orurgencyduring a2weekwashout/run-in period. D rutz R CT Age18+with evidenceof detrusoroveractivity Clinicallysignificantstressincontinence,renalorhepatic disease,any 1999 M ulticenter oncystom etry,along with urinaryfrequency,and diseasewhich theinvestigatorthoughtwouldm akethepatientunsuitable, U SA/Canada eitherurgeincontinenceorurinaryurgency. U TI,interstitialcystitis,hem aturia,anycatheteriz ation,behavioraltraining within14d,unstabledoseof anydrug with anticholinergic sideeffects, previousseriousadverseeffectsonO x y,m eanvoidedvolum e/d>3L ,or riskof urinaryretention. Im m ediate R elease vs Im m ediate R elease (IR vs IR ) O xybutynin(O xy)vs F lavoxate (F la) *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 9 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Interventions (drug,regim en, O th erinterventions/ M eth od ofO utcom e A ssessm entand Tim ing of Y ear duration) m edications A ssessm ent Abram s Tol2m g twicedaily N onereported M icturitiondiaryassessedat2,4,8,and12weeks 1998 D osecouldbedroppedto1m g during first Patientassessm entof severityof sym ptom sbasedon6- 2weeksif nottolerated pointscale(0= noproblem s,6= severeproblem s) O x y5m g threetim esdaily Changebetweenbaselineand12weeksdefinedas D osecouldbedroppedto2. Placebo threetim esdaily x 12wks D osereductiontoTol1m g orO x y5m g twicedailyallowedduring first2wks. Im m ediate R elease vs Im m ediate R elease (IR vs IR ) O xybutynin(O xy)vs F lavoxate (F la) *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 10 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials N um berscreened/ A ge O th erpopulation A uth or, eligible/ G ender ch aracteristics N um berwith drawn/ Y ear enrolled Eth nicity (diagnosis,etc) lostto fu/analyz ed Abram s N um ber Agerange19-80yrs Previousdrug therapy:Tol52%,O x y 37(10Tol,20O x y,7Pl) 1998 screened/eligiblenot M eanageTol55,O x y58,Pl 60%,Pl75% reportedwithdrawing dueto stated 58 M eanm icturitions/24h:12Tol,11O x y, adverseeffects,noother 293enrolled 76% fem ale 12Pl withdrawalsorlosstofollow-up (118Tol,118O x y,57 M eanincontinenceepisodes/24h:2. D rutz 277enrolled(Tol109, m eanage:Tol63yrs,O x y66 % hyperreflex ia:Tol7,O x y7,Placebo5 57withdrew 1999 O x y112,Placebo56) yrs,placebo62yrs % Previousdrug therapy:Tol45,O x y 147analyz ed(70Tol,41O x y,36 % fem ale:Tol81,O x y72, 45,Placebo55 placebo) Placebo80 % with incontinence:Tol83,O x y92, 27ex cludedduetodose % Caucasian:Tol87,O x y94, placebo89 reductions Placebo93 % PriorU rinarytractsurgery:Tol27, 46ex cludedduetoprotocol O x y45,placebo34 violations Im m ediate R elease vs Im m ediate R elease (IR vs IR ) O xybutynin(O xy)vs F lavoxate (F la) *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 11 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Y ear O utcom es Abram s Changeinm eannum berof voids/24hrsatweek12: 1998 -2. O x yN S) Changeinm eannum berof incontinenceepisodes/24hrsatweek12:(n= 92Tol,88O x y,40Pl) -1. O x yN S) Changeinsubjectiveassessm entof sym ptom satweek12: Im proved50% Tol,49% O x y,47% Pl D rutz PP analysis: 1999 Changeinm eanm icturitions/d: Tol-2. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 12 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, A dverse effects assessed? Y ear H ow assessed Abram s Alladverseeventswererecordedandcategoriz edbyintensity(m ild,m oderate,severe). Thelikelihoodof 1998 relationship tostudydrug wasevaluatedforseriousadverseeventsandpatientwithdrawnif deem ed m edicallynecessaryorpatientwishedwithdrawal. Atleastoneadverseeventreported:89% Tol,97% O x y,81% Pl(Tolvs. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 13 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1.

