Methylphenidate transdermal system for the treatment of attention ...

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DRUG EVALUATION

Methylphenidate transdermal system for the treatment of attention-deficit/hyperactivity disorder Thomas Rugino Children’s Specialized Hospital, 94 Stevens Road, Toms River, NJ 08755, USA Tel.: +1 732 797 3826; Fax: +1 732 797 3830; [email protected]

Keywords: ADHD, Daytrana®, methylphenidate transdermal system, stimulants part of

The methylphenidate transdermal system (MTS) is the only nonoral medication approved by the US FDA for treating the symptoms of attention-deficit/hyperactivity disorder (ADHD). MTS patches deliver methylphenidate through the skin directly into the bloodstream, largely circumventing the first-pass metabolism of the GI tract and liver that occurs with orally administered methylphenidate. Clinical studies in school-aged children have shown MTS to be well tolerated and effective in the treatment of ADHD. Adverse effects most commonly seen in clinical studies are consistent with those seen with the use of other methylphenidate products and include decreased appetite, insomnia, headache, nausea, vomiting, anorexia and weight loss. When worn for the recommended 9 h, MTS demonstrated significant reductions in the core symptoms of ADHD from 2 through 12 h post-application.

The methylphenidate transdermal system (MTS, [Daytrana®], Shire US Inc., PA, USA) is a patch that delivers racemic methylphenidate (MPH) through the skin directly into the bloodstream. MTS was approved by the US FDA in 2006 for the treatment of attentiondeficit/hyperactivity disorder (ADHD) in children 6–12 years of age. The transdermal patch contains a multipolymeric adhesive matrix that serves to both hold the drug and adhere the patch to the skin. The MTS utilizes DOT Matrix™ technology (Noven Pharmaceuticals, FL, USA) to create an efficient, diffusion-based patch that provides reproducible blood levels of medication. Racemic MPH is solubilized in acrylic in very high concentrations and mixed with a pressure-sensitive adhesive to form evenly-dispersed, concentrated pockets of drug. The concentration gradient results in highly efficient diffusion of the drug out of the adhesive layer and into the stratum corneum. The precise content ratios of the drug/adhesive layer control the rate of drug delivery. It should be noted that diffusion of MPH from the patch into the skin is dependant upon the concentration gradient (i.e., from a higher concentration in the patch into a lower concentration in the skin). Because of this, the MPH content in the patch is far greater than what is delivered into the skin when used as directed. MTS is available in patch sizes corresponding to 10-, 15-, 20-and 30-mg doses when worn for 9 h (Table 1). The efficacy, safety and duration of action of MTS have been established in clinical studies of school-aged children.

10.2217/14796708.2.6.613 © 2007 Future Medicine Ltd ISSN 1479-6708

Mechanism of action

Racemic MPH is composed of equal parts d- and l-threo enantiomers; d-MPH is thought to be the more pharmacologically active enantiomer [1,2]. MPH is a CNS stimulant and is thought to affect the major catecholamines (dopamine and norepinephrine) by blocking reuptake of these neurotransmitters into presynaptic neurons, thereby increasing their concentration in the extraneuronal space [3]. Although the exact mechanism(s) are unknown, this increased neurotransmitter availability is thought to be responsible for the cognitive and behavioral improvements seen in individuals with ADHD [3,4]. Pharmacokinetics & metabolism

Although extensively absorbed in the GI tract, the absolute bioavailability of orally administered MPH is low and variable, with a mean of 28–31% in children [5]. This low oral bioavailability is the result of extensive and enantioselective first-pass metabolism, with the l-isomer being eliminated faster than the d-isomer. MPH is primarily metabolized through de-esterification to the inactive metabolite ritalinic acid and urinary elimination of ritalinic acid accounts for approximately 80% of the dose [6]. CES1A1 is a human isoenzyme that has been found to be expressed in the following relative abundance: liver >> stomach > colon [7]. While analyzing the metabolic activity of several human carboxylesterases on dl-MPH, Sun et al. found that the catalytic efficiency of the isoenzyme CES1A1 is much greater for hydrolysis of l-MPH than for d-MPH [8]. The authors concluded that CES1A1 is the major enzyme responsible for Future Neurol. (2007) 2(6), 613–620

