Skin Pharmacokinetics of Transdermal Scopolamine: Measurements and Modeling.

Prediction of skin absorption and local bioavailability from topical formulations remains a difficult task. An important challenge in forecasting topical bioavailability is the limited information available about local and systemic drug concentrations post application of topical drug products. Commercially available transdermal patches, such as Scopoderm (Novartis Consumer Health UK), offer an opportunity to test these experimental approaches as systemic pharmacokinetic data are available with which to validate a predictive model. The long-term research aim, therefore, is to develop a physiologically based pharmacokinetic model (PBPK) to predict the dermal absorption and disposition of actives included in complex dermatological products. This work explored whether in vitro release and skin permeation tests (IVRT and IVPT, respectively), and in vitro and in vivo stratum corneum (SC) and viable tissue (VT) sampling data, can provide a satisfactory description of drug "input rate" into the skin and subsequently into the systemic circulation. In vitro release and skin permeation results for scopolamine were consistent with the previously reported performance of the commercial patch investigated. New skin sampling data on the dermatopharmacokinetics (DPK) of scopolamine also accurately reflected the rapid delivery of a "priming" dose from the patch adhesive, superimposed on a slower, rate-controlled input from the drug reservoir. The scopolamine concentration versus time profiles in SC and VT skin compartments, in vitro and in vivo, taken together with IVRT release and IVPT penetration kinetics, reflect the input rate and drug delivery specifications of the Scopoderm transdermal patch and reveal the importance of skin binding with respect to local drug disposition. Further data analysis and skin PK modeling are indicated to further refine and develop the approach outlined.

Statistical considerations and impact of the FDA draft guidance for assessing adhesion with transdermal delivery systems and topical patches for ANDAs.

Until 2016, a ratio of means (ROM) non-inferiority (NI) test was recommended in FDA product-specific guidances (PSGs) to evaluate adhesion performance for prospective generic transdermal delivery systems (TDS). However, the ROM NI test had low power for well-adhering TDS, which were becoming increasingly prevalent. Mathematical proof and simulation revealed that the low power wasn't because the non-normality of adhesion data violated the normality assumption of parametric methods; it was because the ROM NI test was coupled with an adhesion scale where scores approached 0 as adhesion got better. In June 2016, FDA published a draft general guidance on TDS adhesion and recommended a new statistical approach, replacing the ROM NI test with a difference-of-means (DOM) NI test, using the same scale and primary endpoint (mean adhesion scores). An analysis of 40 TDS adhesion studies submitted in ANDAs after the publication of the 2016 draft guidance suggests that, consistent with simulation results, the new statistical approach markedly improves the low power, and thereby reduces the sample size required by the old approach for moderately to well-adhering TDS, while retaining comparable power for poorly adhering TDS. The new statistical approach thus enhances the potential approvability and patient access to well-adhering generic TDS.

The experience of sexuality in adults with intellectual disability.

BACKGROUND: People with intellectual disability have the same sexual needs as those without any disability, yet their sexuality is often restricted by reluctant attitudes and/or fears based on irrational beliefs. The aim of this study is to describe and analyse different areas of sexuality in adults with mild or moderate intellectual disability. METHOD: The sample consisted of 180 men and 180 women attending occupational centres. All the participants were administered a questionnaire about sexuality adapted to their characteristics. RESULTS: Results show that 84.2% have had sexual relationships with another person, this percentage being higher in females and in people aged between 38 and 55 years old. Condoms are used by 41.4%. The most frequently used contraceptive methods are the pill (39.6%), transdermal patch (30.2%) and intrauterine device (6.7%). 9.4% of the women and 2.8% of the men has experienced sexual abuse. CONCLUSION: In conclusion, there is a need to draw up educational programmes, differentiated according to gender and adapted to their reality, which include contents related with sexual health, sexual abuse and condom use.

A nationwide study of the extent and factors associated with fentanyl use in Australia.

