Fixed Combination Group Research Articles

Treatment intensification following glucagon-like peptide-1 receptor agonist in type 2 diabetes: Comparative effectiveness analyses between free vs. fixed combination of GLP-1 RA and basal insulin. RESTORE-G real-world study

Background and aimsAdd-on of basal insulin (BI) to intensify the ongoing therapy with glucagon-like peptide 1 receptor agonist (GLP-1 RA) is recommended, but it is unclear if free or fixed combination of BI and GLP-1 RA produce similar outcomes. A retrospective comparative effectiveness analysis of the add-on of glargine 300 U/mL (Gla-300) to ongoing GLP-1 RA vs. switch to fixed ratio combination of degludec and liraglutide (iDegLira) was performed. Methods and resultsReal-world data collected in electronic medical records by 32 Italian diabetes clinics. Propensity score (PS) adjustment was applied to assess changes in glycated hemoglobin (HbA1c), fasting blood glucose (FBG), body weight, and BI dose after 6 months from Gla-300 or iDegLira initiation.Compared to iDegLira group (N = 260), Gla-300+GLP-1 RA group (N = 255) had older age and higher levels of HbA1c (9.1 vs. 8.9%). After 6 months, statistically significant greater FBG improvement [estimated mean difference and 95% confidence intervals: −24.05 mg/dl (−37.04; −11.06; p = 0.0003) and BI dose increase [+0.03 U/kg (95%CI 0.00; 0.06); p = 0.009] were found in the free vs. fixed combination group, although low doses of BI (0.2 U/kg) were reached in both groups. Trends of larger HbA1c and body weight reductions with the free combination were also found, without reaching the statistical significance. ConclusionAlthough inertia in insulin initiation and titration was documented in both groups, higher benefit on FBG control was obtained with free vs. fixed combination, likely due to a better titration of BI and GLP-1 RA.

84-LB: Intensification of Glucagon-Like Peptide-1 Receptor Agonists Therapy with Glargine 300 U/mL or IDegLira—The RESTORE-G Real-World Study

Combined use of basal insulin (BI) and glucagon-like peptide 1 receptor agonist (GLP1-RA) deserves consideration for the synergistic effects on glucose profile. Nevertheless, it is unclear if the addition of BI to the ongoing GLP1-RA therapy in free or fixed combination is associated with different outcomes. Aim of this RESTORE-G sub-study was to perform a propensity-score adjusted comparative effectiveness analysis of the two most innovative BIs for intensifying GLP1-RA therapy (±oral agents), i.e. Glargine 300 U/mL in free combination (Gla-300) vs. the fixed ratio combination of insulin degludec + liraglutide (IDegLira). Table shows sample sizes, patients characteristics and effectiveness results. Compared to IDegLira, Gla-300 group had older age, worse metabolic control, and higher starting BI doses. After 6 months, statistically significant larger FBG reduction and BI dose increase were found in the free vs. fixed combination group. Trends of larger HbA1c and weight reductions with the free combination were also found, without reaching the statistical significance. In conclusion, higher benefits on FBG control in free vs. fixed combination has been found in people uncontrolled on GLP-1 RA, likely due to a better titration of the components. However, inertia in insulin initiation was documented in both groups. Disclosure R. Candido: None. A. Nicolucci: Board Member; AstraZeneca, Research Support; Novo Nordisk, Sanofi, Sobi, Shionogi & Co., Ltd., AlfaSigma, Speaker's Bureau; Boehringer Ingelheim and Eli Lilly Alliance. M. Rossi: Research Support; Sanofi, Novo Nordisk, Shionogi & Co., Ltd., AlfaSigma. M. Larosa: None. R. Napoli: Advisory Panel; Sanofi, Eli Lilly and Company, Novo Nordisk, Research Support; Novo Nordisk, AstraZeneca, Speaker's Bureau; Sanofi, Eli Lilly and Company, Novo Nordisk, AstraZeneca, MSD Life Science Foundation. Restore-g study group: n/a. Funding Sanofi

ROSuvastatin and Amlodipine as free or fixed combination on theRApeutic taRgets and treatment Adherence in hypertensive, hypercholesterolemic individuals. ROSA RARA: a spontaneous, observational study conducted by italian outpatient cardiologists

Background: Hypertension and LDL hypercholesterolemia often coexist, and their effective treatment has favorable implications for cardiovascular health. We aimed at defining the impact of amlodipine and rosuvastatin as free or fixed combinations on blood pressure (BP) and LDL-cholesterol, and the satisfaction with treatment, in hypertensive individuals with LDL hypercholesterolemia. Methods: A spontaneous longitudinal observational study was conducted at Italian cardiology outpatients clinics. Eligible individuals (age ≥ 18y, informed consent, stable 5 or 10 mg amlodipine therapy in addition to a RAAS inhibitor, stable 10 or 20 mg rosuvastatin therapy) underwent home and office BP and LDL-cholesterol assessment at 12 and 24 weeks. BP and LDL-cholesterol control rates and satisfaction with the fixed combination were assessed. Results: 285 participants were enrolled (51%M; 67 ± 10y; 94 on the free combination). At 12 weeks, mean BP and LDL-cholesterol were reduced in both groups, with higher hypertension control rates in the fixed combination group; at 24 weeks they were further reduced compared with baseline, and home systolic BP was lower in the fixed than the free combination group (121.9 ± 17.6 vs 129.4 ± 8.5 mmHg; p = 0.03). Patients in the fixed combination reported higher satisfaction with this regimen than with the free combination. Conclusions: The fixed combination of calcium channel blocker and statin appears to have advantages in terms of clinical efficacy and patients’ satisfaction.