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Sedation Fair First-generation antihistamines (diphenhydramine generic kamagra 100 mg with amex erectile dysfunction treatment in tampa, chlorpheniramine) more sedating than newer-generation agents buy kamagra 100 mg fast delivery cough syrup causes erectile dysfunction. Cetirizine and levocetirizine were more sedating than loratadine and desloratadine generic 50 mg kamagra with amex erectile dysfunction protocol foods. Some evidence suggested that cetirizine may be more sedating than fexofenadine purchase 50mg kamagra free shipping impotence kidney disease. There was no significant difference in reports of sedation between loratadine and fexofenadine in 1 observational study. Headache Fair Headache was reported with similar rates in cetirizine, loratadine, and fexofenadine. Cardiac effects Fair A large, fair-quality cohort study provided evidence of a significant risk of cardiac arrhythmias with cetirizine compared with non-use. A nonsignificant increase in risk was noted with loratadine. Limited evidence suggested no QTc prolongation with loratadine and fexofenadine. Bitter taste/nasal Fair Incidence was higher with azelastine than discomfort olopatadine in head-to-head trials but indirect assessment suggested minimal difference between groups. Children No head-to-head data on adverse Insufficient evidence on comparative events except 2 events in cetirizine safety. Fair-quality evidence on the safety of cetirizine and loratadine. Limited evidence on the safety of desloratadine and fexofenadine. Fair evidence that cetirizine does not significantly prolong QTc interval. Limited evidence (1 study each) that desloratadine and fexofenadine did not prolong QTc interval. Subgroups Are there subgroups of patients based on demographics (age, racial groups, gender), concomitant medications (drug-drug interactions), co-morbidities (drug-disease interactions or pregnancy), for which one newer antihistamine is more effective or associated with fewer adverse effects? Age, gender, There was insufficient evidence to We did not identify head-to-head race/ethnicity determine whether any of the comparative studies of drug interactions. Asthma or atopic Fair There were no differences in rate of dermatitis adverse events in patients with allergic rhinitis and asthma or atopic dermatitis. Pregnancy Fair There was minimal increase risk of birth defects observed with newer antihistamines in pregnant women. Newer antihistamine drug exposure in pregnant women did not significantly increase the risk of hypospadias in male infants. Abbreviations: AR, allergic rhinitis; CIU, chronic idiopathic urticaria; ECG, electrocardiogram; NS, not significant; NSD, no significant difference; PAR, perennial allergic rhinitis; QT, cardiac output; QTc, corrected QT interval for heart rate; RCT, randomized controlled trial; SAR, seasonal allergic rhinitis; SD, significant difference; TSS, total symptom score. Antihistamines Page 35 of 72 Final Report Update 2 Drug Effectiveness Review Project REFERENCES 1. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Second-generation antihistamines: actions and efficacy in the management of allergic disorders. Safety and tolerability of treatments for allergic rhinitis in children. Therapeutic advantages of third generation antihistamines Expert Opin Inv Drug. Allergic rhinitis and impairment issues in schoolchildren: A consensus report. Current concepts and therapeutic strategies for allergic rhinitis in school-age children. Consensus statement on the treatment of allergic rhinitis. European Academy of Allergology and Clinical Immunology. Bousquet J, Van Cauwenberge P, Khaltaev N, ARIA Workshop Group, World Health Organization. International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Allergic rhinitis: epidemiology and natural history. Allergic rhinitis: definition, epidemiology, pathophysiology, detection, and diagnosis. Malone DC, Lawson KA, Smith DH, Arrighi HM, Battista C. A cost of illness study of allergic rhinitis in the United States. Management of allergic rhinitis in the working-age population. Washington, DC: Agency for Healthcare Research and Quality (AHRQ); March 2003. Allergic rhinitis: basic pathophysiology and therapeutic strategies. Clinical prescribing of allergic rhinitis medication in the preschool and young school-age child: what are the options? Wright AL, Holberg CJ, Martinez FD, Halonen M, Morgan W, Taussig LM. Epidemiology of physician-diagnosed