Sensitivity of Pharmacokinetics to Differences in the Particle Size Distribution for Formulations of Locally Acting Mometasone Furoate Suspension-Based Nasal Sprays.

To assess bioequivalence of locally acting suspension-based nasal sprays, the U.S. FDA currently recommends a weight-of-evidence approach. In addition to in vitro and human pharmacokinetic (PK) studies, this includes a comparative clinical endpoint study to ensure equivalent bioavailability of the active pharmaceutical ingredient (API) at the site of action. The present study aimed to assess, within an in vitro/in vivo correlation paradigm, whether PK studies and dissolution kinetics are sensitive to differences in drug particle size for a locally acting suspension-based nasal spray product. Two investigational suspension-based nasal formulations of mometasone furoate (MF-I and MF-II; delivered dose: 180 µg) differed in API particle size and were compared in a single-center, double-blind, single-dose, randomized, two-way crossover PK study in 44 healthy subjects with oral charcoal block. Morphology-directed Raman spectroscopy yielded volume median diameters of 3.17 µm for MF-I and 5.50 µm for MF-II, and dissolution studies showed that MF-II had a slower dissolution profile than MF-I. The formulation with larger API particles (MF-II) showed a 45% smaller Cmax and 45% smaller AUC0-inf compared to those of MF-I. Systemic bioavailability of MF-I (2.20%) and MF-II (1.18%) correlated well with the dissolution kinetics, with the faster dissolving formulation yielding the higher bioavailability. This agreement between pharmacokinetics and dissolution kinetics cross-validated both methods and supported their use in assessing potential differences in slowly dissolving suspension-based nasal spray products.

Patient and caregiver opinions about an FDA-developed generic drug educational handout: A pilot cross-sectional survey.

OBJECTIVE: To examine patient and caregiver opinions and "receptivity" regarding generic drug educational material in terms of content, format and design, delivery channel, and level of satisfaction. METHODS: Interviewer-administered surveys were conducted with patients and caregivers who were clients of a regional medication management program or pharmacy services clinic to gather perceptions about generic drugs and input on a generic drug educational handout developed by the U.S. Food and Drug Administration (FDA). Survey questions were developed by the investigators and pretested before use. Data were analyzed using descriptive statistics, and responses to open-ended questions were assessed using qualitative content analysis. Survey psychometrics were examined using exploratory factor analysis (EFA). RESULTS: Of the 100 survey participants, most (93%) had positive perceptions about generic drug safety and effectiveness after reading the handout. Most participants were satisfied or very satisfied with the handout's content (87%) as well as format and design (92%). However, more than 20% of participants were still unsure about the benefits and risks of generic drugs compared with those of brand drugs, and more than 15% were still unsure about which benefits and risks mattered most to them. The participants' preferred source for the handout was a pharmacy (49%) or doctor's office (27%). In an EFA of the survey instrument, 2 factors emerged related to the educational handout's content: (1) generic drug information, a 7-item factor (Cronbach alpha = 0.882); and (2) personal relevance, a 3-item factor (Cronbach alpha = 0.692). CONCLUSION: The findings indicate an overall positive "receptiveness" toward generic drug informational materials from patients and caregivers, which highlights the feasibility and importance of educational outreach programs about generic drugs targeted toward this population. Future studies may focus on more diverse populations and tailor materials to the needs of specific patient and caregiver subgroups and health literacy levels.

Preferences for patient medication information: what do patients want?

This study investigated respondent preferences on how best to display patient medication information (PMI) that accompanies prescription medications to promote comprehension and appropriate usage. The authors identified 30 individuals diagnosed with select immune disorders, 30 with other chronic diseases, and 30 from the general public and had them review one of two PMI handouts that varied by format, organization, and content. The authors explored preferences for the PMI handout using one-on-one interviews. The authors analyzed the qualitative data to identify relevant themes and patterns using NVivo9 qualitative software. The majority of respondents noted that the formats of the two PMI handouts were more informative than those they currently receive from the pharmacist, with a preference for the 2-column, segmented design. However, respondent PMI preferences varied by age, education, and health status. Patients need simpler and more concise drug information to make better decisions about their health. Current PMI handouts are dense and complex, which can be confusing and not reader friendly. To improve PMI understandability and usefulness, the U.S. Food and Drug Administration is working with stakeholders, consumer advocates, and academics. Findings from this study may help inform future development of more user-friendly PMI.

