The Respimat ® Soft Mist Inhaler: Implications of Drug Delivery Characteristics for Patients Abstract Successful treatment for respiratory diseases relies on effective delivery of medication to the lungs using an inhalation device. Different inhalers have distinct characteristics affecting drug administration and patient adherence, which can impact clinical outcomes. We report on the development of the Respimat® soft mist inhaler (SMI) and compare key attributes with metered-dose inhalers (MDIs) and dry powder inhalers (DPIs). The Respimat SMI, a pocket-sized device generating a single-breath, inhalable aerosol, was designed to enhance drug delivery to the lungs, reduce the requirements for patient coordination and inspiratory effort, and improve the patients’ experience and ease of use. The drug deposition profile with Respimat SMI is favorable compared with MDIs and DPIs, with higher drug deposition to the lung and peripheral airways. The slow velocity and long spray duration of the Respimat SMI aerosol also aid patient coordination. Clinical equivalence has been demonstrated for maintenance treatment of chronic obstructive pulmonary disease using once-daily tiotropium between Respimat SMI (5 µg) and HandiHaler DPI (18 µg). In comparative studies, patients preferred Respimat SMI to MDIs and DPIs; they reported that Respimat SMI was easy to use and felt the inhaled dose was delivered. The Respimat SMI, designed to generate a slow-moving and fine mist, is easy to use and effectively delivers drug treatment to the lungs. The patient-centered design of Respimat SMI improved patient satisfaction, and may help to promote long-term adherence and improve clinical outcomes with asthma and chronic obstructive pulmonary disease.

Pharmacokinetics and Safety of Posaconazole Administered by Intravenous Solution and Oral Tablet in Healthy Chinese Subjects and Effect of Food on Tablet Bioavailability Abstract Background and Objectives New intravenous and solid oral formulations of the antifungal agent posaconazole have been developed. This randomized, open-label, crossover study in 18 healthy adult Chinese male and female subjects evaluated the pharmacokinetics of single-dose posaconazole (oral 300-mg posaconazole tablet fasted, intravenous 300-mg posaconazole solution fasted, and oral 300-mg posaconazole tablet with standard high-fat breakfast). Primary objectives were to determine the single-dose pharmacokinetics of posaconazole in healthy Chinese subjects when administered as an intravenous solution and as an oral tablet under fasted conditions and the effect of food on the absorption of posaconazole. Methods The three treatments consisted of the following: a single oral dose of posaconazole 300 mg (fasted), a single oral dose of posaconazole 300 mg (high-fat breakfast), and a single intravenous dose of posaconazole 300 mg (fasted). Blood samples for pharmacokinetic analysis were collected before dosing and at regular intervals after dosing. Adverse events were monitored throughout. The pharmacokinetic population included the per-protocol population. The safety population included all subjects who received one or more doses of the study drug. Results Time to maximum plasma concentration of intravenous posaconazole coincided with the end of infusion; the half-life (t½) was 25.76 h. Geometric mean (% coefficient of variation) values of area under the plasma concentration–time curve from time 0 extrapolated to infinity (AUC0–∞) and maximum plasma concentration (Cmax) were 59,925 (36.2%) h·ng/mL and 3999 (28.5%) ng/mL, respectively. The posaconazole tablet had a time to maximum plasma concentration of 4 h and a t½ of 25.21 h after fasting. Geometric mean (coefficient of variation) values of AUC0–∞ and Cmax were 25,263 (39.9%) h·ng/mL and 674.5 (29.6%) ng/mL, respectively. Standard high-fat breakfast increased the exposure of posaconazole approximately twofold with geometric mean ratios (high-fat breakfast/fasted) for AUC0–∞ and Cmax of 2.06 (90% confidence interval 1.86–2.30) and 1.95 (90% confidence interval 1.65–2.31), respectively. The geometric mean absolute bioavailability of the tablet formulation was 42.2% in the fasted state and 87.1% under high-fat breakfast conditions. The most commonly reported adverse events were nausea, vomiting, dizziness, and first-degree atrioventricular block for intravenous posaconazole 300 mg and nausea for oral posaconazole 300 mg (high-fat breakfast). All adverse events were mild and resolved without sequelae. Conclusions Posaconazole was generally well tolerated in healthy Chinese male and female subjects. The safety and the high-fat breakfast and fasted pharmacokinetics of posaconazole in healthy Chinese subjects are within exposures demonstrated to be generally well tolerated and efficacious and compare reasonably well with the overall posaconazole data across Western countries.