allergic rhinitis in childhood. Improvement of quality of life by treatment with cetirizine in patients with perennial allergic rhinitis as determined by a French Antihistamines Page 36 of 72 Final Report Update 2 Drug Effectiveness Review Project version of the SF-36 questionnaire. Quality of life in adults and children with allergic rhinitis. Overview of allergic diseases: diagnosis, management, and barriers to care. Chronic urticaria: aetiology, management and current and future treatment options. Impact of azelastine nasal spray on symptoms and quality of life compared with cetirizine oral tablets in patients with seasonal allergic rhinitis. Efficacy of azelastine nasal spray in patients with an unsatisfactory response to loratadine. Efficacy of desloratadine, 5 mg, compared with fexofenadine, 180 mg, in patients with symptomatic seasonal allergic rhinitis. Ciprandi G, Pronzato C, Ricca V, Passalacqua G, Danzig M, Canonica GW. Loratadine treatment of rhinitis due to pollen allergy reduces epithelial ICAM-1 expression. Corren J, Storms W, Bernstein J, Berger W, Nayak A, Sacks H. Effectiveness of azelastine nasal spray compared with oral cetirizine in patients with seasonal allergic rhinitis. Hampel F, Ratner P, Mansfield L, Meeves S, Liao Y, Georges G. Fexofenadine hydrochloride, 180 mg, exhibits equivalent efficacy to cetirizine, 10 mg, with less drowsiness in patients with moderate-to-severe seasonal allergic rhinitis. Howarth PH, Stern MA, Roi L, Reynolds R, Bousquet J. Double-blind, placebo- controlled study comparing the efficacy and safety of fexofenadine hydrochloride (120 and 180 mg once daily) and cetirizine in seasonal allergic rhinitis. Efficacy and tolerability of loratadine versus fexofenadine in the treatment of seasonal allergic rhinitis: a double-blind comparison with crossover treatment of nonresponders. Shah SR, Nayak A, Ratner P, Roland P, Michael Wall G. Antihistamines Page 37 of 72 Final Report Update 2 Drug Effectiveness Review Project 35. A monocenter, double-blind, randomized trial, with two parallel groups comparing the clinical efficacy of levocetirizine 5 mg capsules and desloratadine 5 mg capsules taken once a day over 3 weeks of treatment in adult subjects suffering from seasonal allergic rhinitis (SAR) due to grass pollen [completed]. Comparison of the efficacy, safety and quality of life provided by fexofenadine hydrochloride 120 mg, loratadine 10 mg and placebo administered once daily for the treatment of seasonal allergic rhinitis. Comparison of the efficacy and safety of bilastine 20 mg vs desloratadine 5 mg in seasonal allergic rhinitis patients. Desloratadine for the treatment of cypress pollen-induced allergic rhinitis. Meltzer EO, Jalowayski AA, Vogt K, Iezzoni D, Harris AG. Effect of desloratadine therapy on symptom scores and measures of nasal patency in seasonal allergic rhinitis: results of a single-center, placebo-controlled trial. Desloratadine improves quality of life and symptom severity in patients with allergic rhinitis. Levocetirizine modulates lymphocyte activation in patients with allergic rhinitis. Evaluation of the efficacy and safety of levocetirizine during 8 weeks preceding and following the anticipated onset of the grass pollen season in subjects suffering from seasonal allergic rhinitis associated with pollen-induced asthma [completed]. Bernstein JA, Prenner B, Ferguson BJ, Portnoy J, Wheeler WJ, Sacks HJ. Double-blind, placebo-controlled trial of reformulated azelastine nasal spray in patients with seasonal allergic rhinitis. Efficacy and tolerability of azelastine nasal spray in patients with allergic rhinitis compared to placebo and budesonide. Safety and efficacy of azelastine nasal spray (Astelin NS) for seasonal allergic rhinitis: a 4-week comparative multicenter trial. Efficacy and safety of azelastine nasal spray at a dose of 1 spray per nostril twice daily. A double- blind, controlled trial to assess the safety and efficacy of azelastine nasal spray in seasonal allergic rhinitis. Effectiveness of azelastine nasal solution in seasonal allergic rhinitis. Improved quality of life among seasonal allergic rhinitis patients treated with olopatadine HCl nasal spray 0. Safety and efficacy of olopatadine hydrochloride nasal spray for the treatment of seasonal allergic rhinitis. Safety and efficacy of olopatadine hydrochloride nasal spray for the treatment of seasonal allergic rhinitis to mountain cedar. Martinez-Cocera C, De Molina M, Marti-Guadano E, et al.