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DRUG EVALUATION – Rugino

Table 1. MTS sizes and delivery of methylphenidate. MPH dose delivered over 9 h* (mg)

Dosage rate (mg/h)*

Patch size cm2

MPH content per patch (mg)

10

1.1

12.5

27.5 41.3

15

1.6

18.75

20

2.2

25

55

30

3.3

37.5

82.5

*Nominal in vivo delivery rate in pediatric subjects 6 to 12 years of age when applied to the hip, based on 9-h wear time. These are the MTS doses available by prescription [10]. MPH: Methylphenidate; MTS: Methylphenidate transdermal system.

the first-pass stereoselective metabolism of dlMPH [8]. When dl-MPH is orally administered, the plasma concentrations of the l-isomer are negligible within a short time period. However, via the transdermal route, dl-MPH largely circumvents first-pass metabolism and plasma concentrations of d-MPH are consistent with those produced by oral formulations, whereas the concentrations of l-MPH are higher than that seen with oral administration (∼50–60% of the d-isomer) [2]. The multidose pharmacokinetics of MTS have been determined in a randomized, doubleblind, placebo-controlled, crossover trial conducted in a laboratory classroom setting that followed a 5-week, open-label, dose-optimization lead-in phase [9]. Patches were worn for 9 h each day. Pharmacokinetic measures were obtained from 74 pediatric subjects 6–12 years of age. The percentage of subjects on each MTS patch dosage after optimization were 9.5% (seven out of 74) on the MTS 10 mg, 43.2% (32 out of 74) on the MTS 15 mg, 36.5% (27 out of 74) on the MTS 20 mg and 10.8% (eight out of 74) on the MTS 30 mg. On the laboratory classroom day, prior to application of the patch at each individual optimized dose of 10, 15, 20 or 30 mg, the residual plasma concentrations (mean ± standard deviation) of d-MPH remaining from application on the previous day were 0.79 ± 0.23, 1.5 ± 1.05, 1.71 ± 1.71 and 3.65 ± 4.40 ng/ml, respectively, indicating that there is minimal accumulation of MPH at steady state. The mean percentage of d- and l-MPH delivered over the 9-h dosing period was generally similar across all four dosages and ranged from 38 to 45% of the total MPH dose contained within the patch: the mean apparent dose delivered via the patch comprised equal proportions of both d- and l-MPH. Following application of the MTS on the laboratory classroom day, d- and l-MPH were steadily absorbed into the systemic 614

Future Neurol. (2007) 2(6)

circulation with maximum plasma concentrations occurring at a median Tmax of 7.1–8.8 h for d-MPH and 7.1–7.3 h for l-MPH. Following removal of the patch after 9 h of wear, plasma concentrations of d- and l-MPH appeared to decline in a generally monophasic manner (Figure 1). The mean l-MPH terminal elimination half-life values were between 1.2 and 1.8 h. Although the elimination halflife values of d-MPH were unable to be calculated, mean plasma concentrations of d-MPH at 12 h after patch application (3 h after patch removal) were approximately 41–59% of Cmax – indicative of an elimination half-life of approximately 3 h. Also consistent with an approximate 3-h elimination half-life, plasma concentrations at 15 h after removal of the preceding day’s MTS patch ranged from 4.0–7.8% of Cmax [9]. This is consistent with elimination rates previously reported for orally administered MPH [1]. The AUC0–12h and Cmax for d- and l-MPH increased in a generally dose-proportional manner over the entire range of doses. Application to inflamed skin is reported to increase both the rate and extent of absorption. Cmax and AUC may be increased by approximately threefold compared with normal values and Tmax is decreased to 4 h. Similarly, application of direct heat such as heating pads, electric blankets and so on. to the MTS patch while applied may increase MPH release from the patch more than twofold [10]. It is essential to understand that the dosing of MTS is based on average absorption over a 9-h wear time when applied to the hip in children 6–12 years of age. The dosage of oral preparations is based on the mass of MPH in the tablet or capsule. As described above, much of an oral dose is lost to first-pass metabolism. Thus, a 10-mg dose of MTS delivers a greater amount of MPH into the system than a 10-mg dose of oral MPH. future science group

Methylphenidate transdermal system – DRUG

Figure 1. Mean plasma concentration of d- and l-MPH in pediatric patients treated with MTS. MTS 10 mg MTS 15 mg