Changes in Prescription of Psychotropic Drugs After Introduction of Polypharmacy Reduction Policy in Japan Based on a Large-Scale Claims Database Abstract Background and Objectives In Japan, polypharmacy reduction policy, which reduces the reimbursement of medical cost, was introduced to address unnecessary psychotropic polypharmacy. The rule was applied to the prescriptions of three or more anxiolytics or three or more hypnotics in the policy introduced in 2012. The prescriptions of four or more antidepressants or four or more antipsychotics were added to the rule in the policy revised in 2014. Furthermore, the prescriptions of three or more drugs of anxiolytics, hypnotics, antidepressants, or antipsychotics were subject to the reduction criteria of the policy revision in 2016. Benzodiazepine receptor agonists (BZs) are classified both into anxiolytics and hypnotics, and the reduction rule was not applied to the category of BZs before April 2018. This study aimed to examine the effect of the policy on the prescriptions of four drug categories as well as BZs from the point of view of the number of drugs and doses. Methods This was a retrospective observational study using a large-scale Japanese health insurance claims database. Patients who were prescribed at least one psychotropic drug (anxiolytic, hypnotic, antidepressant, or antipsychotic) during the study period (from April 2011 to March 2017) were selected. Segmented regression analysis was used to analyze the proportions of patients with three or more or four or more drugs as well as patients above clinically recommended doses, and the means of the average daily doses by drug category. Results A total of 312,167 patients were identified as a study population. The proportions of patients with three or more drugs in anxiolytics, hypnotics, antidepressants, and antipsychotics significantly decreased after the introduction or revisions of the policy, but not BZs. The proportions of patients with three or more drugs in March 2017 were 0.9%, 2.0%, 1.2%, 2.4%, and 8.9% in anxiolytics, hypnotics, antidepressants, antipsychotics, and BZs, respectively. The effect of the policy in reducing the proportions of patients above clinically recommended doses was identified in antipsychotics after the revision in 2016, but not identified in the sum of anxiolytics and hypnotics as well as BZs after the revision in 2014, and antidepressants after the revision in 2016. The proportions of monotherapy were increased from April 2011 to March 2017 only for antidepressants (76.9% → 80.8%) and antipsychotics (79.8% → 82.1%), and not changed or decreased for anxiolytics (85.2% → 85.7%), hypnotics (78.6% → 77.6%), sum of anxiolytics and hypnotics (68.1% → 65.7%), BZs (68.0% → 67.3%), and sum of psychotropic drugs (52.1% → 49.9%). Conclusions The polypharmacy reduction policy reduced the proportions of patients with three or more drugs in four drug categories, but not BZs. Only limited effects were seen for reducing the proportions of patients above clinically recommended doses. The policy was revised in April 2018 again. Further investigation is needed to examine the effect of the revision in 2018.

Individualized Protease Inhibitor Monotherapy: The Role of Pharmacokinetics and Pharmacogenetics in an Aged and Heavily Treated HIV-Infected Patient Abstract Antiretroviral therapy has changed the history of HIV infection from a lethal disease to a chronic infection, with the emergence of long-term adverse effects. Herein we present a case of a heavily treated HIV-infected man in whom antiretroviral toxicity had been observed. The lopinavir/ritonavir plasma concentrations at standard doses were significantly above the recommended levels. Pharmacogenetic analysis revealed a polymorphism in the DRD3 gene associated with a decrease in the rate of drug metabolism. Additionally, the patient’s low body mass index could have contributed to a greater degree of patient exposure to the drug. After the withdrawal of tenofovir disoproxil and the establishment of individualized protease inhibitor monotherapy at reduced doses, a decrease in the intensity of adverse events was observed, while the clinical outcomes were maintained. The pharmacokinetic-pharmacogenetic analysis was shown to be a tool of huge interest for the management and durability of antiretroviral therapy.