OBJECTIVE: To examine fentanyl utilisation in the Australian community and determine the geographic and socio-demographic factors associated with higher rates of fentanyl utilisation. METHODS: National sales data (supplied by IMS Health) were used to estimate fentanyl utilisation (in pack sales and milligrams) in Australia during 2013, mapped to Australian Bureau of Statistics (ABS) Statistical Local Areas (SLAs) and Remoteness Areas. Socio-demographic characteristics and total population estimates of SLAs were obtained from the ABS. SLA-level data on sex, age distribution, income, occupations involving physical labour and number of pharmacies, were included in linear regression analyses to examine their association with fentanyl use. RESULTS: An estimated 12.3 kg (or 859,518 packs) of fentanyl was sold across Australia in 2013, equating to an average of 0.55 mg/person over the year. Transdermal patches accounted for the majority (99%; 850,923 packs) of fentanyl sales. South Australia had the highest rate of utilisation per person. Rates of fentanyl utilisation were higher among more remote areas in three jurisdictions. Overall, higher utilisation rates were observed in SLAs that were less populated (ß 0.12; p < 0.001) and those with a higher proportion of older people (ß 0.12; p < 0.001), low-income households (ß 0.12; p < 0.001) and people working in jobs requiring physical labour (ß 0.08; p < 0.05). CONCLUSIONS: Transdermal fentanyl patches account for the majority of fentanyl utilisation in the Australian community. There is marked variation in fentanyl utilisation across geographic areas, with higher use apparent in areas with a higher proportion of older people and indicators of greater socio-economic disadvantage.

Why Stop Now? Extended and Continuous Regimens of Combined Hormonal Contraceptive Methods.

Combined hormonal contraceptives (CHCs) have traditionally been prescribed in 28-day cycles, with 21 days of active hormones followed by a 7-day hormone-free interval. Extended and continuous CHC regimens, defined as regimens with greater than 28 days of active hormones, offer many benefits, including a decrease in estrogen-withdrawal symptoms and likely greater efficacy because of more reliable ovulation suppression. Bleeding profiles are favorable, and unscheduled bleeding decreases over time with these regimens. Extended and continuous regimens of combined oral contraceptives and the contraceptive vaginal ring are safe and have high user acceptability and satisfaction. However, despite numerous benefits, extended and continuous CHC regimens are underused.

Pharmacy claims data versus patient self-report to measure contraceptive method continuation.

OBJECTIVE: To compare self-reported 12-month continuation of oral contraceptive pills (OCPs), patch, and ring versus continuation by pharmacy claims data. STUDY DESIGN: Women in the Contraceptive CHOICE Project who chose OCPs, the patch, or the ring as their initial method were included. Continuation was assessed by periodic telephone survey and by obtaining prescription claims data. Continuation was defined as no gap of more than 30 days. Kaplan-Meier survival functions were used to estimate continuation rates and cumulative unintended pregnancy rates. Kappa statistic assessed the level of agreement between self-report and claims data. RESULTS: We analyzed 1510 women who initiated use by 3 months and provided information on discontinuation. Of OCP users, 59% continued their method at 12 months by self-report versus 38% by pharmacy claims. Patch and ring users had self-reported/pharmacy continuation of 45%/28% and 57%/37%, respectively. Kappa coefficients and their 95% confidence intervals between the two measurements were 0.46 (0.40, 0.52), 0.54 (0.39, 0.68), and 0.54 (0.47, 0.61) for OCP, patch, and ring, respectively. Among women who self-reported continuation, unintended pregnancy rates were 0.4% in those who continued by pharmacy claims versus 4.9% in those who discontinued according to claims data. CONCLUSION: Contraceptive continuation rates differ by self-report versus pharmacy claims with women overestimating their continuation by self-report. IMPLICATIONS: This article directly compares contraception continuation rates by self-report and by pharmacy claims data. The study suggests that previously reported continuation rates from survey data overestimate specific method use.

Use of prescription contraceptive methods in the UK general population: a primary care study.

OBJECTIVE: To determine prescription contraceptive use in the UK. DESIGN: Observational study using a primary care database. SETTING: The Health Improvement Network (THIN). POPULATION: Women in THIN aged 12-49 years in 2008, registered with their primary care doctor for at least 5 years, and with a prescription history of at least 1 year were included. METHODS: THIN was searched using the Read and MULTILEX codes for the following methods: combined oral contraceptives (COCs), progestogen-only pills (POPs), copper intrauterine devices (Cu-IUDs), the levonorgestrel-releasing intrauterine system (LNG-IUS), progestogen-only implants, progestogen-only injections, and contraceptive patches. MAIN OUTCOME MEASURES: Prevalence, switching, and duration of prescriptions. RESULTS: A cohort of 194 054 women was identified. The prevalence of contraceptive use was: COCs, 16.2% (95% confidence interval, 95% CI 16.1-16.3%); POPs, 5.6% (95% CI 5.5-5.6%); Cu-IUD, 4.5% (95% CI 4.4-4.5%); LNG-IUS, 4.2% (95% CI 4.1-4.2%); progestogen-only implants, 1.5% (95% CI 1.5-1.6%); progestogen-only injections, 2.4% (95% CI 2.3-2.4%); and contraceptive patches, 0.1% (95% CI 0.1-0.2%). Within 1 year, 9.8% of new COC users switched to alternative COCs, and 9.0% changed to a different method. Among new COC users who did not switch method, 34.8% did not continue use beyond 3 months, and were no longer using a prescription contraceptive. CONCLUSIONS: Among users of oral contraceptives who did not switch method, over one-third did not continue use beyond 3 months. This supports current UK guidelines recommending a follow-up consultation with a healthcare professional 3 months after the first prescription of COCs.