Effects of Netarsudil and Latanoprost Alone and in Fixed Combination on Corneal Endothelium and Corneal Thickness: Post-Hoc Analysis of MERCURY-2.

IntroductionTo describe the changes in endothelial cell density (ECD), the coefficient of variation (CV), the percentage of hexagonal cells (%HEX), and central corneal thickness (CCT) following 3 months of therapy with netarsudil 0.02%/latanoprost 0.005% fixed combination, and to compare these changes with those seen with netarsudil 0.02% or latanoprost 0.005% in eyes with ocular hypertension or open-angle glaucoma.MethodsA subset of subjects enrolled in a Phase 3 evaluation of the intraocular pressure-lowering efficacy and safety of netarsudil 0.02%/latanoprost 0.005% fixed combination once daily (QD) versus each of its individual components underwent corneal endothelial cell imaging by specular microscopy and ultrasound pachymetry at baseline and following 3 months of therapy. Images were evaluated in masked fashion at an independent reading center. Changes from baseline to 3 months in ECD, CV, %HEX, and CCT were compared between treatment groups.ResultsData from 415 subjects obtained at both baseline and Month 3 were included in this post hoc analysis. Changes from baseline to Month 3 in ECD, CV, and %HEX were clinically insignificant in all three groups, and the changes in the netarsudil/latanoprost fixed combination group demonstrated no statistical difference from those seen in the netarsudil and latanoprost groups. Mean CCT decreased more in the fixed combination group (− 6.4 µm) than in either the netarsudil group (− 3.3 µm, p = 0.0248) or the latanoprost group (− 1.2 µm, p < 0.0001).ConclusionsNetarsudil 0.2%/latanoprost 0.005% fixed combination QD for 3 months in eyes with ocular hypertension or open-angle glaucoma had no clinically significant effects on endothelial cell density or morphology. The significant decrease in CCT in the fixed combination group compared to the two individual component groups may indicate that the potential effects of each drug on CCT are additive, although the magnitude of the observed effects is likely of negligible clinical significance.Clinicaltrials.gov IdentifierNCT02674854.

Brinzolamide–brimonidine fixed combination for the prevention of intraocular pressure elevation after phacoemulsification

To evaluate the effectiveness of brinzolamide-brimonidine fixed combination to control the intraocular pressure elevation throughout the first 24 h following uncomplicated phacoemulsification cataract surgery. A total of 62 patients who underwent phacoemulsification cataract surgery were included in this prospective randomized comparative case series. The brinzolamide-brimonidine fixed combination group (34 eyes) was administered a single dose of brinzolamide-brimonidine fixed combination immediately after phacoemulsification. No treatment was administered in the control group (28 eyes). Intraocular pressure was measured 1 day before surgery (baseline) and at 6, 12 and 24 h postoperatively. The brinzolamide-brimonidine fixed combination group had significantly lower intraocular pressure at 6, 12 and 24 h after phacoemulsification compared to baseline (p < 0.0001 for all comparisons), while in control group, intraocular pressure was significantly higher at 6 and 12 h after surgery compared to baseline (p < 0.001 and p < 0.0001, respectively). In control group, an intraocular pressure elevation ⩾ 5 mm Hg was noted in 32.4% of the eyes at 6 and 12 h and in 5.9% of eyes at 24 h after surgery, while in brinzolamide-brimonidine fixed combination group, only 8.8% of the eyes at 6 h postoperatively had such an intraocular pressure elevation. The administration of a single drop of brinzolamide-brimonidine fixed combination effectively prevented intraocular pressure elevations and intraocular pressure spikes during the first 24 h after uneventful phacoemulsification.