Awareness of, and Compliance with, Domperidone Revised Labeling After a Risk-Minimization Activity in Europe Abstract Background and Objective Risk-minimization measures (RMM), including label revisions were implemented in Europe for domperidone because of evidence of increased incidence of cardiac arrhythmia and sudden cardiac death. In accordance with the guideline on good pharmacovigilance practices, the European Medicines Agency Pharmacovigilance Risk Assessment Committee requested to conduct two studies to evaluate the effectiveness of these risk minimization measures. Methods In Belgium, France, Germany, Spain, and the UK, surveys were conducted to assess physicians’ knowledge on the updated domperidone labeling information, and a drug-utilization study (DUS) was conducted using healthcare databases to assess domperidone prescribing patterns before and after the RMM. Four DUS sensitivity analyses (scenarios) evaluated uncertainty regarding domperidone treatment duration and indication. Results Among 1805 physicians participating in the survey, most were aware of the approved indication (nausea and vomiting, 80%), treatment duration (≤ 7 days, 70%), and maximum adult daily dose (10 mg three times daily, 84%). Only 33% selected the on-label indication from a list of indications for which they would prescribe domperidone. Awareness was low for medications contraindicated for concomitant use (26%) and contraindicated conditions (4%). In the DUS, under the optimistic scenario, a large improvement in labeling compliance from pre- to post-implementation period was observed in France (27% vs. 69%), while Belgium, Germany, Spain, and the UK showed small improvements (< 10%). In the other scenarios, there was little to no improvement in compliance with the revised labeling from the pre- to post-implementation periods in most countries. Conclusions The survey findings documented that most physicians in all five countries were aware of the main aspects of the revised labeling. Results of the DUS were inconclusive regarding the effect of the RMM and compliance with the revised labeling for all countries except France.

Tropicamide/Phenylephrine/Lidocaine Intracameral Injection: A Review in Cataract Surgery Abstract Tropicamide 0.02%/phenylephrine 0.31%/lidocaine 1% injectable solution (Mydrane®) is the first fixed-dose mydriatic/anaesthetic combination approved for intracameral use in adults undergoing cataract surgery. In a phase 3 trial in this setting, intracameral tropicamide/phenylephrine/lidocaine was at least as effective as a standard topical regimen of tropicamide plus phenylephrine in enabling successful capsulorhexis without the use of additional mydriatics. The intracameral preparation, which is administered via a single injection, provides rapid and sustained mydriasis through to the end of surgery, with recipients spending around half as long in preoperative/surgery rooms as standard topical regimen recipients in the phase 3 study. Moreover, significantly more of the intracameral than topical regimen recipients were free from pain or pressure in the eye/orbit before intraocular lens (IOL) implantation and had an IOL implanted without complications. Intracameral tropicamide/phenylephrine/lidocaine also displayed mydriatic efficacy in patients with diabetes in this trial. Overall, the preparation was generally well tolerated, with no serious adverse events leading to hospitalization or permanent vision loss. Thus, tropicamide/phenylephrine/lidocaine injectable solution is an emerging option for mydriasis/anaesthesia in adults undergoing cataract surgery.