Mean d-MPH plasma concentration, ng/ml

A 50

40

30

20

10

0

0

1

2

3

4 5 6 7 8 9 10 11 Time post-dose (h) Patch removed

12

0

1

2

3

4 5 6 7 8 9 10 11 Time post-dose (h) Patch removed

12

B Mean l-MPH plasma concentration, ng/ml

MTS 20 mg MTS 30 mg

50

40

30

20

10

0

(A) Mean plasma concentration of d-MPH. Lower limit of quantification (0.25 ng/ml). (B) Mean plasma concentration of l-MPH. Lower limit of quantification (0.25 ng/ml). MPH: Methylphenidate; MTS: Methylphenidate transdermal system. Adapted from [9].

Clinical efficacy

The efficacy of MTS for the treatment of ADHD in children aged 6 to 12 years has been evaluated in several randomized, double-blind, placebocontrolled [11–14] and open-label studies [15,16]. All studies were conducted in children 6–12 years of age and patches of 10, 15, 20 or 30 mg were worn for 9 h each day unless otherwise specified. Key efficacy results are described below. McGough and colleagues evaluated the efficacy and time course of MTS in a rigorous laboratory classroom study [11]. Study participants were initiated on MTS 10 mg and titrated in an open-label fashion to their individual optimized future science group

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EVALUATION

dose (up to 30 mg) over 5 weeks using a 9-h patch wear time. Following dose optimization, 80 participants were randomized in a doubleblind fashion to receive MTS or placebo for 1 week and then crossed over to the opposite treatment for the following week. At the end of each randomized treatment week, the children participated in a laboratory classroom day designed to assess the time-response of medication (details of which have previously been described [17]). MTS was shown to be significantly superior to placebo in measures of classroom behavior and math test performance. Efficacy was evident at the first time-point measured 2 h after application. When patches were removed after 9 h of wear, the MTS treatment group continued to show significant improvement on measures of behavior through to the last assessment time at 12 h (p < 0.01; Figure 2) [11]. This study demonstrated that when MTS is removed after 9 h of wear, clinical effects have still been observed 3 h after patch removal. In a similar laboratory classroom study, Wilens and colleagues assessed the variable wear times of 4 and 6 h [14]. Participants were dose optimized over a 5-week period and wore MTS for 9 h each day of the 8-week trial except for three laboratory classroom days that occurred on one day of each of the last three study weeks. Participants were randomly crossed over to each of three treatments on the laboratory classroom days: MTS 4 h, MTS 6 h or placebo. Although significantly better than placebo at all post-dose time points (2, 4, 6, 8 and 10 h; p < 0.0001), within 2 h of patch removal, mean measures of both behavior and math test performance progressively approached predose (baseline) levels for both the 4- and 6-h MTS wear times. This study demonstrated that, even with shorter weartimes, clinical efficacy may be apparent for several hours after the patch is removed, allowing clinicians to individualize treatment through both dose and wear time. A large, randomized clinical trial was conducted in a naturalistic setting with efficacy assessed by clinicians [12], parents and teachers [13]. The intent-to-treat population included 270 boys and girls (mean age: 9 years) randomized to MTS, osmotic-release MPH or placebo. Assigned treatments were dose-optimized over 5 weeks followed by a 2-week dose-maintenance period. Clinician-rated efficacy, measured by the change from baseline to study end point on the ADHD-Rating Scale-IV (ADHD-RS-IV) total score, showed significant 615


clinicians on the Clinical Global ImpressionsImprovement scale (p < 0.0001) and by parents on the Parent Global Assessment scale (p < 0.0001) [15].

