New Treatment Options for Attention-Deficit/Hyperactivity Disorder (ADHD): Part I. Transdermal Methylphenidate and Lisdexamfetamine

Marcia L. Buck, PharmD, FCCP; Kristi N. Hofer, PharmD; Michelle W. McCarthy, PharmD

Disclosures

Pediatr Pharm. 2008;14(3) 

In This Article

Transdermal Methylphenidate

On April 6, 2006, the FDA approved the first methylphenidate transdermal system (MTS) for the management of ADHD in children 6 to 12 years of age. The patch contains methylphenidate dispersed in a multi-polymeric adhesive and is designed to provide consistent drug absorption over a 9-hour period. Unlike oral once-daily products, the duration of effect can be adjusted with the MTS patch by changing the duration of time worn. This may provide the opportunity for better individualization of treatment and greater day to day flexibility based on patient needs. In addition, the MTS patch may be of benefit in children unable to swallow tablets or capsules.[1,2,3,4]

Clinical Studies in Children

In 2005, Pelham and colleagues reported the results of a multicenter, double-blind, randomized dose-ranging study of the MTS patch in 36 children with ADHD between 7 and 12 years of age.[5] Patients received either a placebo or a 6.25 cm2, 12.5 cm2, or 25 cm2 MTS patch each day, in random order. All patches were worn for a 12-hour period. Trained counselors documented behavior using daily report cards. The authors found significant dose-related improvement in ability to follow rules and fewer episodes of noncompliance, interruption, complaining, conduct problems, and negative verbalizations for both the 12.5 cm2 and 25 cm2 patches. All measures except complaining and conduct problems were significantly improved in the 6.25 cm2 group. The manufacturer subsequently decided not to pursue marketing of the 6.25 cm2 patch.

The efficacy and safety of the MTS patch were assessed in a 2006 randomized, double-blind, placebo-controlled study conducted in a controlled laboratory classroom setting.[6] A total of 93 children between 6 and 12 years of age were randomized to receive MTS or placebo patches over a 5 week dose-titration. The patient sample was 72% male and consisted of 13 children (17%) with inattentiveness, 4 (5%) with hyperactivity/impulsivity, and 62 (79%) with combined ADHD symptoms.

Children receiving the MTS patch performed significantly better on the Swanson, Kotkin Agler, M-Flynn, and Pelham (SKAMP) Teacher Ratings Scale and the Permanent Product Measure of Performance (PERMP) Derived Measures scores completed by the investigators from 2 to 12 hours after patch application, with a 9-hour wear-time. The least squares mean for the SKAMP-Deportment scores for the MTS group showed greater improvement than the placebo patch group, with significantly lower scores (3.2+0.58 compared to 8.0+0.58, p<0.0001). The least squares mean for the SKAMP-Attention scores showed similar improvement: 6.2+0.50 for the MTS group, compared to 9.9+0.50 for the controls (p<0.0001). Scores on the ADHD-Rating Scale-IV (ADHD-RS-IV) and the Conners' Parent Rating Scale-Revised Short Version, as well as the Clinical Global Impression (CGI) and Parent Global Assessment scales, demonstrated similar statistically significant differences compared to the placebo group.

Pharmacokinetics

In a pharmacokinetic study conducted by the manufacturer in children 6-12 years of age, the average peak serum concentration after 9 hours of MTS application was 39 ng/mL (range 0-114 ng/mL). Peak concentrations were inversely correlated to age, with an average of 25 ng/mL in 12 year olds and 53 ng/mL in 6 year olds. Methylphenidate undergoes hepatic metabolism to inactive byproducts, with an average elimination half-life of 3 to 4 hours.[2]

Drug Interactions

Methylphenidate should not be administered with monoamine oxidase inhibitors. Administration of methylphenidate may decrease the metabolism of warfarin, phenobarbital, phenytoin, and many antidepressants. Dosage adjustment may be necessary in patients requiring these drugs. Patients receiving concomitant alpha-2 agonists (clonidine or guanfacine) should be closely monitored for additive cardiovascular effects.[1,2]