Effects of additional context information in prescription drug information sheets on comprehension and risk and efficacy perceptions.

OBJECTIVE: To determine how additional explanatory text (context) about drug side effects in a patient medication information handout affected comprehension and perceptions of risk and efficacy. METHODS: We conducted an online experiment with a national sample of 1,119 U.S. adults with rheumatoid arthritis and related conditions, sampled through random-digit dialing, address-based sampling, and online ads. We randomized participants to receive one of several versions of a patient information handout for a fictitious drug, either with or without additional context, then measured comprehension and other outcomes. RESULTS: Additional qualitative context about warnings and side effects resulted in lower comprehension of side effect information, but not information about uses of the drug or warnings. The effect of additional context on risk perceptions depended on whether the medication handout was delivered online or through the mail. Those who received a hardcopy of the handout with additional context had higher perceived risk of side effects than those who saw the version without additional context. CONCLUSION: More clarifying information is not always better and may lead to cognitive overload, inhibiting comprehension. PRACTICE IMPLICATIONS: Additional research should further explore effects of context in online vs. hard-copy formats before practice implications can be determined.

Patient Perceptions of Switching to a Generic Dry Powder Inhaler - Increased Understanding Through Journey Mapping.

Purpose: This qualitative study explored patients' attitudes about and perceptions of generic dry powder inhaler (DPI) substitution for the brand product and patients' views of generic product quality, efficacy, design, and usability. Methods: Forty COPD and asthma patients (36 adults, four adolescents), who were actively using a brand DPI product, participated in one of six focus groups. Participants completed a journey mapping exercise to assess attitudes and opinions about a scenario where they refill their prescription and unexpectedly receive a generic DPI instead of their brand DPI. The focus groups were audio recorded, transcribed, and analyzed thematically. Results: The hypothetical scenario of unexpectedly receiving a generic DPI elicited mixed feelings including: happiness and relief about potential cost savings, confusion, disappointment, anger, and/or frustration with the unexpected switch. Participants in most groups anticipated anxiety or hesitation in using the generic DPI due to concerns about potential differences in usability, uncertainty about correct use, and questions about efficacy. Participants across all groups said they would ask a pharmacist or healthcare provider for information or answers to their questions, and some participants said they would use online resources. When participants held the brand and generic DPI devices, most preferred the brand DPI device and found it easier, less cumbersome, or more convenient to use (due to size and weight). However, many participants reiterated that the potential reduced cost of the generic DPI would be a primary factor in their decision-making related to generic DPI substitution for their brand DPI. Conclusion: Patients experienced a mixture of positive and negative feelings when faced with an unexpected generic DPI substitution. Some patients have doubts about their ability to successfully navigate differences in generic device design, and most expressed the desire to participate in discussions and decision-making with their HCP about generic DPI sameness and substitution.

Systematic Evaluation of the Effect of Formulation Variables on In Vitro Performance of Mometasone Furoate Suspension-Metered Dose Inhalers.

