"The U.S. Food and Drug Administration today allowed marketing of the first medical device based on brain function to help assess attention-deficit/hyperactivity disorder (ADHD) in children and adolescents 6 to 17 years old. When used as part of "...
Mechanism Of Action
Methylphenidate is a CNS stimulant. Its mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known, but methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and to increase the release of these monoamines into the extraneuronal space.
Methylphenidate is a racemic mixture comprised of the d-and l-enantiomers. The d-enantiomer is more pharmacologically active than the l-enantiomer.
The pharmacokinetics of Daytrana when applied to the hip for 9 hours have been studied in ADHD patients 6 to 17 years old.
The amount of methylphenidate absorbed systemically is a function of both wear time and patch size. In patients with ADHD, peak plasma levels of methylphenidate are reached at about 10 hours after single application and 8 hours after repeat patch applications (12.5 cm² to 37.5 cm²) when worn up to 9 hours.
On single dosing with Daytrana to children or adolescents, there was a delay of, on average, 2 hours before dmethylphenidate was detectable in the circulation. On repeat dosing, low concentrations (1.2-3.0 ng/mL in children and 0.5-1.7ng/mL in adolescents, on average across the dose range) were observed earlier in the profile, due to carry-over effect. Following the application of Daytrana once daily with a 9 hour wear time, the mean pharmacokinetic parameters of d-methylphenidate in children and adolescents with ADHD after 4 weeks of therapy are summarized in Table 3.
Table 3 : Mean Plasma d-Methylphenidate
Pharmacokinetic Parameters After Repeated 9-Hour Applications of Daytrana or
Oral ER-MPH for up to 28 days to Pediatric ADHD Patients (Aged 6 – 17 years)
|Parameter||Daytrana1 12.5 cm² (N=12)||Daytrana2 37.5 cm² (N=10)||Oral ER-MPH3 18 mg||Oral ER-MPH3 54 mg|
|Cssmax (ng/mL)||15.7 ± 9.39||42.9 ± 22.4||8.37± 4.14||26.1 ± 11.2|
|Cssmin (ng/mL)||1.04 ± 1.17||1.96± 1.73||0.708 ± 1.08||1.19 ± 1.54|
|AUCSS (ng•hr/mL)||1 63 ± 101||447 ± 230||97.7 ± 67.0||317± 160|
|tlag (h)4||0 (0 - 2.0)||0 (0 - 1.0) 16||0||0|
|Cssmax (ng/mL)||8.32 ± 4.60||16.5 ± 6.94||5.23 ± 1.72||18.0 ± 6.97|
|Cssmin (ng/mL)||0.544 ± 0.383||1.02 ± 0.629||0.360 ± 0.478||1.50 ± 0.937|
|AUCss (ng•hr/mL)||85.7± 50.0||167 ± 66.0||59.7 ± 19.1||216 ± 80.8|
|tlag (h)4||0 (0 - 2.0)||0 (0 - 2.0)||0||0|
|1Dose maintained fixed for 28 days;
2Dose escalated at 7 day intervals from 12.5 cm² through 18.75 cm² and 25 cm² to 37.5 cm²;
3Dose escalated at 7 day intervals from 18 mg through 27 mg and 36 mg to 54 mg;
4Median (minimum – maximum); tlag = Last Sampling Time Prior to Time of First Quantifiable Plasma Concentration
Following administration of Daytrana 12.5 cm² to pediatric and adolescent ADHD patients daily for 7 days, there were 13% and 14% increases, respectively, in steady state area under the plasma concentration-time curve (AUCss) relative to that anticipated on the basis of single dose pharmacokinetics (AUC0-∞); after 28 days administration, these increments increased to 64% and 76%, respectively. Cmax increased by nearly 69% and 100% within 4 weeks of daily administration of the starting dose in children and adolescents, respectively.
The observed exposures with Daytrana could not be explained by drug accumulation predicted from observed single dose pharmacokinetics and there was no evidence that clearance or rate of elimination changed between single and repeat dosing. Neither were they explainable by differences in dosing patterns between treatments, age, race, or gender. This suggests that transdermal absorption of methylphenidate may increase with repeat dosing with Daytrana; on average, steady-state is likely to have been achieved by approximately 14 days of dosing.
In the single- and multiple dose study described above, exposure to l-methylphenidate was 46% of the exposure to d-methylphenidate in children and 40% in adolescents. l-methylphenidate is less pharmacologically active than d-methylphenidate [see Pharmacodynamics].
In a phase 2 PK/PD study in children aged 6-12 years, 2/3 of patients had 2-hour d-MPH concentrations < 5 ng/mL on chronic dosing, and at 3 hours 40% of patients had d-MPH concentrations < 5 ng/mL [see Clinical Studies].
When Daytrana is applied to inflamed skin both the rate and extent of absorption are increased as compared with intact skin. When applied to inflamed skin, lag time is no greater than 1 hour, Tmax is 4 hours, and both Cmax and AUC are approximately 3-fold higher.
When heat is applied to Daytrana after patch application, both the rate and the extent of absorption are significantly increased. Median Tlag occurs 1 hour earlier, Tmax occurs 0.5 hours earlier, and median Cmax and AUC are 2-fold and 2.5-fold higher, respectively.
