2.1 Pretreatment Screening

Prior to treating patients with methylphenidate transdermal system, assess:

•

for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)].

•

the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating methylphenidate transdermal system [see Warnings and Precautions (5.15)].

2.2 Recommended Dosage

It is recommended that methylphenidate transdermal system be applied to the hip area 2 hours before an effect is needed and should be removed 9 hours after application. Dosage should be titrated to effect. The recommended dose titration schedule is shown in the table below. Dose titration, final dosage, and wear time should be individualized according to the needs and response of the patient.

Patients converting from another formulation of methylphenidate should follow the above titration schedule due to differences in bioavailability of methylphenidate transdermal system compared to other products.

2.3 Application

The parent or caregiver should be encouraged to use the administration chart included with each carton of methylphenidate transdermal system to monitor application and removal time, and method of disposal. It is recommended that parents or caregivers apply and remove the transdermal system for children; responsible adolescents may apply or remove the transdermal system themselves if appropriate. If a transdermal system was removed without the parent or caregiver's knowledge, or if a transdermal system is missing from the carton or pouch, the parent or caregiver should be encouraged to ask the child when and how the transdermal system was removed. The Medication Guide includes a timetable to calculate when to remove methylphenidate transdermal system, based on the 9-hour application time.

The adhesive side of methylphenidate transdermal system should be placed on a clean, dry area of the hip. The area selected should not be oily, damaged, or irritated. Apply methylphenidate transdermal system to the hip area avoiding the waistline, since clothing may cause the transdermal system to rub off. When applying the transdermal system the next morning, place on the opposite hip at a new site if possible.

If patients or caregivers experience difficulty separating the transdermal system from the release liner or observe transfer of adhesive to the liner, tearing and/or other damage to the transdermal system during removal from the liner, the transdermal system should be discarded and a new transdermal system should be applied. Patients or caregivers should inspect the release liner to ensure that no adhesive containing medication has transferred to the liner. If adhesive transfer has occurred, the transdermal system should be discarded. Refer to the Instructions for Use for recommendations for discarding used methylphenidate transdermal systems.

Methylphenidate transdermal system should be applied immediately after opening the individual pouch and removing the protective liner. Do not use if the individual pouch seal is broken or if the transdermal system appears to be damaged. Do not cut transdermal systems. Only intact transdermal systems should be applied. The transdermal system should then be pressed firmly in place with the palm of the hand for approximately 30 seconds, making sure that there is good contact of the transdermal system with the skin, especially around the edges. Exposure to water during bathing, swimming, or showering can affect transdermal system adherence. Methylphenidate transdermal systems should not be applied or re-applied with dressings, tape, or other common adhesives. In the event that a transdermal system does not fully adhere to the skin upon application, or becomes partially or fully detached during wear time, the transdermal system should be discarded and a new transdermal system may be applied at a different site. The total recommended wear time for that day should remain 9 hours regardless of the number of transdermal systems used.

All patients should be advised to avoid exposing the methylphenidate transdermal system application site to direct external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds, etc., while wearing the transdermal system [see Warnings and Precautions (5.10)]. When heat is applied to methylphenidate transdermal system after transdermal system application, both the rate and the extent of absorption are significantly increased. The temperature-dependent increase in methylphenidate absorption can be greater than 2-fold [see Clinical Pharmacology (12.3)]. This increased absorption can be clinically significant and result in overdose of methylphenidate [see Overdosage (10)].

Methylphenidate transdermal systems should not be stored in refrigerators or freezers.

2.4 Removal of Methylphenidate Transdermal System

Methylphenidate transdermal systems should be peeled off slowly. If necessary, transdermal system removal may be facilitated by gently applying an oil-based product (i.e., petroleum jelly, olive oil, or mineral oil) to the transdermal system edges, gently working the oil underneath the transdermal system edges. If any adhesive remains on the skin following transdermal system removal, an oil-based product may be applied to transdermal system sites in an effort to gently loosen and remove any residual adhesive that remains following transdermal system removal.

In the unlikely event that a transdermal system remains tightly adhered despite these measures, the patient or caregiver should contact the physician or pharmacist. Nonmedical adhesive removers and acetone-based products (i.e., nail polish remover) should not be used to remove methylphenidate transdermal systems or adhesive.