The therapeutic benefits of metered dose inhalers (MDIs) in pulmonary disorders are mainly driven by aerosol performance, which depends on formulation variables (drug and excipients), device design, and patient interactions. The present study provides a comprehensive investigation to better understand the effect of formulation variables on mometasone furoate (MF) suspension-based MDI product performance. The effects of MF particle size (volume median diameter; X50) and excipient concentration (ethanol and oleic acid, cosolvent, and surfactant, respectively) on selected critical quality attributes (delivered dose (DD), fine particle dose of particles lesser than 5 µm (FPD < 5), ex-throat dose and median dissolution time (MDT)) were studied. Eight MF-MDI formulations (one per batch) were manufactured based on a reduced factorial design of experiment (DOE) approach, which included relevant formulation levels with varying X50 (1.1 and 2 µm), concentration of ethanol (0.45, 0.9, 1.8, and 3.6%w/w), and oleic acid (0.001 and 0.025%w/w). The in vitro evaluation of these MF-MDI formulations indicated the importance of drug particle's X50, oleic acid, and ethanol canister concentration as critical formulation variables governing the performance of MF suspension-based MDI products. The effect of these formulation variables on DD, FPD < 5, ex-throat dose, and MDT was subsequently utilized to develop empirical relationships linking formulation factors with effects on in vitro performance measures. The developed strategy could be useful for predicting MF-MDI product performance during MDI product development and manufacturing. The systematic DOE approach utilized in this study may provide insights into the understanding of the formulation variables governing the MF-MDI product performance.

Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.8, and C-3.7), differing only in type and composition of lactose fines, exhibited median mass aerodynamic diameter (MMAD) of 4.5 µm (A-4.5), 3.8 µm (B-3.8), and 3.7 µm (C-3.7) and varied in dissolution rates (A-4.5 slower than B-3.8 and C-3.7). In vitro total lung dose (TLDin vitro) was determined as the average dose passing through three anatomical mouth-throat (MT) models and yielded dose normalization factors (DNF) for each DPI formulation X (DNFx = TLDin vitro,x/TLDin vitro,A-4.5). The DNF was 1.00 for A-4.5, 1.32 for B-3.8, and 1.21 for C-3.7. Systemic PK after inhalation of 500 µg FP was assessed in a randomized, double-blind, four-way crossover study in 24 healthy volunteers. Peak concentrations (Cmax) of A-4.5 relative to those of B-3.8 or C-3.7 lacked bioequivalence without or with dose normalization. The area under the curve (AUC0-Inf) was bio-IN-equivalent before dose normalization and bioequivalent after dose normalization. Thus, PK could detect differences in pulmonary available dose (AUC0-Inf) and residence time (dose-normalized Cmax). The differences in dose-normalized Cmax could not be explained by differences in in vitro dissolution. This might suggest that Cmax differences may indicate differences in regional lung deposition. Overall this study supports the use of PK studies to provide relevant information on the pulmonary performance characteristics (i.e., available dose, residence time, and regional lung deposition).

Patients' Understanding of the Relationship Between Their Diabetes and Periodontal Disease.

INTRODUCTION: There is a paucity of research on awareness, education, and interventions that address increased risk of developing periodontal disease, the sixth complication of diabetes. Examining the knowledge of patients with diabetes and understanding of the bidirectional relationship between periodontal disease and diabetes could inform future diabetes self-management care. We assessed the knowledge and understanding of the bidirectional relationship between diabetes and periodontal disease; examined gender, education, and income differences in this knowledge and understanding, as well as other differences in dental hygiene practices. METHODS: A Web-based survey was conducted using a convenience sample of patients with diabetes. RESULTS: A total of 927 patients with diabetes participated in the study. Gender and education were significantly associated with knowledge and understanding of the bidirectional relationship between diabetes and periodontal disease in patients with diabetes. After controlling for diabetes duration, dental insurance status, and other covariates, males had less knowledge and understanding of the bidirectional relationship between diabetes and periodontal disease compared with females (P < .0001). Those with higher education (P < .002) and those who received health care provider recommendations to obtain regular dental visits (P < .00001) had greater understanding of the association between diabetes and periodontal disease. CONCLUSIONS: This study highlights the need for 1) educating male and low-education patients with diabetes in particular about their increased risk of periodontal disease and the need for regular dental visits, and 2) health care providers and dental health providers to work together to address the needs of their diabetic patients.

Healthcare provider opinions about a generic drug educational newsletter.