Mean SKAMP-deportment score

Figure 2. Mean SKAMP rating scale scores. 10 9 8 7 6 5 4 3 2 1 0

Safety & tolerability

MTS 1

2

3

Placebo

4 5 6 7 8 Time post-dose (h)

9

10 11 12

Patch removed

Deportment subscale scores by time point during a laboratory classroom study of MTS with a 9-h wear time. Intent-to-treat population: n = 79. p < 0.01 at all time points for MTS compared with placebo using ANOVA. Note: a lower score indicates improvement. MTS: Methylphenidate transdermal system; SKAMP: Swanson, Kotkin, Agler, M-Flynn and Pelham. Adapted from [11].

improvements in ADHD symptoms for both active treatment groups versus placebo (p < 0.0001) [12]. Significant improvements from baseline to end point were also observed for both active treatment groups versus placebo in teacher ratings (by the Conners’ Teacher Rating Scale-Revised total score; p < 0.0001) and parent ratings (by the Conners’ Parent Rating Scale-Revised total score; p < 0.05) [13]. Additionally, the long-term efficacy of MTS in pediatric patients with ADHD has been demonstrated in a 12-month, open-label safety and efficacy study [15]. Patients that participated in previous MTS trials were eligible for enrollment. Those patients entering from previous studies already receiving optimized doses of MTS continued on their same dose for the length of the study. Those patients who were not currently receiving optimized doses of MTS upon entering this trial underwent a titration and dose-optimization period for the first month of the study. Dose adjustments were allowed throughout the study as deemed necessary by the investigator at each study site. A total of 327 patients were enrolled, of which 326 received study medication and 157 completed the entire 12 months of the study. At end point, there was a significant improvement in the mean ADHD-RS-IV total score compared with baseline (p < 0.0001). In addition, compared with ratings from the first week of the study, significantly more subjects were rated as very much improved or much improved at end point by 616


Adverse events were assessed and recorded at each study visit. Treatment with MTS patches was generally well tolerated in the children participating in the clinical trials previously discussed and the majority of (98–99%) treatmentemergent adverse events reported were mild-tomoderate in intensity [11,13–15]. In the first laboratory classroom study, many of the treatmentemergent adverse events were transient and typically resolved with repeated dosing. The majority occurred during the dose-optimization phase and included decreased appetite, anorexia, headache, insomnia and upper abdominal pain [11]. In the variable wear time laboratory classroom study [14], the most common treatment-emergent adverse events were decreased appetite, headache, insomnia and upper abdominal pain. Because patients utilized a wear time of 9 h for all but the three laboratory classroom days during this 8-week trial, the effects of shorter wear times on the incidence of adverse events could not be assessed. In the 7-week, short-term, naturalistic study, the most common treatment-emergent adverse events (occurring in ≥5% and two-times placebo) in patients receiving MTS were decreased appetite, insomnia, nausea, vomiting, decreased weight, tic, affect lability, nasal congestion, anorexia and nasopharyngitis [12,13]. In the long-term study, the most commonly reported treatment-emergent adverse events over the course of the study are summarized in Table 2 [15]. Reasons for discontinuation from the trial included: withdrawl of consent (n = 40), lost to follow-up (n = 36), adverse events (n = 29), application-site reaction (n = 22), protocol violation (n = 9), prohibited medication required (n=1), and reasons listed as ‘other’ (n = 33). One patient who was officially terminated from the study because of a protocol violation (pre-existing seizure disorder; included in the n = 9 above) also experienced an adverse event of syncope, leading to discontinuation of the study drug (this is not included in the n = 29 adverse events above). The results suggest that the general safety profile of long-term MTS treatment, using a flexible dosing regimen (10–30 mg/9-h wear time), is consistent with other studies using oral methylphenidate treatment [18–20]. future science group


EVALUATION

Table 2. Most commonly reported treatment-emergent adverse events (≥ 5% of subjects) during treatment with MTS in a 12-month study. Adverse event

Subjects (%) Treatment duration (weeks)

Treatment duration (months)

1

2

3

4

3

6

9

12 (n = 159)

(n = 325)

(n = 283)

(n = 281)

(n = 274)

(n = 269)

(n = 215)

(n = 181)

Decreased appetite

24.6

26.1

26

26.3

27.1

25.6

23.2

21.4

Headache

16.6

16.6

16.7

17.2

17.8

18.6

18.2

17.6 18.2

URTI

12.3

12.4

12.5

12.8

14.9

17.7

17.1

Cough

11.7

12

12.1

12

12.6

14.4

16

17

Pyrexia

10.2

9.5

9.6

9.9

11.5

11.6

13.3

13.2

Decreased weight

10.2

11

10.7

10.9

11.5

12.1

12.7

12.6

Insomnia

8.9

9.9

9.6

9.5

9.3

8.8

7.7

6.3 7.5

Abdominal pain (upper)