Prophylactic Sildenafil in Preterm Infants at Risk of Bronchopulmonary Dysplasia: A Pilot Randomized, Double-Blinded, Placebo-Controlled Trial Abstract Background Bronchopulmonary dysplasia (BPD) is the need for oxygen therapy at 36 weeks postmenstrual age (PMA). Sildenafil has been shown to enhance the lung alveolarization and vascularization in newborn animal models after lung injury and has possible therapeutic potential for the prevention of BPD. Objective To perform a proof-of-concept, Phase II, pilot randomized, double-blind, clinical trial to study the efficacy of sildenafil in preventing BPD, in postnatal (< 24 h), extremely and very preterm infants. Methods This Phase II, pilot randomized, double-blind, clinical trial was conducted in the Neonatal Intensive Care Unit of Women’s Wellness and Research Center, Doha, Qatar during 2012–2014. Infants of 240/7–296/7 weeks’ gestation were eligible if they needed respiratory or oxygen support ≥ 25% at randomization, and if they were at a postnatal age of < 24 h at randomization. Forty preterm infants were randomly assigned to receive off-label oral sildenafil (0.5 mg/kg every 6 h) or a placebo solution, for one week. The primary endpoints were the incidence of BPD and death at 36 weeks PMA, and the side effects. Secondary outcomes included the incidence of BPD and the respiratory support at day 28 of life, duration of oxygen use, fraction of inspired oxygen use at 36 weeks and 28 days of life, duration of hospitalization, and the incidence of significant retinopathy of prematurity, severe intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, patent ductus arteriosus, and late sepsis. Results No significant differences were observed between the sildenafil and placebo study groups in mortality at 36 weeks PMA (10% vs 20%, p = 1), respiratory support at 36 weeks (30% vs 25%, p = 0.57), and side effects (0% vs 0%). For all other secondary outcomes, no significant differences were detected. Conclusions While not associated with side effects, off-label oral sildenafil did not demonstrate benefits in the prevention of BPD or death in the extreme and very preterm infants. Future studies of dosing and efficacy that target different regimens of sildenafil are warranted before sildenafil is recommended for the prevention of BPD.

Effect of Combination Therapy of Endothelin Receptor Antagonist and Phosphodiesterase-5 Inhibitor on Clinical Outcome and Pulmonary Haemodynamics in Patients with Pulmonary Arterial Hypertension: A Meta-Analysis Abstract Background The combination of an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor having different biological targets has become an integral part of the treatment of pulmonary arterial hypertension; however, several clinical studies have reported conflicting results. Objective The objective of this meta-analysis was to evaluate the effect of an endothelin receptor antagonist and phosphodiesterase-5 inhibitor combination in pulmonary arterial hypertension. Methods After performing a comprehensive literature search in MEDLINE, Cochrane and the International Clinical Trial Registry Platform, reviewers assessed eligibility and extracted data from seven relevant articles (publications till December 2018). PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed in the selection, analysis and reporting of findings. The odds ratio and mean difference were calculated to estimate the difference in clinical worsening, 6-minute walking distance, pulmonary vascular resistance and N-terminal pro-brain natriuretic peptide between the groups. Quality assessment was performed using the risk of bias assessment tool and a meta-regression for probable variables affecting effect size. Results The random-effect model analysis revealed an odds ratio of 0.56 [95% confidence interval (CI) 0.41–0.76; p = 0.0002] for clinical worsening, mean difference of 15.64 (95% CI 2.67–28.61; p = 0.02) for 6-minute walking distance, − 1.66 (95% CI − 3.82 to 0.50; p = 0.13) for pulmonary vascular resistance and − 21.04 (95% CI − 26.87 to − 15.22; p < 0.00001) for N-terminal pro-brain natriuretic peptide. The meta-regression showed no statistically significant association between the dose and duration of treatment and outcomes (odds ratio of clinical worsening and mean difference of 6-minute walking distance). Conclusions In pulmonary arterial hypertension, endothelin receptor antagonist and phosphodiesterase-5 inhibitor combination therapy significantly improved 6-minute walking distance, clinical worsening and N-terminal pro-brain natriuretic peptide compared with the monotherapy but did not offer any advantage in improving pulmonary vascular resistance. PROSPERO Registration No CRD42018091133.