PP.26.02] FREE VERSUS FIXED COMBINATION ANTIHYPERTENSIVE THERAPY FOR ESSENTIAL ARTERIAL HYPERTENSION

Objective: Most patients with arterial hypertension (HTN) require more than one blood pressure (BP)-lowering drug to achieve BP target. In a free drug combination, each BP-lowering drug is administered as a separate pill, while in a fixed drug combination, BP-lowering drugs are combined in a single pill. The objective of this systematic review is to compare the beneficial and harmful effects of using a fixed versus free combination of BP-lowering agents in patients with essential HTN. Design and method: We conducted a comprehensive search that included the Cochrane CENTRAL, MEDLINE, and EMBASE. We included randomized clinical trials (RCTs) addressing the objective of the review and assessing at least one of the following outcomes: BP-lowering efficacy, rapidity in achieving BP target, compliance, incidence of side effects, mortality, and morbidity outcomes. Two review authors independently and in duplicate selected eligible studies then abstracted relevant information and assessed risk of bias using standardized data extraction forms. The primary meta-analyses used a random-effects model. Results: We identified seven eligible RCTs with a total of 397 participants. Meta-analysis for the pre-specified outcome of efficacy in controlling BP showed a non-significant reduction of mean systolic BP of 0.81 mmHg (95% CI -3.25, 1.64) favoring the fixed combination group. As for the outcome of adverse events, meta-analysis results showed a non-significant 13% risk reduction favoring the free combination group (risk ratio 1.13, 95% CI 0.85, 1.5). Quality of evidence was low for both outcomes. Rapidity in achieving BP target was assessed in one trial, and the results favored the fixed combination group. Adherence to treatment was assessed in three trials, no pooled analysis was possible due to either missing data or differences in the methods of outcome measurement. The included trials were short term, none assessed mortality and morbidity.Conclusions: The available low quality evidence does not confirm or rule out a substantive difference in benefits or harms between fixed combination and free combination of anti-hypertensive regimen in the management of patients with HTN. Well designed RCTs with a long duration of follow-up and assessment of morbidity and mortality outcomes are needed.

Free versus Fixed Combination Antihypertensive Therapy for Essential Arterial Hypertension: A Systematic Review and Meta-Analysis.

BackgroundIn a free drug combination, each Blood pressure (BP)-lowering drug is administered as a separate pill, while in a fixed drug combination several BP-lowering agents are combined in a single pill. Using a single pill may enhance compliance and simplify treatment, which would translate into better clinical outcomes. The objective of this meta-analysis is to compare the effects of using a fixed combination versus free combination of BP-lowering agents in the management of patients with essential hypertension.MethodsWe searched Cochrane CENTRAL, MEDLINE, and EMBASE for randomized clinical trials (RCTs) addressing the objective of the review and assessing at least one of the following outcomes: BP-lowering efficacy, rapidity in achieving BP target, compliance, incidence of side effects, mortality, and morbidity. Two review authors independently selected eligible studies, abstracted data, and assessed risk of bias of included trials. The primary meta-analyses used a random-effects model.ResultsWe identified seven RCTs with a total of 397 participants. Meta-analysis of efficacy in controlling BP showed a non-significant reduction of mean systolic BP of 0.81 mmHg (95% CI -3.25, 1.64) favoring the fixed combination group. As for adverse events, results showed a non-significant 13% risk reduction favoring the free combination (risk ratio 1.13, 95% CI 0.85, 1.5). Low quality of evidence was noted for both outcomes. Rapidity in achieving BP target was assessed in only one trial, and the results favored the fixed combination. Adherence to treatment was assessed in three trials, no pooled analysis was possible for this outcome. None of the included trials assessed mortality and morbidity.ConclusionThe available low quality evidence does not confirm or rule out a substantive difference between fixed combination and free combination therapy in the management of HTN. Well designed RCTs with a long duration of follow-up and assessment of morbidity and mortality outcomes are needed.

A comparative study on safety and efficacy of travoprost and brimonidine/timolol fixed combination in patients of primary open angle glaucoma

Background: The purpose of this study was to compare and evaluate the clinical efficacy of topically applied travoprost 0.004% eye drops versus brimonidine/timolol fixed combination eye drops in the management of primary open-angle glaucoma. Methods: In this prospective, randomized study, 65 patients received either travoprost eye drops once daily in the morning (n=33) or brimonidine/timolol fixed combination eye drops twice daily (n=32). Intra ocular pressure (IOP) was assessed at 2, 4, 8, and 12 weeks. The primary outcome measure was mean reduction in IOP. Results: Thebaseline mean IOP values were similar between two groups. Mean reduction of IOP in the right eye for brimonidine/timolol fixed combination group was 9±2.9 mmHg, whereas in the left eye it was 10.9±2.8 mmHg. In the travoprost group, the reduction in IOP of the right eye was 7.8±2.9 mmHg (p=0.0002) and 7.5±3.4 mmHg (p=0.0001) in the left eye. The mean reduction of IOP for the brimonidine/timolol group was 9.95 mmHg and for the travoprost group it was 7.6 mmHg (p<0.0001) in both the eyes. Conclusions: The fixed combination brimonidine/timolol twice daily demonstrated superior mean IOP lowering efficacy compared to travoprost 0.004% in patients with open-angle glaucoma.

Safety and efficacy of bimatoprost/timolol fixed combination in Chinese patients with open-angle glaucoma or ocular hypertension.

