Methylphenidate Transdermal System Research Articles

Systematic review of transdermal treatment options in attention-deficit/hyperactivity disorder: implications for use in adult patients.

Adults with attention-deficit/hyperactivity disorder (ADHD) often face delays in diagnosis and remain untreated, despite significant negative impacts. To evaluate the safety and efficacy of transdermal treatment options in children, adolescents, and adults, a systematic literature review was conducted, with a focus on the implications of transdermal therapies for ADHD in adults. A MEDLINE/Embase/BIOSIS/SCOPUS database search was conducted December 4, 2019, for English-language articles of interventional clinical trials using transdermal formulations for the treatment of ADHD without publication date limit. Assessed outcomes included efficacy, safety, adherence, abuse potential, cost efficacy, and health-related quality of life. Of 23 eligible publications, 18 were in children or adolescents (n=1699; range 23-305), and 5 in adults (n=274; range 14-90); all included methylphenidate transdermal system (MTS). All seven pediatric publications reporting change in ADHD symptomology from baseline reported a significant improvement with MTS treatment. Similarly, in three adult publications, ADHD symptoms improved significantly with MTS treatment. Safety findings in pediatric and adult studies were comparable; the most frequently reported treatment-emergent adverse events (TEAEs), namely, headache, decreased appetite, and insomnia, were reported in 13/16 (81%) of publications reporting specific TEAEs. MTS-related dermal reactions were mostly mild and transient. Discontinuation due to dermal reactions was reported in 10 studies (range 0%-7.1% [1 of 14 patients]). MTS compliance was high when assessed (97%-99%). Transdermal therapies provide a useful treatment formulation for ADHD. Studies of MTS and other transdermal formulations, such as amphetamine, in adult patients are needed in this underserved population.

Chemical Leukoderma Associated with Methylphenidate Transdermal System: Data From the US Food and Drug Administration Adverse Event Reporting System

To identify and characterize cases of chemical leukoderma, an underrecognized adverse event, associated with the methylphenidate transdermal system (MTS) reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS). We searched the Food and Drug Administration Adverse Event Reporting System for reports of chemical leukoderma associated with MTS, received by the Food and Drug Administration from April 6, 2006 to December 23, 2014. We identified 51 cases of chemical leukoderma reported with the use of MTS. The median age was 11 years; 43 cases reported leukoderma at or near the application site only, and 7 reported leukoderma at other parts of the body in addition to the application site; 1 case did not provide enough information to confirm the affected site. The time to onset ranged from 2 months to 4 years after the initiation of MTS. MTS was discontinued in 31 cases. Thirteen patients were prescribed treatment for repigmentation. Three cases reported continued spread of leukoderma after MTS was discontinued. Nineteen cases were diagnosed as vitiligo, including 5 cases reporting histologic features consistent with vitiligo. Leukoderma was persistent in all cases. The median follow-up interval after the discontinuation of MTS in 23 cases was 14 months. As outlined in recent changes to the prescribing information for MTS, health care professionals need to be aware of the potential risk of chemical leukoderma caused by MTS, especially given that chemical leukoderma is often misdiagnosed as idiopathic vitiligo. MTS should be discontinued at the earliest sign of pigment loss and other treatment options considered.

36.3 TREATMENT EFFECTS ON EARLY MORNING FUNCTIONING IN CHILDREN WITH ATTENTION-DEFICIT/HYPERACTIVITY DISORDER

Children with ADHD frequently manifest behavioral difficulties in the mornings before going to school. The aim of this presentation is to highlight the effects of atomoxetine, methylphenidate transdermal system (MTS), and adjunctive guanfacine extended-release (GXR) plus stimulants to treat before-school ADHD symptoms and improve functioning in children with ADHD.

Topical Treatment for ADHD May Alter Skin Color

The methylphenidate transdermal system (Daytrana), a patch used to treat attention deficit–hyperactivity disorder, can produce a permanent loss of skin color. Such losses usually develop close to where the patches are worn, although they may develop elsewhere on the body.

