Pharmacodynamics

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.

Pharmacokinetics

The pharmacokinetics of Daytrana™ (methylphenidate transdermal) when applied to the hip for 9 hours have been studied in ADHD patients 6 to 12 years old.

Absorption

When Daytrana™ (methylphenidate transdermal) was titrated to effect in the pivotal phase III clinical efficacy study, after at least 6 weeks of therapy with 9 hour wear times when applied to alternating hips, the mean peak d-methylphenidate (d-MPH) plasma concentration was 39 ng/mL with a range of 0 – 114 ng/mL. These mean peak concentrations varied inversely by age ranging from 25 ng/mL, (range 2 – 80 ng/mL) in 12 year olds, to 53 ng/mL (range 18 – 83 ng/mL) in 6 year olds.

Daytrana™ (methylphenidate transdermal) mean peak d-MPH concentrations were approximately 1.9-fold higher than the highest observed concentrations after a once-daily oral methylphenidate formulation over a period of 7.5 to 10.5 hours, when Tmax typically occurs. These higher concentrations were observed for all children 6 – 12 years of age, both overall and when grouped by age. The Daytrana™ (methylphenidate transdermal) peak concentrations on chronic dosing were also higher than Cmaxs seen with Daytrana™ (methylphenidate transdermal) after single dosing, or 4 days of multiple dosing. With single doses of Daytrana™ (methylphenidate transdermal) , peak concentrations were comparable to Cmaxs from single doses of the once daily oral MPH formulation.

The observed exposures with Daytrana™ (methylphenidate transdermal) 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 chronic therapy with the methylphenidate transdermal system.

On multiple dosing of the transdermal system, exposure to l-methylphenidate was 27% to 45% lower, on average, than exposures to d-methylphenidate. For comparison, little if any l– methylphenidate was detectable after administration of a once daily oral MPH formulation. l-methylphenidate is less pharmacologically active than d-methylphenidate.

The average lag time (i.e., the time until any d-MPH is detectable in the circulation) was 3.1 hours, (range 1- 6 hours) with Daytrana™ (methylphenidate transdermal) in the single dose study. In the phase II PK/PD study, 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 -Study 1).

When Daytrana™ (methylphenidate transdermal) 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™ (methylphenidate transdermal) after patch application, both the rate and the extent of absorption are significantly increased. Median Tlag occurs 1 hour earlier and 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.

Dose Proportionality

Following a single 9-hour application of Daytrana™ (methylphenidate transdermal) patch doses of 10 mg / 9 hour to 30 mg / 9 hour 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. AUC_0-t of l-methylphenidate was only slightly greater than proportional to patch dose.

Distribution

Upon removal of Daytrana™ (methylphenidate transdermal) , 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™ (methylphenidate transdermal) 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, l-methylphenidate is systemically available after oral administration due to first pass metabolism, whereas after transdermal administration of racemic methylphenidate exposure to l-methylphenidate is nearly as high as to d-methylphenidate.

The mean elimination t1/2 from plasma of d-methylphenidate after removal of Daytrana™ (methylphenidate transdermal) in children aged 6 to 12 years was approximately 3 to 4 hours. The t1/2 of l-methylphenidate was shorter than for d-methylphenidate and ranged from 1.4 to 2.9 hours, on average.

Food Effects

The pharmacokinetics or the pharmacodynamic food effect performance after application of Daytrana™ (methylphenidate transdermal) has not been studied, but because of the transdermal route of administration, no food effect is expected.

Adhesion

In a study of 20 mg / 9 hour (25 cm²) transdermal systems > 95% of patches were greater than 90% adhered, and the remainder were 75% - 90% adhered. No patients discontinued therapy during clinical trials due to adhesion failure.

In the event a patch does not fully adhere to the skin upon application, or is partially or fully detached during wear time, the patch should be discarded according to the directions provided in this label (see DOSAGE AND ADMINISTRATION -- Disposal of Daytrana™ (methylphenidate transdermal) ), and a new patch should be applied. If a patch is replaced, the total recommended wear time for that day should remain 9 hours. (see DOSAGE AND ADMINISTRATION – Application).

Patches should not be applied or re-applied with dressings, tape, or other common adhesives.

Special Populations

Gender

The pharmacokinetics of methylphenidate after single and repeated doses of Daytrana™ (methylphenidate transdermal) were similar between boys and girls with ADHD, after allowance for differences in body weight.

Race

The influence of race on the pharmacokinetics of methylphenidate after administration of Daytrana™ (methylphenidate transdermal) has not been defined.

Age

The pharmacokinetics of methylphenidate after administration of Daytrana™ (methylphenidate transdermal) have not been studied in children less than 6 years of age.

Renal Insufficiency

There is no experience with the use of Daytrana™ (methylphenidate transdermal) in patients with renal insufficiency.

Hepatic Insufficiency

There is no experience with the use of Daytrana™ (methylphenidate transdermal) in patients with hepatic insufficiency.

Clinical Studies

Daytrana™ (methylphenidate transdermal) 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 old who met Diagnostic and Statistical Manual (DSMIV-TR®) criteria for ADHD. The patch wear time was 9 hours in both 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™ (methylphenidate transdermal) was applied for 9 hours before removal. There was a 5-week open-label Daytrana™ (methylphenidate transdermal) 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™ (methylphenidate transdermal) and placebo in change from baseline in SKAMP Deportment Scores were statistically significant in favor of Daytrana™ (methylphenidate transdermal) beginning at 2 hours and remained statistically significant at all subsequent measured time points through 12 hours after application of the Daytrana™ (methylphenidate transdermal) patch.

In Study 2, conducted in the outpatient setting, Daytrana™ (methylphenidate transdermal) 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™ (methylphenidate transdermal) 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.

Last reviewed on RxList: 1/5/2010
This monograph has been modified to include the generic and brand name in many instances.