Lowering intraocular pressure (IOP) is currently the only therapeutic approach in primary open-angle glaucoma. and the fixed-combination medications are needed to achieve sufficiently low target IOP. A multicenter prospective study in the Chinese population was needed to confirm the safety and efficacy of Bimatoprost/Timolol Fixed Combination Eye Drop in China. In this study, we evaluated the safety and efficacy of Bimatoprost/Timolol Fixed Combination with concurrent administration of its components in Chinese patients with open-angle glaucoma or ocular hypertension. In this multicenter, randomized, double-masked, parallel controlled study, patients with open-angle glaucoma or ocular hypertension who were insufficiently responsive to monotherapy with either topical β-blockers or prostaglandin analogues were randomized to one of two active treatment groups in a 1:1 ratio at 11 Chinese ophthalmic departments. Bimatoprost/timolol fixed combination treatment was a fixed combination of 0.03% bimatoprost and 0.5% timolol (followed by vehicle for masking) once daily at 19:00 P.M. and concurrent treatment was 0.03% bimatoprost followed by 0.5% timolol once daily at 19:00 P.M. The primary efficacy variable was change from baseline in mean diurnal intraocular pressure (IOP) at week 4 visit in the intent-to-treat (ITT) population. Primary analysis evaluated the non-inferiority of bimatoprost/ timolol fixed combination to concurrent with respect to the primary variable using a confidence interval (CI) approach. Bimatoprost/timolol fixed combination was to be considered non-inferior to concurrent if the upper limit of the 95% CI for the between-treatment (bimatoprost/timolol fixed combination minus concurrent) difference was ≤ 1.5 mmHg. Adverse events were collected and slit-lamp examinations were performed to assess safety. Between-group comparisons of the incidence of adverse events were performed using the Pearson chi-square test or Fisher's exact test. Of the enrolled 235 patients, 121 patients were randomized to receive bimatoprost/timolol fixed combination and, 114 patients were randomized to receive concurrent treatment. At baseline the mean value of mean diurnal IOP was (25.20 ± 3.06) mmHg in the bimatoprost/timolol fixed combination group and (24.87 ± 3.88) mmHg in the concurrent group. The difference between the treatment groups was not statistically significant. The mean change from baseline in mean diurnal IOP (± standard deviation) in the bimatoprost/timolol fixed combination group was (-9.38 ± 4.66) mmHg and it was (-8.93 ± 4.25) mmHg in the concurrent group (P < 0.01). The difference between the two treatment groups (bimatoprost/timolol fixed combination minus concurrent) in the change from baseline of mean diurnal IOP was -0.556 mmHg (95% CI: -1.68, 0.57, P = 0.330). The upper limit of the 95% CI was less than 1.5 mmHg, the predefined margin of non-inferiority. Adverse events occurred in 26.4% (32/121) of the bimatoprost/timolol fixed combination patients and 30.7% (35/114) of the concurrent patients. The most frequent adverse event was conjunctival hyperemia, which was reported as treatment related in 16.5% (20/121) in the bimatoprost/timolol fixed combination group and 18.4% (21/114) in the concurrent group (P > 0.05). Bimatoprost/Timolol Fixed Combination administered in Chinese patients with open-angle glaucoma or ocular hypertension was not inferior to concurrent dosing with the individual components. Safety profiles were similar between the treatment groups.

Antidiabetic therapy in real practice: indicators for adherence and treatment cost

BackgroundType 2 diabetes has become a disease with a high economic and social impact. The ARNO Observatory is a clinical data warehouse consisting of a network of local health care units (ASL) scattered throughout the Italian territory which collects data on health care consumption for about 10.5 million people. The purpose of this study was to evaluate the use of antidiabetic drugs with particular reference to type of treatment. The analyses were carried out on a sample of 169,375 patients treated with oral blood glucose-lowering drugs in 2008 from a total population of 4,040,624 health care beneficiaries at 12 local health care units in the ARNO Observatory.MethodsPatients were considered “on treatment with oral blood glucose-lowering drugs” if they had received at least one prescription of an antidiabetic drug (Anatomical Therapeutic Chemical code A10B) during 2008. The patients were divided into three treatment groups, ie, monotherapy, fixed-combination drugs, and dual therapy. The following indicators were assessed: number of patients treated with an oral antidiabetic drug, mean number of hospitalizations, mean number of specialist examinations, and mean expenditure per treated patient. Adherence was assessed using the medication possession ratio indicator (MPR).ResultsPatients treated with oral blood glucose-lowering drugs comprised 4.2% of the investigated population, and had an average age of 68.9 years. The mean annual number of hospitalizations was lower in the dual therapy group (298 versus 328 per 1000 patients in the sample), while the average number of specialist examinations was lower in the fixed-combination group (30.1 versus 35.1). Patients on monotherapy showed a better percentage of adherence for glimepiride (70.5%) and pioglitazone (70.4%), whereas the best adherence in the fixed-combination therapy group was recorded for metformin + pioglitazone (75.5%). The average annual cost per diabetic patient was €2388, with differences between the monotherapy (€2321), fixed-combination (€2270), and dual therapy (€2465) groups. Fixed combination therapy involved a lower mean expenditure for insulin, other drugs, and specialist and diagnostic care. Thiazolidinediones (such as pioglitazone) showed the lowest average annual cost per patient among the monotherapies, with a marked decrease in costs for hospitalization, specialist care, and diagnostics.ConclusionThe results of our study should be extended to other regional/national reference local health care units in order to define and compare average standard costs per pathology throughout the wide sample considered in this research work. Appropriate drug prescribing is of critical importance in order to achieve therapeutic objectives and to optimize the use of resources in modern health care systems.