2.5 Dose/Wear Time Reduction and Discontinuation

Methylphenidate transdermal system may be removed earlier than 9 hours if a shorter duration of effect is desired or late day side effects appear. Plasma concentrations of d-methylphenidate generally begin declining when the transdermal system is removed, although absorption may continue for several hours. Individualization of wear time may help manage some of the side effects caused by methylphenidate. If aggravation of symptoms or other adverse events occur, the dosage or wear time should be reduced, or, if necessary, the drug should be discontinued. Residual methylphenidate remains in used transdermal systems when worn as recommended.

4.1 Hypersensitivity to Methylphenidate

Methylphenidate transdermal system is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product (fluoropolymer-coated polyester, hydrophobic colloidal silica, mineral oil, polyester/ethylene vinyl acetate laminate film backing, polyisobutylene adhesive and white ink). The white ink contains acrylic polymers, polyethylene wax, polytetrafluoroethylene, polyvinylpyrrolidone, sodium dioctyl sulfosuccinate and titanium dioxide [see Description (11)].

4.2 Monoamine Oxidase Inhibitors

Methylphenidate transdermal system is contraindicated during treatment with monoamine oxidase inhibitors, and within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result).

5.1 Abuse, Misuse, and Addiction

Methylphenidate transdermal system has a high potential for abuse and misuse. The use of methylphenidate transdermal system exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methylphenidate can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2)]. Misuse and abuse of CNS stimulants, including methylphenidate transdermal system, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing methylphenidate transdermal system, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their caregivers or families about these risks. Advise patients to store methylphenidate transdermal system in a safe place, preferably locked, and instruct patients to not give methylphenidate transdermal system to anyone else. Throughout methylphenidate transdermal system treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

Methylphenidate transdermal system has special disposal instructions. Instruct patients to find a take back location to dispose of unused or expired methylphenidate transdermal system. If a take back program is unavailable, instruct them to:

1.

Remove methylphenidate transdermal system from its pouch, separate it from its liner, fold it in half with the adhesive sides touching each other, and immediately flush the used transdermal system down the toilet, and

2.

Place the pouch and liner in a container, close the container, and throw out the container in the trash (advise patients not to flush the pouch and liner down the toilet).

5.2 Risks to Patients with Serious Cardiac Disease

Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage.

Avoid methylphenidate transdermal system use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

5.3 Increased Blood Pressure and Heart Rate

CNS stimulants may cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may have larger increases.

Monitor all methylphenidate transdermal system-treated patients for hypertension and tachycardia.

5.4 Psychiatric Adverse Reactions

5.5 Seizures

There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued.

5.6 Priapism

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on the methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation).

Methylphenidate transdermal system-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

5.7 Peripheral Vasculopathy, including Raynaud’s phenomenon

Stimulant medications, including methylphenidate transdermal system, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports and at therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant.

Careful observation for digital changes is necessary during methylphenidate transdermal system treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate transdermal system-treated patients who develop signs or symptoms of peripheral vasculopathy.

5.8 Long-Term Suppression of Growth in Pediatric Patients

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period.

Closely monitor growth (weight and height) in methylphenidate transdermal system-treated pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted.

5.9 Chemical Leukoderma

Methylphenidate transdermal system use may result in a persistent loss of skin pigmentation at and around the application site. Loss of pigmentation, in some cases, has been reported at other sites distant from the application site. Chemical leukoderma can mimic the appearance of vitiligo, particularly when the loss of skin pigmentation involves areas distant from the application site. Individuals with a history of vitiligo and/or a family history of vitiligo may be more at risk. Skin depigmentation may persist even after methylphenidate transdermal system use is discontinued. Monitor for signs of skin depigmentation, and advise patients to immediately inform their healthcare provider if changes in skin pigmentation occur. Discontinue use of the methylphenidate transdermal system in patients with chemical leukoderma.

5.10 Contact Sensitization

In an open-label study of 305 subjects conducted to characterize dermal reactions in children with ADHD treated with methylphenidate transdermal system using a 9-hour wear time, one subject (0.3%) was confirmed by transdermal system testing to be sensitized to methylphenidate (allergic contact dermatitis). This subject experienced erythema and edema at methylphenidate transdermal system application sites with concurrent urticarial lesions on the abdomen and legs resulting in treatment discontinuation. This subject was not transitioned to oral methylphenidate.

Use of methylphenidate transdermal system may lead to contact sensitization. Methylphenidate transdermal system should be discontinued if contact sensitization is suspected. Erythema is commonly seen with use of methylphenidate transdermal system and is not by itself an indication of sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the transdermal system site. Confirmation of a diagnosis of contact sensitization (allergic contact dermatitis) may require further diagnostic testing.