Bilayered transmucosal drug delivery system of pravastatin sodium: statistical optimization, in vitro, ex vivo, in vivo and stability assessment.

The objective of the present study was to develop a mucoadhesive sustained release bilayered buccal patch of pravastatin sodium using Eudragit S100 as the base matrix so as to surmount hepatic first pass metabolism and gastric instability of the drug. A 3² full factorial design was employed to study the effect of independent variables viz. levels of HPMC K4M and carbopol 934P on % cumulative drug release, mucoadhesion time and mucoadhesive force. Amount of carbopol 934P and HPMC K4M significantly influenced characteristics like swelling index, in vitro mucoadhesive force, drug release, and mucoadhesion time. In vitro evaluation revealed that formulations exhibited satisfactory technological parameters. The mechanism of drug release was found to be non-Fickian diffusion. Different permeation enhancers were investigated to improve the permeation of drug from the optimized patches (F9) across the buccal mucosa. Formulation [F9 (P3)] containing 4% (v/v) dimethyl sulfoxide exhibited desirable permeation of drug. Histopathological studies performed using goat buccal mucosa revealed no mucosal damage. Bioavailability studies in rabbits demonstrated that [F9 (P3)] significantly higher C(max) (67.34 ± 3.58 ng/ml) and AUC0₋∞ (350.27 ± 9.59 ng/ml×h) (p < 0.05) of pravastatin sodium from optimized patch than IR tablet (C(max) 58.73 ± 4.63 ng/ml and AUC0₋∞ 133.80 ± 8.25 ng/ml×h). Formulation [F9 (P3)] showed sustained drug plasma concentration over a period of 10 h which was significantly longer than oral tablet (p < 0.05). Stability studies as per ICH guidelines established physical stability of the patch and chemical stability drug. The present study established potential of the optimized mucoadhesive buccal patches to circumvent the hepatic first-pass metabolism, gastric instability and to improve bioavailability of pravastatin sodium.

Continuation rate of combined hormonal contraception: a prospective multicenter study.

BACKGROUND: Data from clinical trials regarding continuation of use and contraceptive efficacy do not always apply to the general public. Therefore, a study among typical users was conducted to assess the continuation rate at the end of 12 cycles of combined hormonal contraceptive methods, reasons for discontinuation, and the Pearl index. METHODS: Prospective, observational, and multicenter study of 3443 women aged 18 to 49 years starting one of the three combined hormonal contraception methods available in Spain (the vaginal ring, the contraceptive pill, and the transdermal skin patch). RESULTS: The study population (intention-to-treat analysis) included 3443 women, of whom 45.4% were included in the vaginal ring group, 42.6% the pill group, and 12.1% the skin patch group. The continuation rate at 12 cycles was 45.9% for the pill, 42.3% for the vaginal ring, and 26.0% for the skin patch. The Pearl index was 0.61 (95% confidence interval [CI] 0-1.2) for the pill, 0.61 (95% CI 0-1.1) for the vaginal ring, and 2.34 (95% CI 0.3-9) for the skin patch (p<0.001). CONCLUSION: At 12 cycles, the vaginal ring and the pill showed similar continuation rates and effectiveness, which were significantly higher than the skin patch.

Adolescents' experiences using the contraceptive patch versus pills.

STUDY OBJECTIVE: To compare use of the weekly transdermal contraceptive patch (patch) with daily combined hormonal contraceptive pills (pills) in adolescents. DESIGN: Prospective longitudinal study of adolescents' self-selected (non-randomized) use of the patch or pills. SETTING: Urban, university hospital-affiliated, adolescent outpatient clinic. PARTICIPANTS: 13-22-year-old female adolescents seeking hormonal contraception, 40 who chose the patch and 40 who chose pills. INTERVENTIONS: Data were collected via self-report on paper questionnaires at three-cycle intervals for a total of up to nine cycles. MAIN OUTCOME MEASURES: Method continuation, perfect use, method satisfaction, quality of life, and side effects, including menstrual changes and perceived mood changes. RESULTS: After nine cycles, 38% of patch users and 60% of pill users were still using the method they had chosen at enrollment. There were no significant differences between the groups in self-reported perfect use. No differences were found in quality of life or side effects. Both patch and pill users noted menses became lighter and more predictable and reported decreased depression prior to their menses; only the pill group reported improvement in premenstrual anger. Method satisfaction was similar in both groups except patch users were more likely to report that their contraceptive method improved normal daily activities. CONCLUSIONS: Despite apparent advantages of the patch over the pill, adolescents using both methods continue to face challenges achieving perfect and sustained contraceptive use.