Comparison of the Therapeutic Efficacy of a Fixed Low-Dose Combination of Cinnarizine and Dimenhydrinate with Betahistine in Vestibular Neuritis

Vestibular neuritis (VN) is a strongly disabling disease of the peripheral vestibular system. Rapid and effective relief of symptoms is important to allow patients to promptly return to normal physical activity. The aim of this prospective, randomized, double-blind study was to evaluate the efficacy of a fixed low-dose combination of cinnarizine and dimenhydrinate in unilateral VN in comparison with betahistine in terms of improvement of vertigo and concomitant symptoms, and performance in neurotological testing. Sixty-two patients were randomized to receive either cinnarizine 20 mg/dimenhydrinate 40 mg as a fixed combination or betahistine 12 mg, each three times daily for 4 weeks. Vertigo and concomitant symptoms, activities of daily living (ADL), posturography and a battery of vestibulo-ocular tests, registered by electronystagmography including spontaneous nystagmus, bithermal caloric and rotatory test, among others, were assessed at baseline (t(0)), after 1 week (t(1w)) and after 4 weeks (t(4w)). The primary endpoint was the Mean Vertigo Score (MVS) at t(1w), a composite of 12 individual scores for unprovoked and provoked vertigo, each assessed using a 10 cm visual analogue scale (VAS). Non-inferiority of the fixed combination versus betahistine would be assumed if the two-sided 95% confidence intervals (CIs) for between-group differences in MVS lay entirely below the non-inferiority margin of 1.25 (12.5% of VAS range). The fixed combination led to significantly greater improvements in MVS than betahistine both at t(1w) (primary endpoint) and at t(4w) (95% CI for the difference in baseline-adjusted means -0.95, -0.64 at t(1w), -0.77, -0.44 at t(4w); p < 0.001). Vegetative symptoms and ADL also improved significantly more under the fixed combination than under betahistine at t(1w) (p < 0.001, each parameter) and t(4w) (p < 0.001 and p < 0.01, respectively), both showing a nearly complete remission at t(4w). In the two groups, pathological posturography and electronystagmography parameters normalized during the 4-week treatment. The fixed combination group showed an earlier recovery of spontaneous nystagmus than the betahistine group (t(1w), p < 0.001) and slightly higher improvements in asymmetry of rotation-induced nystagmus at t(1w) and t(4w) (p = 0.041, each time point). No significant differences were found between the treatments in abatement of spontaneous nystagmus at t(4w) and decrease of caloric lateralization or improvement of equilibrium (sensory organization test [SOT], conditions 5/6) at t(1w) and t(4w). No patient reported any adverse event. The results showed that the fixed low-dose combination of cinnarizine and dimenhydrinate is an effective and well tolerated option for symptomatic treatment in unilateral VN. The fixed combination led to significant improvements in vertigo and ADL within the first week, and to a nearly complete recovery after 4 weeks. Neurotological testing revealed no signs of a possible detrimental influence of the 4-week treatment with the fixed combination compared with betahistine in terms of recovery of caloric responsiveness and abatement of rotation-induced nystagmus.

Comparison of Cinnarizine/Dimenhydrinate Fixed Combination with the Respective Monotherapies for Vertigo of Various Origins

Vertigo may arise from dysfunction in the peripheral and/or the central vestibular system. Simultaneous activity of a medication at both sites will serve to improve the efficacy of antivertigo treatment. The aim of this study was to compare the efficacy and tolerability of a fixed combination of the peripherally acting cinnarizine (20 mg) plus the centrally acting dimenhydrinate (40 mg) with those of equally dosed monotherapies in the treatment of vertigo of various origins. This prospective, randomized, double-blind, active-controlled, multicentre study included patients who assessed at least one vertigo symptom as being of at least medium intensity (≥2) on a 5-point visual analogue scale (VAS; ranging from 0 = not present to 4 = very strong) and who had pathological vestibulospinal movement patterns and/or nystagmus reactions. Patients were randomly assigned to receive either cinnarizine 20 mg/dimenhydrinate 40 mg as a fixed combination, cinnarizine 20 mg as monotherapy or dimenhydrinate 40 mg as monotherapy, each three times daily for 4 weeks. Patients were examined at baseline (t(0)), and after 1 week (t(1w)) and 4 weeks (t(4w)) of treatment. The primary efficacy endpoint was the decrease in mean vertigo score (MVS) at t(4w), which was calculated by averaging the total score for 12 individual vertigo symptoms, each assessed using the 5-point VAS. The study included 182 patients, of whom 177 were evaluable for efficacy. The mean ± SD reduction in MVS after 4 weeks of treatment with the fixed combination (-1.44 ± 0.56) was significantly greater than the reductions with each of the active treatments alone (cinnarizine -1.04 ± 0.53; dimenhydrinate -1.06 ± 0.56; p = 0.0001, both comparisons). Cinnarizine 20 mg/dimenhydrinate 40 mg as a fixed combination was associated with a significantly higher responder rate (78% of patients with MVS ≤0.5 at t(4w)) than the monotherapies. The odds ratios for MVS ≤0.5 at t(4w) in the cinnarizine or dimenhydrinate groups versus the fixed combination group were 0.345 and 0.214, respectively. The fixed combination reduced concomitant vegetative symptoms significantly more effectively than cinnarizine at both t(1w) (p < 0.05) and t(4w) (p < 0.01). Nine patients reported 15 adverse events (AEs) [three AEs for the fixed combination, six AEs each for cinnarizine and dimenhydrinate]. At t(4w) the tolerability of the treatments was rated as very good or good by almost all patients in all groups (fixed combination and dimenhydrinate 96.6% each; cinnarizine 98.3%). The fixed combination of cinnarizine 20 mg/dimenhydrinate 40 mg was an effective and well tolerated treatment for patients with vestibular vertigo of central and/or peripheral origin. The efficacy of the fixed combination exceeded that of each of the equally dosed active substances given as monotherapy, leading to higher responder rates, and showed a very good and comparable tolerability with a similar or even smaller rate of adverse events than the active substances given alone.