Permanent skin discoloration possible with Daytrana patch

The Food and Drug Administration has warned that the Daytrana patch (methylphenidate transdermal system) may cause permanent skin color changes. The Daytrana patch, for attention‐deficit hyperactivity disorder, now has a new warning on the label to describe chemical leukoderma. This is a skin condition that causes the skin to lose color due to repeated exposure to specific chemical compounds. The condition is not physically harmful, but it is disfiguring. The areas of skin color loss described with the Daytrana patch ranged up to 8 inches in diameter. This condition is not thought to be reversible, which may cause emotional distress.

Reliability and Validity of the Before-School Functioning Scale in Children With ADHD

Objective: Children with ADHD frequently manifest behavioral difficulties in the morning prior to school. We sought to assess the reliability and validity of the Before-School Functioning Questionnaire (BSFQ) as a measure of morning behaviors impaired by ADHD. Method: We used pre-treatment data from a randomized crossover study of 6- to 12-year-old participants comparing the methylphenidate transdermal delivery system (MTS) with a placebo transdermal system (PTS) for a total of 4 weeks. Results: The BSFQ investigator–rated scale shows very good internal homogeneity (Cronbach’s α = .91), good test–retest reliability (r = .60), good concurrent validity (r range = .42-.86), and a strong treatment effect (effect size = −.93). The self-rated BSFQ showed lower levels of reliability and validity. Conclusion: The investigator-rated BSFQ should be used in future trials of ADHD medications aimed at assessing efficacy in the morning before school.

Transdermal Therapy for Attention-Deficit Hyperactivity Disorder with the Methylphenidate Patch (MTS)

Transdermal technology is currently approved in the US for the administration of more than 20 medications. This current review describes the clinical research pertaining to the use of a methylphenidate patch in the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents. PubMed searches were conducted using the search term ‘methylphenidate transdermal system’, and were limited to clinical trials. No limits were set for dates of publication. A total of 21 citations were identified. Studies evaluating the safety and efficacy of the methylphenidate transdermal system (MTS) in children and adolescents were included in this review. Additional studies were identified from bibliographies and the ‘Related Citations’ section of PubMed searches. The MTS delivers a range of methylphenidate doses using a drug-in-adhesive matrix patch. According to current labeling, the patch should be applied to the hip once daily for a maximum of 9 h. Serum methylphenidate levels increase over wear time, with mean time to maximum concentration (t max) reached between 8 and 10 h for a 9-h wear time, and the elimination half-life for methylphenidate is 3–4 h after patch removal. In clinical trials, ADHD symptoms were measured using the ADHD Rating Scale, Version IV, and several parent-, teacher-, and patient-rated scales. Treatment effects show statistically significant differences from baseline symptom scores starting at the first evaluation, 2 h after the patch is applied, with significant benefit lasting up to 12 h with a 9-h wear time. Adverse events with the MTS are similar to those seen with other formulations of methylphenidate, with the exception of skin-related reactions at the site of application, which were generally mild to moderate in severity. The incidence of contact allergic dermatitis with MTS is <1 %. Statistically significant improvements in health-related quality of life and medication satisfaction were also observed with the MTS compared with placebo, and after switching from oral extended-release (ER) methylphenidate. Transdermal drug delivery is an effective and safe means of administering methylphenidate for patients with ADHD.

The Effect of Personality Disorder Symptoms on Response to Treatment With Methylphenidate Transdermal System in Adults With Attention-Deficit/Hyperactivity Disorder