Topical Glycopyrronium Tosylate in Primary Axillary Hyperhidrosis: A Profile of Its Use Abstract Glycopyrronium tosylate (Qbrexza™) is available as single-use, pre-moistened cloths and has been approved in the USA for the topical treatment of primary axillary hyperhidrosis in adults and children ≥ 9 years of age. Glycopyrronium tosylate is effective in reducing patient-reported severity of disease and gravimetrically measured sweat production in this patient population; improvements have been shown to be maintained throughout long-term treatment (up to 48 weeks). Glycopyrronium tosylate is generally well tolerated, with most adverse events being mild to moderate in severity. Glycopyrronium tosylate thus provides a self-administered, non-invasive alternative to topical antiperspirant therapy and clinic-based treatments in adults with primary axillary hyperhidrosis, and is the only alternative to topical antiperspirants specifically approved in children and adolescents ≥ 9 years of age.

Efficacy and Safety of a Fixed Combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg vs Betahistine Dihydrochloride 16 mg in Patients with Peripheral Vestibular Vertigo: A Prospective, Multinational, Multicenter, Double-Blind, Randomized, Non-inferiority Clinical Trial Abstract Background and Objective Vertigo derived from peripheral vestibular disorders is quite frequently encountered in daily clinical practice and can be a severely disabling symptom associated with substantial impairment of health-related quality of life for the affected patients. Betahistine, a structural analogue of histamine and presumably the most widely prescribed anti-vertigo drug worldwide, has previously been shown to be an effective and safe treatment for these patients. The objective of the present study was to evaluate whether the fixed combination of cinnarizine and dimenhydrinate (Arlevert®) is non-inferior and thus a potentially useful alternative to betahistine dihydrochloride in the treatment of patients suffering from peripheral vestibular vertigo. Methods In this prospective, multicenter, double-blind, randomized, non-inferiority clinical trial, outpatients from 8 ENT clinics in Austria, Bulgaria, the Czech Republic and Russia were randomly assigned to receive three times daily one tablet of either the fixed combination cinnarizine 20 mg/dimenhydrinate 40 mg or betahistine dihydrochloride 16 mg for 4 weeks. Primary endpoint was the reduction of the mean vertigo score (MVS), a validated 12-item composite score defined as the mean of 6 vertigo symptoms (dystasia and walking unsteadiness, staggering, rotary sensation, tendency to fall, lift sensation, blackout) and 6 trigger factors for vertigo (change of position, bowing, getting up, driving by car/train, head movements, eye movement), after 4 weeks of therapy, as judged by the patient on a 5-point visual analogue scale (VAS). The non-inferiority margin was set to 0.3. Secondary outcomes included the patient’s and investigator’s judgment of global efficacy, the patient’s rating of impairment of daily activities, and safety/tolerability of the treatments. Results Three hundred and six patients (mean age 53.5 years, approximately 60% female) were enrolled and randomized to the fixed combination cinnarizine/dimenhydrinate (n = 152) or betahistine (n = 154) groups; 297 patients completed the study and 294 (146 and 148, respectively) were valid for the per-protocol analysis, which was used for the non-inferiority analysis. Treatment with cinnarizine/dimenhydrinate led to a stronger reduction of the MVS [least squares mean (LSM)] after 4-week therapy (primary endpoint) in comparison to betahistine (0.395 vs 0.488; difference: − 0.093, 95% CI − 0.180; − 0.007, p = 0.035); since the upper limit of the two-sided 95% confidence interval was not only below the non-inferiority margin of 0.3, but also entirely below 0, superiority of the fixed combination could be demonstrated. The combination preparation was also more effective after 1 week of therapy and received more favorable patient’s ratings on overall efficacy and impairment of daily activities. Both treatments were very well tolerated. Only 12 patients (3.92%) reported 13 non-serious adverse events; 2 cinnarizine/dimenhydrinate-treated patients discontinued the study prematurely due to adverse events as compared to 5 betahistine-treated patients. Conclusion The fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg was found to be not only non-inferior, but superior to betahistine 16 mg in the improvement of peripheral vestibular vertigo. Furthermore, taking into account a good and slightly favorable safety profile, the present study provides evidence that the fixed-combination preparation is a potent and even superior alternative to betahistine in the treatment of vertigo related to peripheral vestibular disorders. Study Registration EudraCT No. 2011-004025-27.