Observational study of patients switched to the fixed travoprost 0.004%/timolol 0.5% combination in Croatia

The purpose of this study was to assess both the benefits of a 3-month travoprost 0.004%/timolol 0.5%fixed combination (trav/tim) regimen in comparison with previous medications for the control of intraocular pressure (IOP) and the tolerability of these drug regimens in glaucoma patients. An observational, non-interventional, open-label study of 406 eyes with primary open angle glaucoma and ocular hypertension was thus undertaken. One drop of trav/tim fixed combination was administered in the evening for 3 months. Patients were divided into five groups according to previous drug regimens: timolol 0.5% monotherapy; betaxolol 0.5% monotherapy; latanoprost 0.005% monotherapy; travoprost 0.004% monotherapy; and dorzolamide 2%/timolol 0.5% fixed combination. Upon medication substitution, the trav/tim fixed combination provided better IOP control and tolerability in all five patient groups. At the 3-month follow up, the mean IOP changes from previous therapy were as follows: 5.2 ± 2.7 mmHg (20.8% change) in timolol 0.5% group; 5.7 ± 2.2 mmHg (22.5% change) in betaxolol 0.5% group; 3.8 ± 2.6 mmHg (24.5% change) in latanoprost 0.005% group; 4.4 ± 2.8 mmHg (20% change) in travoprost 0.004% group; and 3.4 ± 4.1 mmHg (14.5% change) in dorzolamide 2%/timolol 0.5% fixed combination group. The difference between baseline and trav/tim combination patient satisfaction at the 3-month follow-up was significant. Thus, the trav/tim fixed combination provided better IOP control and tolerability than previous mono- or polytherapies.

Compliance with Antihypertensive Therapy in the Elderly

Treatment regimens that require fewer dosage units and less frequent dosing to decrease the complexity and cost of care are among the strategies recommended to improve compliance with antihypertensive therapy. Simplifying therapy may be particularly important for elderly patients, who are more likely to have co-morbid conditions and to be taking multiple medications. To determine rates of compliance with antihypertensive therapy and total costs of care among elderly Medicaid recipients treated with fixed-dose combination amlodipine besylate/benazepril versus a dihydropyridine calcium channel antagonist and ACE inhibitor prescribed as separate agents (free combination). A longitudinal, retrospective, cohort analysis of South Carolina Medicaid claims for ambulatory services, hospital services, Medicare crossover, and prescription drug for the years 1997-2002. Follow-up was 12 months from the index date, defined as the first prescription dispensing date for a study drug. South Carolina Medicaid beneficiaries aged >or=65 years. Outcomes variables included compliance defined as the medication possession ratio (MPR), which was the total days' supply of drug (excluding last prescription fill) divided by the length of follow-up (with number of hospital days subtracted from the numerator and denominator). We hypothesized that elderly individuals receiving fixed-dose combination amlodipine besylate/benazepril HCl would be more compliant with therapy than those receiving a dihydropyridine calcium channel antagonist and ACE inhibitor as free combination. There were 2336 individuals in the fixed-combination group and 3368 in the free-combination group. The mean age was 76.0 +/- 7.2 years, and 82.6% were female. Compliance rates were significantly higher with fixed-dose versus free-combination therapy (63.4% vs 49.0%; p < 0.0001). The average total cost of care for patients receiving the fixed-dose combination was $US3179 compared with $US5236 (2002 values) for the free-combination regimen. In multivariate regression analyses on the log of total cost of care, average total costs increased by 0.5% for each 1-unit increase in MPR, and for each additional co-morbidity (measured by the chronic disease score) there was an increase of 10.4%. However, average total costs were reduced by 12.5% for patients using fixed-dose versus free-combination therapy (p < 0.003). Use of fixed-dose amlodipine besylate/benazepril HCl by elderly Medicaid recipients was associated with improved compliance and lower healthcare costs compared with a dihydropyridine calcium channel antagonist and ACE inhibitor prescribed as separate agents.