BACKGROUND: Increasing the prescribing and dispensing of generic drugs, compared to branded drugs, may increase patient access to affordable drug treatments. Healthcare providers have information needs regarding generic drugs, but available, tailored education materials designed for provider use are lacking. OBJECTIVES: To examine healthcare provider opinions and receptivity regarding generic drug educational materials in content, format and design, delivery channel, and level of satisfaction. METHODS: A national online survey was conducted in summer 2018 to gather practicing healthcare prescribers' (i.e., physicians, nurse practitioners, physician assistants) and pharmacists' opinions on an educational newsletter developed through a collaboration between the investigators and the U.S. Food and Drug Administration (FDA). Survey data were analyzed using descriptive statistics. Quantitative analyses were performed using SPSS version 24 (IBM, Armonk, NY), while responses to open-ended questions were assessed using qualitative content analysis in Excel. RESULTS: A total of 208 surveys were completed. Overall, participants expressed positive opinions about the newsletter's content and format/design. About 69% of prescribers and 60% of pharmacists stated the newsletter gave information that will help them better serve patients. While 15% of surveyed pharmacists stated that they did not have resources to help them get information on generic drug availability and cost, more prescribers (37%) responded similarly. Both prescribers and pharmacists preferred to receive this newsletter via email from the FDA or a professional association. CONCLUSIONS: Findings indicate the feasibility of educational outreach programs about generic drugs targeted towards healthcare providers. There is room for improvement in making prescribers and pharmacists aware of resources for learning about generic drug availability and cost. Future studies may test alternate versions of the newsletter that have been tailored to the needs of specific provider specialties or provider practices serving specific patient sub-groups, as well as preferred dissemination frequency.

Evaluating daytime alertness in individuals with Restless Legs Syndrome (RLS) compared to sleep restricted controls.

BACKGROUND AND PURPOSE: Restless Legs Syndrome (RLS) is a common sensorimotor disorder often associated with significant chronic sleep loss. Previous studies looking at the effects of sleep loss on daytime function in RLS individuals, using subjective reporting techniques have yielded mixed results. In this study we used more objective measures of alertness and compared RLS subjects who are off treatments and chronically sleep restricted to chronic sleep-restricted controls. SUBJECTS AND METHODS: The final sample consisted of 20 RLS subjects (10 male and 10 female) and 13 sleep-restricted controls (seven male and six female). Thirteen controls underwent a 14-day chronic partial sleep-restriction protocol in order to closely match the degree of chronic sleep loss reportedly experienced by untreated RLS patients. On the final day of the protocol each subject performed a morning and evening Suggested Immobilization Test (SIT) which served as a modified Maintenance of Wakefulness Test (MWT). RLS and control groups were compared for differences in alertness as measured objectively by the sleep latency on the morning and evening SITs. RESULTS: The RLS subjects had a longer sleep latency on the morning and evening SIT than controls (t=3.80, p=0.001, U=31.0, p<0.001, respectively). Even after controlling for the potential arousal impact associated with increased leg activity, RLS individuals still demonstrated a higher degree of objective alertness (p=0.023, p=0.006, Fisher's exact test). CONCLUSIONS: RLS subjects, despite having, if anything, greater sleep loss, displayed greater sustained alertness than sleep-restricted controls. Thus, the heightened degree of alertness demonstrated by RLS patients may be in contrast to the perceived impairment in mood, vigor, and vigilance commonly reported in previous studies.

Communicating benefits and risks of generic drugs to consumers: Patient and caregiver opinions of two FDA-developed educational materials.