Contraindications/Precautions

In clinical trials, the MTS patch has been well tolerated. McGough and colleagues found no significant differences in adverse event reporting between the MTS and placebo patch groups.[6] As with other methylphenidate preparations, the MTS patch is contraindicated in patients with glaucoma, marked anxiety, hypertension or other pre-existing cardiovascular conditions. It should be used with caution in patients with tics or Tourette syndrome.[2,3]

Adverse Effects

The adverse effect profile of the MTS patch is similar to that of oral methylphenidate. In clinical trials, the most commonly reported adverse effects were: decreased appetite (26%), insomnia (13%), nausea (12%), vomiting (10%), decreased weight (9%), tics (7%), nasal congestion (6%) affect lability (6%), nasopharyngitis (5%), and anorexia (5%).[2]

Patients receiving methylphenidate should be regularly assessed for changes in mood, sleep patterns, heart rate or blood pressure, as well as growth parameters.[1,2] In 2007, Farone and Giefer studied the effects of the MTS patch on growth in 127 children between 6 and 12 years of age.[7] Patients were followed for up to 3 years. Use of the patch was associated with small, but statistically significant, delays in growth (height, weight, and body mass index) compared to age-matched norms. The effects on weight and body mass index were directly related to the dose. As in previous studies with other methylphenidate preparations, the effects were most evident during the first year of treatment and became less pronounced by the end of the study.

Erythema is common at the site of patch placement and typically does not require patch removal or discontinuation of treatment. If accompanied by edema, papules, or vesicles, it may be a sign of contact sensitization. In a study conducted by the manufacturer, prolonged exposure at a single application site resulted in contact sensitization in adults. Severe dermatologic reactions appear to be rare, but have been reported.[1,2]

Dosing Recommendations

The recommended method for dose titration consists of initiating therapy with the 10 mg (12.5 cm2 or 1.1 mg/h) patch. If needed, the dose may be increased at weekly intervals, using the larger patch sizes: 15 (18.75 cm2 or 1.65 mg/h), 20 mg (25 cm2 or 2.2 mg/h), and 30 mg (37.5 cm2 or 3.3 mg/h). Recommendations for converting patients from oral methylphenidate to the MTS patch are still under development. Arnold and colleagues have suggested that a 10 mg (12.5 cm2) patch will provide a similar response to 5 mg oral methylphenidate given 3 times daily or 18 mg of the methylphenidate osmotic release product (Concerta®), due to the lack of the first-pass effect with the transdermal route.[4] At this time, however, the manufacturer still recommends that patients being converted from oral methylphenidate to the patch begin the titration with the lowest patch size, due to the differences in transdermal drug absorption.[2]

The MTS patch should be applied 2 hours before optimal symptom control is needed and removed 9 hours after application. Symptom control typically lasts for 2 to 3 hours after removal. The patch should be applied to a clean, dry spot on the hip. Application on the arm or leg may result in greater variation in drug absorption. The site should be rotated daily and inspected each day after patch removal. The patch should not be applied to inflamed skin. Any residual adhesive may be removed with a cotton ball dipped in vegetable or mineral oil, avoiding vigorous rubbing. Once removed, the patch may be folded onto itself and flushed down the toilet.[2,3]

The patch may be worn when bathing or swimming. Use of any heat source, such as a heating pad or blanket, at the patch site should be avoided. Heat increases the extent of drug absorption. Redness or itching at the site is common, but parents should be instructed to contact their health care provider if swelling or blistering occurs. [2,3]

Availability and Cost

The MTS patch (Daytrana™; Shire) is available in 10, 15, 20, and 30 mg sizes as described previously.[2,3] The average wholesale price for a box of 30 patches, any size, is currently $143.28.[8] At this price, the patch is approximately the same monthly expense as the once-daily oral products.

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