A Fixed Combination of Cinnarizine/Dimenhydrinate for the Treatment of Patients with Acute Vertigo Due to Vestibular Disorders

Vestibular dysfunction commonly leads to - often severe - vertigo symptoms. The objective of this study was to compare the antivertiginous efficacy and tolerability of a fixed combination of cinnarizine/dimenhydrinate with those of betahistine in patients with acute vertigo due to vestibular disorders. Sixty-six patients experiencing acute vertigo attacks participated in this prospective, double-blind, three-centre, comparative study. Patients who assessed at least one vertigo symptom as being of medium intensity (> or =2) on a 5-point visual analogue scale (VAS; from 0 = no symptoms to 4 = very severe symptoms) were randomly allocated to treatment with the fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg three times daily or betahistine 12 mg three times daily for 4 weeks. The primary efficacy endpoint was change in mean vertigo score, as determined by patients' assessments of 12 individual vertigo symptoms on the 5-point VAS after 4 weeks of treatment. Treatment with the fixed combination led to significantly greater improvements in mean vertigo scores than the reference therapy betahistine after 4 weeks of therapy (p = 0.013). The differences were clinically relevant, based on the Mann-Whitney estimator. Furthermore, the incidence of vertigo-associated vegetative symptoms was significantly reduced after 1 (p = 0.004) and 4 weeks (p = 0.023) in the fixed-combination group relative to the betahistine group. Three patients, all of them in the betahistine group, reported adverse events, none of which was considered serious. Almost all patients (n = 62) rated the tolerabilities of both medications as very good or good. The fixed combination of cinnarizine/dimenhydrinate was shown to be an effective and very well tolerated treatment option for patients with acute vertigo due to vestibular disorders. The combination proved to be significantly more efficient in reducing vertigo and associated vegetative symptoms than betahistine in such patients.

Local tolerability of Timolol 0,5% / Travoprost 0,004% (Duotrav ®) fixed combination in patients with open‐angle glaucoma

Abstract Purpose: To evaluate short‐middle time tolerability (8 months follow‐ up) of timolol 0,5%/ travoprost0,004% (Duotrav ®) fixed combinantion in patients with open‐angle glaucoma. Methods: Prospective, open trial in which 50 patients was involved with a 8 months follow‐up. Inclusion criteria was primarily failure of beta‐blockers or prostaglandins in monotherapy and need for better IOP control and compliance . Exclusion criteria was patients with clinical contraindications to beta‐blockers and history of allergy to prostaglandins.Follow‐up parameters was: corneal erosions, conjunctival flogosis, ocular symptomatology, intraocular pressure, break‐up time , visual acuity.Primary objectives of the study was analysis of side effects and IOP shift . Secondary objective was patient compliance evaluated by questionnaire. Results: Patients compliance was improved despite to lower rate of side effects.No clinically relevant ocular signs or symptoms regarding lids, conjunctiva and anterior chamber were observed after the drug switch. DUOTRAV® produced a mean IOP reduction of 2.5 mm/Hg (range 1.8 to 3.3) (p&lt; 0.001) .Visual acuity analysis showed no loss of letters at the end of follow‐up and slit lamp examination showed a break‐up time of 9.2 sec for monotherapy and 10 sec for fixed combination group (p &gt;0.01). Conclusions: Results show that in daily‐dosing DUOTRAV seems to be more effective respect to single‐drug treatment in reason of better tolerability®, IOP control , compliance and clinic management.

A Double-Masked, Randomized, Parallel Comparison of a Fixed Combination of Bimatoprost 0.03%/Timolol 0.5% with Non-Fixed Combination Use in Patients with Glaucoma or Ocular Hypertension

To compare the safety and efficacy of the fixed combination product with non-fixed combination use of the same active ingredients in separate bottles (bimatoprost once-daily [qd], and timolol twice-daily [bid]). A bimatoprost 0.03% qd treatment arm was used for validation of the study. This was a double-masked, randomized, parallel study in 445 patients with open-angle glaucoma or ocular hypertension. They were randomized in a ratio of 2:2:1 to receive bilateral treatment with the fixed combination, non-fixed combination treatment, or bimatoprost alone. Comparing the fixed combination and non-fixed combination, the non-inferiority margin of 1.5 mm Hg was met at all three timepoints for mean intraocular pressure (IOP), and a margin of 1.0 mm Hg for mean diurnal IOP. The incidence of conjunctival hyperemia was statistically significantly lower (p=0.014) in the fixed combination group (8.5%, 15/176) compared with the bimatoprost group (18.9%, 17/90) and the non-fixed combination group (12.5%, 22/176). The fixed combination of bimatoprost 0.03%/timolol 0.5% administered once daily was comparable in ocular hypotensive efficacy to the non-fixed combination. The lower propensity of the fixed combination to elicit conjunctival hyperemia suggests a superior comparative benefit/risk assessment of the fixed combination in the treatment of elevated IOP.