This trial was designed to prospectively explore the relationship among personality disorder (PD) symptoms, attention-deficit/hyperactivity disorder (ADHD), and treatment response in a randomized, double-blind, crossover clinical trial of methylphenidate transdermal system (MTS) and to confirm results of a prior exploratory study. 67 adults who met the Utah and/or DSM-IV-TR criteria for ADHD were recruited with no attempt to include or exclude patients with PD. Responders were defined by a 50% improvement on the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), the primary outcome measure. Personality disorder was diagnosed by the clinicians using the Structured Clinical Interview for DSM-IV-TR Axis II Personality Disorders Questionnaire, several self-report scales, and clinical observations. Subjects were categorized as: no PD (PD-negative), 1 PD (PD-positive), and 2 or more PDs (PD-plus). The study was conducted from February 2007 to December 2009 at the Mood Disorders Clinic at the University of Utah School of Medicine, Salt Lake City. 37% (n = 25) were PD-positive, and another 27% (n = 18) were PD-plus. In those with a PD, 65% (n = 28) had a cluster C diagnosis, 44% (n = 19) cluster B, and 5% (n = 12) cluster A. PD-plus subjects had significantly higher levels of oppositional defiant disorder (ODD) symptoms (P = .007) and emotional dysregulation (P = .004). 71% (15/21) of the PD-positive and PD-negative subjects were responders in the MTS arm (P < .001) as opposed to 38% (6/16) of the PD-plus subjects (P = .24). Conversely, the interaction between treatment (placebo versus MTS) and the 3 PD groups was not statistically significant (P = .46) when the total WRAADDS was used as the outcome measure. Personality disorder status was associated with more complex ADHD, especially high levels of emotional dysregulation and ODD symptoms. There was a significant treatment effect for PD-positive and PD-negative, but not PD-plus subjects. ClinicalTrials.gov identifier: NCT00506285.

Methylphenidate Transdermal System in Attention-Deficit Hyperactivity Disorder in Adolescentsy

Attention-deficit hyperactivity disorder (ADHD) is characterized by inattention, hyperactivity, and impulsivity.[2] Globally, ADHD affects approximately 5–10% of children[3] and persists into adolescence in up to 85% of affected individuals.[4] Psychostimulants, such as methylphenidate and amfetamine, are the mainstay of treatment in ADHD.[2] A patch that delivers methylphenidate transdermally (methylphenidate transdermal system; Daytrana®) has been developed for the treatment of ADHD. The patch comprises a backing layer, an adhesive formulation that incorporates methylphenidate and uses DOT Matrix™ technology, and a protective liner, which is removed prior to application.[5] The features and properties of methylphenidate transdermal system (including available patch sizes and the nominal methylphenidate dose delivered by each patch size) are shown in table I. Once applied to the skin, methylphenidate transdermal system releases methylphenidate continuously. A potential advantage of this patch technology is that it allows the duration of the effect to be tailored to the individual by varying the duration of the application (‘wear time’).[6] Table I Features and properties of methylphenidate transdermal system (Daytrana®)[1] Methylphenidate transdermal system is approved in the US for the treatment of ADHD,[5] and its use in children aged 6–12 years with ADHD has been reviewed previously.[7] This profile report examines the use of methylphenidate transdermal system in adolescents aged 13–17 years with ADHD. Adolescents aged 13–17 years with ADHD were randomized to receive methylphenidate transdermal system or placebo transdermal system in a double-blind, multicenter, 7-week trial (core trial).[8] During a 5-week dose-optimization period, patients were titrated to their optimal methylphenidate transdermal system dosage (10, 15, 20, or 30 mg); the dose-optimization period was followed by a 2-week maintenance period, during which patients continued treatment at their optimal dosage. Patches were applied to the hip each morning and worn for 9 hours per day.[8] Following the core trial, eligible patients could receive longer-term therapy with methylphenidate transdermal system 10–30 mg in a noncomparative extension study of ≈6 months duration.[9] According to the results of the core trial, methylphenidate transdermal system 10–30 mg was effective in adolescents aged 13–17 years with ADHD.[8] The mean ADHD-Rating Scale-IV (ADHD-RS-IV) total score (primary endpoint) decreased to a significantly (p < 0.001) greater extent in adolescents receiving methylphenidate transdermal system (n = 143) than in those receiving placebo transdermal system (n = 72), with a least squares mean between-group difference of -9.96 (95% CI -13.39, -6.53). The mean ADHD-RS-IV total score at study end was 17.7 in methylphenidate transdermal system recipients and 27.7 in placebo transdermal system recipients; the mean baseline scores were 36.4 and 36.6 in the corresponding treatment groups.[8] In the extension study, methylphenidate transdermal system recipients experienced a significant (p < 0.001) reduction from the start of the core trial in the mean ADHD-RS-IV total score of 23.0.[9] Methylphenidate transdermal system was generally well tolerated in adolescents with ADHD. The vast majority of treatment-emergent adverse events were of mild to moderate severity in both the short-term core trial[8] and the longer-term extension study.[9] In the core trial, the most frequently reported treatment-emergent adverse events (occurring in ≥5% of methylphenidate transdermal system recipients and in numerically more methylphenidate transdermal system than placebo transdermal system recipients) included decreased appetite, irritability, upper respiratory tract infection, nausea, insomnia, dizziness, and decreased weight.[8] A similar tolerability profile was seen during the extension study.[9] In the core trial, most of the skin reactions to methylphenidate transdermal system comprised mild erythema, and adherence of the methylphenidate transdermal system patch to the skin was rated at ≥90% overall.[8] Changes in the blood pressure and pulse rate observed in the core[8] and extension[9] studies were typical of those seen in patients receiving stimulants.