8

9.2

9.3

9.1

7.4

8.4

8.3

Nasopharyngitis

7.4

6.7

6.8

6.6

8.2

8.8

9.4

9.4

Vomiting

7.1

7.4

7.5

7.7

7.8

7.4

8.8

9.4

Nausea

6.2

6.7

6.8

6.9

7.1

7.4

6.1

5.7

Irritability

6.2

7.1

7.1

7.3

7.1

6.5

6.1

5.7

Pharyngolaryngeal pain

5.8

6.4

6.4

6.6

6.3

6.0

6.6

6.3

Nasal congestion

5.5

6.0

6.0

6.2

6.3

6.5

7.7

8.8

Percentages are based on the number of subjects remaining in the study at the time. MTS: Methylphenidate transdermal system; URTI: Upper respiratory tract infection. Adapted from [15].

Slight transient erythema (pinkness at the patch site) or itching was common during clinical trials and should be expected with transdermal system use. Because transdermal patches have the potential to cause skin irritation, this was specifically assessed during MTS clinical trials. In the first laboratory classroom study [11], the majority of patients reported no evidence or minimal evidence of irritation and no discomfort or mild discomfort at patch application sites. In the variable wear time laboratory classroom study, one patient discontinued the study because of severe pruritus at the patch site at week 7 of the trial [14]. In the naturalistic study, the majority of patients experienced either no irritation or mild erythema with continued patch use throughout the study and for those who reported skin discomfort, the majority (74%) reported the discomfort as itching [21]. In the long-term study spanning 12 months, most skin responses consisted of mild erythema (Figure 3). There were, however, some patients who experienced erythema, edema and papules (n = 15), vesicular eruption (n = 4) and strong reaction spreading beyond the patch site (n = 2). Of those who experienced the strongest reaction, one discontinued treatment after approximately 1 month of future science group


treatment and the other completed the study without a dose reduction [15]. Although no cases of contact sensitization were reported in clinical trials, skin sensitization may occur with the use of MTS. If contact sensitization develops, patients may have systemic sensitization or other systemic reactions if MPH agents are administered by any route. Erythema is commonly seen with MTS use and the reaction alone is not indicative of sensitization. If erythema is accompanied by evidence of a more intense local reaction (edema, papules or vesicles) that does not significantly improve within 48 h or spreads beyond the application site, sensitization may be suspected and should be corroborated by appropriate diagnostic testing. Close medical supervision is necessary if a patient with contact sensitization to MTS is subsequently administered oral MPH [10]. Dosing & administration

MTS should be administered once daily and applied to the hip area approximately 2 h before an effect is needed. The skin should be clean, dry and not oily, damaged or irritated. The patch should be placed on the alternate hip each day, preferably in a different spot than the previous application. Caregivers should avoid application 617


Figure 3. Skin response scores during methylphenidate transdermal system treatment over 12 months. 70 60

Incidence (%)

50 40 30 20 10 0 W1

W2 W3 Week

W4

M3

M6

M8 Month

M12

Time Score = 0 Score = 1

Score = 2 Score = 3

Score = 4 Score = 5

Score = 6 Score = 7

Dermal response scale scores range from 0 to 7, where 0 = no evidence of irritation, 1 = minimal erythema, 2 = definite erythema, 3 = erythema and papules, 4 = definite edema, 5 = erythema, edema and papules, 6 = vesicular eruption and 7 = strong reaction beyond site. Adapted from [15].

to the child’s waistline or where tight clothing may rub it and interfere with adhesion. Since MTS has a pressure sensitive adhesive, it is important for caregivers to press the entire patch firmly into place for about 30 s after application. No patients discontinued therapy during clinical trials because of adhesion failure of the patch. Application sites other than the hip can have different absorption characteristics and have not been adequately studied in efficacy or safety studies [10]. It is recommended that the MTS patch should be worn for 9 h after it is applied, although the effects may last for several more hours. If late-day side effects such as insomnia or appetite loss are troublesome, removing the patch earlier than the recommended 9 h may be tried before reducing the dose/patch size [10]. Used or unneeded patches should be folded and discarded in a lidded container or flushed down the toilet. If any adhesive remains on the skin after removal of the patch, this residue may be removed by gently rubbing the area with lotion or oil; abrasion of the skin to remove residual adhesive should be avoided. Dose titration, final dosage and usage time of MTS should be individualized according to the needs of each patient. It is recommended that all patients start with the lowest patch size (10 mg) 618