A Double-Masked, Randomized, Parallel Comparison of a Fixed Combination of Bimatoprost 0.03%/Timolol 0.5% with Non-Fixed Combination use in Patients with Glaucoma or Ocular Hypertension

To compare the safety and efficacy of the fixed combination product with non-fixed combination use of the same active ingredients in separate bottles (bimatoprost once-daily [qd], and timolol twice-daily [bid]). A bimatoprost 0.03% qd treatment arm was used for validation of the study. This was a double-masked, randomized, parallel study in 445 patients with open-angle glaucoma or ocular hypertension. They were randomized in a ratio of 2:2:1 to receive bilateral treatment with the fixed combination, non-fixed combination treatment, or bimatoprost alone. Comparing the fixed combination and non-fixed combination, the non-inferiority margin of 1.5 mm Hg was met at all three timepoints for mean intraocular pressure (IOP), and a margin of 1.0 mm Hg for mean diurnal IOP. The incidence of conjunctival hyperemia was statistically significantly lower (p=0.014) in the fixed combination group (8.5%, 15/176) compared with the bimatoprost group (18.9%, 17/90) and the non-fixed combination group (12.5%, 22/176). The fixed combination of bimatoprost 0.03%/timolol 0.5% administered once daily was comparable in ocular hypotensive efficacy to the non-fixed combination. The lower propensity of the fixed combination to elicit conjunctival hyperemia suggests a superior comparative benefit/risk assessment of the fixed combination in the treatment of elevated IOP.

Efficacy and tolerability of a fixed low-dose combination of cinnarizine and dimenhydrinate in the treatment of vertigo: A 4-week, randomized, double-blind, active- and placebo-controlled, parallel-group, outpatient study

Background: Most cases of vertigo are attributable to both peripheral and central vestibular disorders. Therefore, it would be of interest to determine whether a combination therapy having both peripheral and central actions would translate into more efficient symptom relief. Objective: This study was conducted to evaluate the efficacy and tolerability of a fixed low-dose combination of cinnarizine 20 mg + dimenhydrinate 40 mg in the treatment of vertigo of central, peripheral, or combined central/peripheral origin. Methods: This was a prospective, multicenter, randomized, double-blind, active- and placebo-controlled, parallel-group, outpatient study in men and women (age >30 years) with central, peripheral, or combined central/peripheral vestibular vertigo. Patients who assessed ≥1 vertigo symptom as being of medium intensity (≥2) on a 5-point visual analog scale (from 0 = no symptoms to 4 = very severe symptoms) and who had abnormal vestibulospinal movement patterns on cramocorpography were eligible. Patients were randomly assigned to receive 1 tablet of the fixed combination of cinnarizine 20 mg + dimenhydrinate 40 mg, cinnarizine 50 mg, dimenhydrinate 100 mg, or placebo 3 times daily for 4 weeks. The primary efficacy end point was the decrease in mean vertigo score (MVS), which was composed of 12 individual vertigo symptoms, each assessed on the 5-point visual analog scale after 4 weeks of treatment. Results: The study enrolled 246 patients, of whom 239 were evaluable for efficacy. Approximately two thirds of the efficacy population were female and one third male. The mean age was 51.3 years, and the mean duration of vertigo was 2.6 years. The least squares mean (SD) change from baseline in MVS was significantly greater in the group receiving the fixed combination (1.37 [0.66]) than in any of the comparator groups (cinnarizine 50 mg: 0.87 [0.53]; dimenhydrinate 100 mg: 0.83 [0.66]; placebo: 0.76 [0.48]; all comparisons, P < 0.001). The differences were clinically relevant, based on the Mann-Whitney estimator. The incidence of vertigo-associated nausea was significantly reduced in the fixed-combination group relative to the comparator groups ( P≤ 0.016). Thirty-four patients reported adverse events, 6 each in the fixed combination and placebo groups, 12 in the cinnarizine group, and 10 in the dimenhydrinate group. None of these adverse events were considered serious. After 4 weeks of treatment, the tolerability of treatment was rated as very good or good by 57 (96.6%) patients in the fixed-combination group; the values for cinnarizine, dimenhydrinate, and placebo were 54 (93.1%), 42 (72.4%), and 50 (87.7%), respectively. Conclusions: In this study, the fixed low-dose combination of cinnarizine 20 mg + dimenhydrinate 40 mg was effective, clinically beneficial, and well tolerated in patients with vestibular vertigo of central and/or peripheral origin. It was significantly more effective in reducing the MVS compared with placebo and the routinely prescribed higher doses of cinnarizine (50 mg) and dimenhydrinate (100 mg).

An open label randomized comparison of mefloquine–artesunate as separate tablets vs. a new co‐formulated combination for the treatment of uncomplicated multidrug‐resistant falciparum malaria in Thailand

Delivering drugs in a fixed combination is essential to the success of the strategy of artemisinin-based combination therapy. This prevents one drug being taken without the protection of the other, reducing the chance of emergence and spread of drug resistant strains of Plasmodium falciparum. A lower tablet burden should also facilitate adherence to treatment. A new fixed combination of mefloquine plus artesunate has been developed. This was compared with the conventional regimen of separate tablets for the treatment of uncomplicated multidrug-resistant falciparum malaria. On the north-western border of Thailand 500 adults and children with uncomplicated falciparum malaria were randomized to receive either the new fixed combination or separate tablets. They were followed up weekly for 63 days. The day 63 polymerase chain reaction-adjusted cure rates were 91.9% (95% CI 88.2-95.6) in the fixed combination group and 89.2% (85.0-93.4) in the loose tablets group (P=0.3). There was a lower incidence of early vomiting in the group receiving the fixed combination. This new fixed combination of mefloquine and artesunate was efficacious, well tolerated and convenient to administer.