Methylphenidate Transdermal System in Attention-Deficit Hyperactivity Disorder in Adolescentsy

Methylphenidate Transdermal System in Attention-Deficit Hyperactivity Disorder in Adolescentsy

Effect of Transdermal Methylphenidate Wear Times on Sleep in Children With Attention Deficit Hyperactivity Disorder

Sleep disturbances are common among children and adolescents with attention deficit hyperactivity disorder. This study sought to evaluate the effects of individualizing wear times of the methylphenidate transdermal system on sleep parameters. In this open-label, randomized trial, 26 children with attention deficit hyperactivity disorder and sleep disturbances were randomized (after dose optimization) to one of four groups with different sequences of patch wear times (i.e., 9, 10, 11, and 12 hours per day wear times each for week in different sequences). The primary endpoint comprised sleep latency. Secondary endpoints included total sleep time, sleep quality, and attention deficit hyperactivity disorder and related signs (assessed with Attention Deficit Hyperactivity Disorder Rating Scale-IV and Connor's Global Impression-Parent). A mixed-effects regression model evaluated the effects of patch wear time on sleep and symptom measures. Patch wear time exerted no significant effect on sleep latency or total sleep time, although a trend toward improved sleep quality was evident (P = 0.059) with longer patch wear times. Sleep parameters were not adversely affected by longer methylphenidate transdermal system patch wear times. Thus, if replicated in larger samples, the individualization of patch wear times should be considered according to the needs and responses of patients.

Oppositional Defiant Disorder in Adults With ADHD

Objective: Oppositional defiant disorder (ODD) is the most common comorbid condition in childhood ADHD. This trial was prospectively designed to explore ODD symptoms in ADHD adults. Method: A total of 86 patients in this placebo-controlled, double-blind trial of methylphenidate transdermal system (MTS) were categorized based on the presence of ODD symptoms in childhood and adulthood, and then were compared for baseline and outcome differences. Results: In all, 42% met Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) criteria for ODD as adults and were significantly more impaired on measures of ADHD, personality disorder, and substance abuse and 27% had childhood ODD that had resolved. Childhood and adult ODD symptoms were significantly correlated. ODD and ADHD symptoms improved significantly with MTS (p < .001), and the most consistently significant results were found in participants with adult ODD. Conclusion: A total of 69% met criteria for ODD as children and/or adults. Understanding how ODD interacts with ADHD to impact personality disorder, substance abuse, and treatment response has important clinical, social, and theoretical implications.

Methylphenidate Transdermal System in Preschool Children with Attention-Deficit/Hyperactivity Disorder

Methylphenidate Transdermal System in Preschool Children with Attention-Deficit/Hyperactivity Disorder

Methylphenidate transdermal system: clinical applications for attention-deficit/hyperactivity disorder

The methylphenidate transdermal system (MTS) provides a novel method of delivery for methylphenidate, a well-studied and effective medication for attention-deficit/hyperactivity disorder. The MTS achieves two major goals. First, the delivery system allows for administration throughout the day with a single patch, thus improving adherence. Second, it is the first approved attention-deficit/hyperactivity disorder medication that is not administered orally, thus bypassing gastrointestinal absorption and first-pass metabolism through the enteric circulation. In this article, we review the current data on MTS, including preclinical, clinical and post-marketing studies, and compare efficacy and tolerability to currently available treatments.