Inappropriate use of high doses of transdermal fentanyl at admission to a palliative care unit.

A retrospective study was conducted to determine the patterns of strong opioid use in patients admitted to a hospice inpatient unit, with special attention to the use of the transdermal fentanyl patch. This study was conducted to validate or negate the subjective feeling that many patients, treated at admittance with the fentanyl patch, received inappropriately high doses compared to patients treated with oral or parenteral opioids. The case notes of 1154 patients were reviewed and data collected on age, sex, diagnosis, care settings, opioid form and dose on referral, maximal dose during admission and opioid use during the last 24 hours of their life. At admission opioids had been prescribed for 47% of patients. Thirty-two percent of these patients received oral morphine. The median dose at admission of those patients was 60 mg (oral morphine equivalent (OME)). Thirty-six percent of the patients on opioids were using the fentanyl patch. The median dose at admission was triple that of the orally treated patients (median 180 mg OME). In the 199 patients using transdermal fentanyl at admission, in most patients the dose of the patch was gradually diminished and finally stopped in 58% of patients. Only 83 kept it until the last 24 hours. We would like to draw attention to the fact that (sometimes inappropriately) high doses of fentanyl were used at admission, probably due to lack of knowledge of the relative strength of the opioid involved and to the failure to recognize the phenomenon of opioid-induced hyperalgesia. In addition, in our experience the long action of the patch can be a disadvantage during the last days and weeks of life, due to the difficulty of dose adjustment and the risk for toxicity.

Use of nicotine replacement therapy for smoking reduction and during enforced temporary abstinence: a national survey of English smokers.

AIMS: To assess the prevalence of nicotine replacement therapy (NRT) use for smoking reduction (SR) and temporary abstinence (TA), the association between the two and the strength of the association between NRT use for SR or TA and socio-demographic characteristics, cigarette consumption and past quit attempts. DESIGN: Cross-sectional monthly surveys. SETTING: England. PARTICIPANTS: A total of 11, 414 smokers. MEASUREMENTS: Participants were asked (i) whether they were reducing the amount they smoked: if so, whether they used NRT; and (ii) whether they used NRT for TA. Demographic characteristics, daily cigarette consumption and whether a quit attempt had been made in the past 12 months were also assessed. FINDINGS: Of the participants, 56% were attempting SR, 14% were using NRT for SR and 14% were using NRT for TA. Use of NRT for SR and TA were highly correlated. The nicotine patch was the most commonly used form of NRT. The use of NRT for SR, compared with unassisted SR, was more common among older smokers, while the use of NRT for TA was more common among women. Cigarette consumption was higher in those using NRT for SR than those attempting SR without NRT. The use of NRT for SR and TA was associated positively with past quit attempts. CONCLUSIONS: Nicotine replacement therapy use for smoking reduction and temporary abstinence is common in England. The use of NRT for SR and TA does not appear to be associated with lower cigarette consumption relative to SR or TA without NRT, but is associated with a higher rate of past quit attempts.

The use of the vaginal ring and transdermal patch among adolescent girls in Finland.

OBJECTIVE: Little is known about the use of the vaginal ring and transdermal patch in representative adolescent populations although these contraceptives are supposed to be a good option for that age group. The aim of this study was to determine the use of the vaginal ring and that of the transdermal patch and to compare these with the use of oral contraceptives (OCs) and emergency contraception in adolescent girls residing in Finland. METHODS: As part of the Adolescent Health and Lifestyle Survey a questionnaire was mailed to a representative sample of girls aged 14, 16 or 18 years residing in Finland. Of these 3029 (72%) responded. RESULTS: The use of the vaginal ring (0.9%) and that of the transdermal patch (0.1%) were uncommon whereas OCs were commonly resorted to (20%). Only 0.6% of girls aged 16 and 2.5% of those aged 18 used the vaginal ring or the transdermal patch. Fifteen percent of girls had ever used emergency contraception. CONCLUSION: The vaginal ring and the transdermal patch are rarely used by adolescents. Our findings suggest that these novel contraceptive methods have not been adopted by family planning services.