BACKGROUND: Increasing prescribing and dispensing of generic drugs, compared to brand drugs, may increase patient access to affordable medications. However, little is known about patients' and caregivers' needs and receptiveness regarding the design of educational materials about generic drugs. METHODS: The research used focus groups of patients and caregivers who were students or employees of one university in the Southeastern U.S. to gather input on the optimal content, format and design, delivery channel, and level of satisfaction for two existing, FDA-developed educational materials about generic drugs (infographic and brochure). RESULTS: Participants stated a need for the materials to modernize their graphics, emphasize generic drug cost-savings for consumers, reduce scare tactics when discussing adverse events, and be disseminated directly from physician's offices and pharmacies. Despite an overall positive impression of the materials, participants wanted more consumer-oriented materials that were tailored to fit the needs of different types of patients/caregivers, including older adults. CONCLUSIONS: This paper discusses how these findings relate to theories of multimedia learning and guidelines for designing health educational materials, as well as implications for the development of tailored generic drug educational materials for use in public health campaigns to improve access to medication therapy.

A further evaluation of the cognitive deficits associated with restless legs syndrome (RLS).

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is a common sensorimotor disorder that peaks in severity during the night and comes on with rest. As a result, this condition often results in significant chronic sleep loss, especially for those with severe disease. Chronic partial sleep restriction has been associated with conditions such as depression, anxiety, chronic pain, and decline in cognitive function. Furthermore, studies have found that RLS patients suffer from these conditions more than their unaffected peers. Thus, the morbidity rate associated with RLS has often been attributed to the chronic sleep loss that frequently accompanies this condition. However, no study has specifically compared RLS sufferers to otherwise normal sleep-restricted controls in order to assess disease morbidity independent of its sleep deprivation effects. In this study, we compared the cognitive function of RLS patients who were off treatment to sleep-restricted control subjects. SUBJECTS AND METHODS: A novel chronic partial sleep-restriction protocol that utilized a 14-day combined inpatient and outpatient design was implemented in order to test the differences in cognitive functioning between RLS patients and sleep-restricted controls. The brief cognitive battery included instruments assessing general intelligence and global executive function in order to control for baseline cognitive function between the groups, and then the effects of sleep loss were assessed using prefrontal lobe-specific tasks. The final sample consisted of 16 RLS (11 male and 5 female) and 13 sleep-restricted control subjects (7 male and 6 female). RESULTS: In order to examine the differences in cognitive functioning between sleep-restricted controls and RLS subjects, independent samples t-tests were conducted. RLS subjects performed significantly better on both the Letter Fluency (t=2.13, p<0.05) and Category Fluency (t=2.42, p<0.05) than sleep-restricted controls. CONCLUSIONS: RLS subjects performed better than the sleep-restricted controls on two tasks that are particularly sensitive to sleep loss. Although previous studies suggest that sleep deprivation may impact the cognitive function of those with RLS, our data suggests that RLS subjects may show a relative degree of sleep loss adaptation. Future investigations that more closely match the sleep loss pattern of RLS subjects to controls are warranted in order to explore these potential traits further.

Influence of patient medication information format on comprehension and application of medication information: A randomized, controlled experiment.

OBJECTIVE: To examine patients' comprehension and application of alternative versions of patient medication information handouts for a fictitious drug, and whether patient characteristics influence patients' ability to understand the handouts. METHODS: A web-based experiment was conducted in which 1397 adults with rheumatoid arthritis, ankylosing spondylitis, or plaque psoriasis were randomly assigned to one of three conditions: (1) a one-page "Bubbles" format; (2) a one-page "Over-The-Counter" (OTC) format; and (3) a four-page document modeled after MedGuides used in 2009 which served as the control arm. Comprehension and application of information in the handouts were the key outcomes of interest. RESULTS: Participants who viewed either the Bubbles or OTC formats had greater comprehension than participants who viewed the MedGuide, but did not have better application scores. No significant differences were noted between the Bubbles and OTC formats. Patient characteristics did not moderate the results. CONCLUSION: Both formats resulted in better comprehension than the MedGuide format used in the study. PRACTICE IMPLICATIONS: Results provide valuable information on how to design patient information to improve patients' understanding of the risks and benefits of the drugs they are prescribed. Results could be extended to inform the content of other types of patient education materials.