Methylphenidate Transdermal System

Methylphenidate transdermal system uses DOT Matrix™ technology and, once applied to the skin, releases methylphenidate continuously. In the US, methylphenidate transdermal system is indicated for use in the treatment of attention-deficit hyperactivity disorder (ADHD). According to the results of a randomized, double-blind, multicentre, 7-week trial (core trial), methylphenidate transdermal system 10-30 mg was effective in adolescents aged 13-17 years with ADHD. The mean ADHD-Rating Scale-IV (ADHD-RS-IV) total score (primary endpoint) decreased to a significantly greater extent in adolescents receiving methylphenidate transdermal system than in those receiving placebo transdermal system. Following the core trial, adolescents could subsequently receive methylphenidate transdermal system in an extension study of ≈6 months duration. From the start of the core trial to the end of the extension study, methylphenidate transdermal system recipients demonstrated a significant reduction in the mean ADHD-RS-IV total score. Methylphenidate transdermal system was generally well tolerated in adolescents with ADHD. The vast majority of treatment-emergent adverse events were of mild to moderate severity in both the short-term core trial and the longer-term extension study.

Evaluating elevated release liner adhesion of a transdermal drug delivery system (TDDS): A study of Daytrana™ methylphenidate transdermal system

Background: Complaints from healthcare providers that the adhesive on the Daytrana™ methylphenidate transdermal drug delivery system (TDDS) adhered to the release liner to such an extent that the release liner could not be removed prompted this study. Daytrana™ has a packaging system consisting of a moisture-permeable pouch contained within a sealed tray containing a desiccant; the tray is impermeable to ambient moisture. The objective of this project was to determine if the Daytrana™ packaging system influenced the difficulty in removing the release liner.Method: Both a sealed tray and an open tray containing sealed pouches were placed into an environmental chamber at 25°C and 60% relative humidity for 30 days; afterwards, release liner removal testing using a peel angle of 90° and a peel speed of 300 mm/min was performed.Results: TDDS from open chamber trays required less force to remove the release liner than did TDDS from closed chamber trays. For the 10 mg/9 h TDDS and the 15 mg/9 h TDDS (the dosages examined), there were substantial differences in release liner removal force between an old lot and a new lot for closed chamber trays but not for open chamber trays.Conclusion: The results demonstrate that for this particular TDDS, storage conditions such as humidity influence release liner adhesion. This project also demonstrates that, to ensure adequate product quality, adhesion needs to become an important design parameter, and the design of a TDDS should consider the ability to remove the release liner under anticipated storage conditions.

Methylphenidate Transdermal System

To characterize dermal reactions and examine methylphenidate (MPH) sensitization in subjects receiving methylphenidate transdermal system (MTS). This multicenter, open-label, dose-optimization study utilized MTS doses of 10, 15, 20, and 30 mg in children aged 6 to 12 years, inclusive (N = 305), with a DSM-IV-TR primary diagnosis of attention-deficit/hyperactivity disorder. The study was conducted between January 8, 2007, and August 23, 2007. Subjects wore MTS on their hips for 9 hours per day, alternating sides daily for a total of 7 weeks. Assessments included the Experience of Discomfort scale, Transdermal System Adherence scale, and Dermal Response Scale (DRS; 0 = no irritation, 7 = strong reaction). On-study reevaluations were conducted to characterize DRS scores ≥ 4. Epicutaneous allergy patch testing was conducted for DRS scores ≥ 6, persistent DRS scores ≥ 4, DRS score increase following an assessment of ≥ 4, or DRS scores of 4 or 5 following elective discontinuation. Approximately half of subjects experienced definite erythema at the patch site that generally dissipated within 24 hours. Four subjects experienced a DRS score of 4 (1%): erythema in 1 subject resolved on study treatment, 2 cases resolved poststudy and subjects tolerated oral MPH, and 1 subject discontinued treatment. The latter subject was referred for patch testing and was diagnosed with allergic contact sensitization to MPH. Few severe dermal effects were seen with MTS treatment. Dermal reactions were characterized as contact dermatitis and dissipated rapidly. On patch testing, 1 subject (0.3%) manifested sensitization to MPH. clinicaltrials.gov Identifier: NCT00434213.