and titrate upwards as needed. The utility of a dose transition chart has been studied in converting patients from oral long-acting MPH formulations to MTS [16]. The dose transition was successful for the majority of patients over the 5-week trial. However, 38% of patients in that trial were titrated to a higher dose and 4% required a lower dose than they were administered at the onset. It is important to note that there may be dramatic differences in the bioavailability of transdermal MPH compared with other products and some patients may require a much lower dose of MTS compared with previous doses of oral MPH. Conclusion

MTS is the first and only nonoral medication available for the treatment of ADHD. Transdermal technology offers novel features and flexibility but also introduces possible challenges with skin effects associated with the patch. As with any medication, the benefits must be weighed against the risks, and therapy should be tailored based on the needs of the patient. Clinical studies have demonstrated the efficacy and safety of MTS in pediatric patients and MTS offers an efficacious option to individualize ADHD treatment. future science group


Future perspective

Recently approved by the US FDA, the prodrug stimulant lisdexamfetamine dimesylate (LDX) is a new molecular entity which, after oral ingestion, is converted to l-lysine, a naturally occurring essential amino acid, and active d-amphetamine, which is responsible for the drug’s activity. A oncedaily, triple-bead formulation of mixed amphetamine salts may soon be available and is expected to offer a longer duration of action than the currently available two-bead formulation. Atomoxetine is the only nonstimulant medication currently FDA approved for the treatment of ADHD. However, a once-daily extended-release Executive summary • The methylphenidate transdermal system (MTS) is a diffusion-based patch that delivers dl-MPH through the skin via a concentration gradient. • The onset of action of MTS can be expected by 2 h post-application (the first time point assessed in clinical trials). When worn for the recommended 9 h in clinical trials, efficacy was still evident at 12 h post-application. • MTS allows for both titration of dose and variability in time of wear (up to 9 hs), allowing for flexibility in day-to-day use. • Adverse events occurring in clinical trials of MTS were mostly (98–99%) mild to moderate in severity. • Skin reactions with MTS use were generally reported as mild erythema and mild discomfort described as itching.

Bibliography Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers. 1. Patrick KS, Markowitz JS: Pharmacology of methylphenidate, amphetamine enantiomers and pemoline in attentiondeficit hyperactivity disorder. Hum. Psychopharmacol. Clin. Exp. 12, 527–546 (1997). 2. Heal DJ, Pierce DM: Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system. CNS Drugs 20(9), 713–738 (2006). •• Recent publication reviewing the pharmacokinetics and pharmacology of methylphenidate and its isomers, and their role in the efficacy and adverse effects in attention-deficit/hyperactivity disorder treatment. 3. Solanto MV: Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a

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formulation of the α-2a adrenoceptor agonist, guanfacine, is in late-stage development for the treatment of ADHD. Research is also emerging on the efficacy of nicotinic agonists for the treatment of ADHD. Access to both longer and more flexible durations of action along with improved tolerability to ADHD treatments should further help clinicians to tailor the medication regimen for individual patient needs. Acknowledgements The author would like to thank Shire Pharmaceuticals and Amy M Horton for providing clinical trial information and assistance in the preparation of this manuscript. Financial disclosure & competing interests Thomas Rugino, MD has participated as a medical consultant and has participated in speakers’ bureau programs for Cephalon, Inc. (PA, USA), Novartis Pharmaceuticals (UK), Shire Pharmaceuticals (PA, USA) and UCB Pharma (NY, USA). He has also participated as a medical consultant for Lexicor Medical Technology LLC (FL, USA). Children’s Specialized Hospital has received research grant funding from Cephalon, Inc, Novartis Pharmaceuticals, Shire Pharmaceuticals, UCB Pharma, Sanofi-Aventis and BristolMyers Squibb Pharmaceutical Research Institute, Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Affiliation • Thomas Rugino, MD Children's Specialized Hospital, 94 Stevens Road, Toms River, NJ 08755, USA Tel.: +1 732 797 3826; Fax: +1 732 797 3830; [email protected]

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