Application sites other than the hip can have different absorption characteristics and have not been adequately studied in safety or efficacy studies.
Following a single 9-hour application of Daytrana patch doses of 10 mg / 9 hours to 30 mg / 9 hours patches to 34 children with ADHD, Cmax and AUC0-t of d-methylphenidate were proportional to the patch dose. Mean plasma concentration-time plots are shown in Figure 1. Cmax of l-methylphenidate was also proportional to the patch dose. AUCo-t of /-methylphenidate was only slightly greater than proportional to patch dose.
FIGURE 1: Mean
Concentration-time Profiles for d-Methylphenidate in all Patients (N=34)
Following Administration of Single Applications (9-Hour Wear Time) of d,l-Methylphenidate
Using Daytrana 10 mg (♦), 20 mg
(◊) and 30 mg (Δ) per 9-Hour Patches
Upon removal of Daytrana, methylphenidate plasma concentrations in children with ADHD decline in a biexponential manner. This may be due to continued distribution of MPH from the skin after patch removal.
Metabolism and Excretion
Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity.
Transdermal administration of methylphenidate exhibits much less first pass effect than oral administration. Consequently, a much lower dose of Daytrana on a mg/kg basis compared to oral dosages may still produce higher exposures of d-MPH with transdermal administration compared to oral administration. In addition, very little, if any, /-methylphenidate is systemically available after oral administration due to first pass metabolism, whereas after transdermal administration of racemic methylphenidate exposure to /-methylphenidate is nearly as high as to d-methylphenidate.
The mean elimination t½ from plasma of d-methylphenidate after removal of Daytrana in children aged 6 to 12 years and adolescents aged 13-17 years was approximately 4 to 5 hours. The t½ of /-methylphenidate was shorter than for d-methylphenidate and ranged from 1.4 to 2.9 hours, on average.
The Cmax and AUC of d-methylphenidate were approximately 50% lower in adolescents, compared to children, following either a 1-day or 7-day administration of Daytrana (10mg/9 hr). Multiple-dose administration of Daytrana did not result in significant accumulation of methylphenidate; following 7 days of Daytrana administration (10 mg/ 9 hr) in children and adolescents, the accumulation index of methylphenidate was 1.1, based on the mean steady state area under the plasma concentration-time curve (AUCss) relative to that anticipated on the basis of single dose pharmacokinetics (AUC0-∞).
The pharmacokinetics or the pharmacodynamic food effect performance after application of Daytrana has not been studied, but because of the transdermal route of administration, no food effect is expected.
The pharmacokinetics of methylphenidate after single and repeated doses of Daytrana were similar between boys and girls with ADHD, after allowance for differences in body weight.
The influence of race on the pharmacokinetics of methylphenidate after administration of Daytrana has not been defined.
The pharmacokinetics of methylphenidate after administration of Daytrana have not been studied in children less than 6 years of age.
There is no experience with the use of Daytrana in patients with renal insufficiency.
There is no experience with the use of Daytrana in patients with hepatic insufficiency.
Daytrana was demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in two (2) randomized double-blind, placebo-controlled studies in children aged 6 to 12 years and one (1) randomized, double-blind, placebo-controlled study in adolescents aged 13 to 17 years who met Diagnostic and Statistical Manual (DSM-IV-TR®) criteria for ADHD. The patch wear time was 9 hours in all three (3) studies.
In Study 1, conducted in a classroom setting, symptoms of ADHD were evaluated by school teachers and observers using the Deportment Subscale from the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale which assesses behavior symptoms in the classroom setting. Daytrana was applied for 9 hours before removal. There was a 5-week open-label Daytrana dose optimization phase using dosages of 10, 15, 20, and 30 mg / 9 hours, followed by a 2-week randomized, double-blind, placebo-controlled crossover treatment phase using the optimal patch dose for each patient or placebo. The mean differences between Daytrana and placebo in change from baseline in SKAMP Deportment Scores were statistically significant in favor of Daytrana beginning at 2 hours and remained statistically significant at all subsequent measured time points through 12 hours after application of the Daytrana patch.
In Study 2, conducted in the outpatient setting, Daytrana or placebo was blindly administered in a flexible-dose design using doses of 10, 15, 20, and 30 mg / 9 hours to achieve an optimal regimen over 5 weeks, followed by a 2-week maintenance period using the optimal patch dose for each patient. Symptoms of ADHD were evaluated by the ADHD-Rating Scale (RS)-IV. Daytrana was statistically significantly superior to placebo as measured by the mean change from baseline for the ADHD-RS-IV total score. Although this study was not designed specifically to evaluate dose response, in general there did not appear to be any additional effectiveness accomplished by increasing the patch dose from 20 mg / 9 hours to 30 mg / 9 hours.
In Study 3, conducted in the outpatient setting, Daytrana or placebo was blindly administered in a flexible-dose design using doses of 10, 15, 20, and 30 mg / 9 hours during a 5-week dose-optimization phase, followed by a 2-week maintenance period using the optimal patch dose for each patient. Symptoms of ADHD were evaluated using the ADHD-Rating Scale (RS)-IV. Daytrana was statistically significantly superior to placebo as measured by the mean change from baseline in the ADHD-RS-IV total score.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association 1994.
Last reviewed on RxList: 5/1/2015
This monograph has been modified to include the generic and brand name in many instances.
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