Genome-wide association study of blood pressure response to methylphenidate treatment of attention-deficit/hyperactivity disorder

We conducted a genome-wide association study of blood pressure in an open-label study of the methylphenidate transdermal system (MTS) for the treatment of attention-deficit/hyperactivity disorder (ADHD). Genotyping was conducted with the Affymetrix Genome-Wide Human SNP Array 6.0. Multivariate association analyses were conducted using the software package PLINK. After data cleaning and quality control we tested 316,934 SNPs in 140 children with ADHD. We observed no genome-wide statistically significant findings, but a SNP in a K(+)-dependent Na(+)/Ca(2+) exchanger expressed in vascular smooth muscle (SLC24A3) was included in our top associations at p<1E-04. Genetic enrichment analyses of genes with ≥1 SNP significant at p<0.01, implicated several functional categories (FERM domain, p=5.0E-07; immunoglobulin domain, p=8.1E-06; the transmembrane region, p=4.4E-05; channel activity, p=2.0E-04; and type-III fibronectins, p=2.7E-05) harboring genes previously associated with related cardiovascular phenotypes. The hypothesis generating results from this study suggests that polymorphisms in several genes consistently associated with cardiovascular diseases may impact changes in blood pressure observed with methylphenidate pharmacotherapy in children with ADHD.

A 6-Month, Open-Label, Extension Study of the Tolerability and Effectiveness of the Methylphenidate Transdermal System in Adolescents Diagnosed with Attention-Deficit/Hyperactivity Disorder

The aim of this study was to evaluate the tolerability and effectiveness of the methylphenidate transdermal system (MTS) over 6 months in adolescents with attention-deficit/hyperactivity disorder (ADHD). This was an industry-sponsored, 30-center, open-label study of subjects aged 13-17 years with ADHD. Subjects were dose-optimized with MTS (10-30 mg/9 hours) over 5 weeks and then dose-maintained for up to 5 months. Tolerability evaluations included treatment-emergent adverse events (TEAEs) and dermal responses. Effectiveness was assessed with the ADHD-Rating Scale-IV (ADHD-RS-IV). A total of 162 subjects received MTS treatment. The majority of TEAEs (>99%) were mild or moderate in intensity, and the most frequently reported TEAE was decreased appetite (15.4%). Thirteen subjects discontinued the study due to TEAEs. The majority (93.6%) of dermatologic reactions indicated mild erythema. There was significant improvement in mean ADHD-RS-IV total scores from study entry to end point (p<0.001). Slightly more than half (54.0%) of subjects completed this 6-month, open-label extension study of MTS; the primary reason for discontinuation was withdrawn consent (36.0%). Reported TEAEs and skin tolerability findings were similar to those observed with MTS use in children and adolescents. MTS treatment resulted in a decrease in ADHD symptoms as rated by clinicians.

Time Course and Predictors of Health-Related Quality of Life Improvement and Medication Satisfaction in Children Diagnosed with Attention-Deficit/Hyperactivity Disorder Treated with the Methylphenidate Transdermal System

The aim of this study was to evaluate the time course and predictors of improvement in health-related quality of life (HRQL) and medication satisfaction in children diagnosed with attention-deficit/hyperactivity disorder (ADHD) and treated with the methylphenidate transdermal system (MTS). Temporal relationships between ADHD symptoms, medication satisfaction, and HRQL measures were examined via latent growth curve, structural path, and growth mixture models. Higher levels of medication satisfaction at the end of titration predicted greater increases in family HRQL (p=0.004) and, to a lesser extent, child HRQL (p=0.068) throughout the study. At 4 of 6 (p<0.05) and 5 of 6 (p<0.10) contemporaneous time points, ADHD symptoms predicted child HRQL. At 2 of 6 (p<0.05) and 3 of 6 (p<0.10) contemporaneous time points, ADHD symptoms predicted family HRQL. ADHD did not predict child or family HRQL improvements at subsequent time points. A uniform pattern of change for child HRQL was noted, with most HRQL change following the pattern of symptom change during titration. Three distinct patterns of change were noted for family HRQL. In most cases, medication satisfaction, ADHD symptoms, and HRQL improved simultaneously, suggesting that HRQL was not a delayed response to improvement in symptoms. Children showed a uniform pattern of improvement in HRQL that followed symptom change; three distinct patterns of change were found for improvement in family HRQL.