Patients sensitized from use of methylphenidate transdermal system, as evidenced by development of an allergic contact dermatitis, may develop systemic sensitization or other systemic reactions if methylphenidate-containing products are taken via other routes, e.g., orally. Manifestations of systemic sensitization may include a flare-up of previous dermatitis or of prior positive transdermal system-test sites, or generalized skin eruptions in previously unaffected skin. Other systemic reactions may include headache, fever, malaise, arthralgia, diarrhea, or vomiting. No cases of systemic sensitization have been observed in clinical trials of methylphenidate transdermal system.

Patients who develop contact sensitization to methylphenidate transdermal system and require oral treatment with methylphenidate should be initiated on oral medication under close medical supervision. It is possible that some patients sensitized to methylphenidate by exposure to methylphenidate transdermal system may not be able to take methylphenidate in any form.

5.11 Patients Using External Heat

Patients should be advised to avoid exposing the methylphenidate transdermal system application site to direct external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds, etc., while wearing the transdermal system. When heat is applied to methylphenidate transdermal system after application, both the rate and extent of absorption are significantly increased. The temperature-dependent increase in methylphenidate absorption can be greater than 2-fold [see Clinical Pharmacology (12.3)]. This increased absorption can be clinically significant and can result in overdose of methylphenidate [see Overdosage (10)].

5.12 Hematologic Monitoring

Periodic CBC, differential, and platelet counts are advised during prolonged therapy.

5.13 Acute Angle Closure Glaucoma

There have been reports of angle closure glaucoma associated with methylphenidate treatment.

Although the mechanism is not clear, methylphenidate transdermal system-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.

5.14 Increased Intraocular Pressure and Glaucoma

There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2)].

Prescribe methylphenidate transdermal system to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate transdermal system -treated patients with a history of abnormally increased IOP or open angle glaucoma.

5.15 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome

CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions (6.2)].

Before initiating methylphenidate transdermal system, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate transdermal system -treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most commonly reported (frequency ≥ 5% and twice the rate of placebo) adverse reactions in a controlled trial in children aged 6-12 included appetite decreased, insomnia, nausea, vomiting, weight decreased, tic, affect lability, and anorexia. The most commonly reported (frequency ≥ 5% and twice the rate of placebo) adverse reactions in a controlled trial in adolescents aged 13-17 were appetite decreased, nausea, insomnia, weight decreased, dizziness, abdominal pain, and anorexia [see Adverse Reactions (6.1)].

The most common (≥ 2% of subjects) adverse reaction associated with discontinuations in double-blind clinical trials in children or adolescents was application site reactions [see Adverse Reactions (6.1)].

The overall methylphenidate transdermal system development program included exposure to methylphenidate transdermal system in a total of 2,152 participants in clinical trials, including 1,529 children aged 6-12, 223 adolescents aged 13-17, and 400 adults. The 1,752 child and adolescent subjects aged 6-17 years were evaluated in 10 controlled clinical studies, 7 open-label clinical studies, and 5 clinical pharmacology studies. In a combined studies pool of children using methylphenidate transdermal system with a wear time of 9 hours, 212 subjects were exposed for ≥ 6 months and 115 were exposed for ≥ 1 year; 85 adolescents were exposed for ≥ 6 months. Most patients studied were exposed to methylphenidate transdermal system sizes of 12.5 cm2, 18.75 cm2, 25 cm2, or 37.5 cm2, with a wear time of 9 hours.

In the data presented below, the adverse reactions reported during exposure were obtained primarily by general inquiry at each visit, and were recorded by the clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of events into a smaller number of standardized event categories.

6.2 Postmarketing Experience

In addition, the following adverse reactions have been identified during the post-approval use of methylphenidate transdermal system. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to methylphenidate transdermal system exposure.

Cardiac Disorders: palpitations.

Eye Disorders: visual disturbances, blurred vision, increased intraocular pressure, mydriasis, and accommodation disorder.

General Disorders and Administration Site Disorders: fatigue, application site reactions such as bleeding, bruising, burn, burning, dermatitis, discharge, discoloration, discomfort, dryness, eczema, edema, erosion, erythema, excoriation, exfoliation, fissure, hyperpigmentation, hypopigmentation, induration, infection, inflammation, irritation, pain, papules, paresthesia, pruritus, rash, scab, swelling, ulcer, urticaria, vesicles, and warmth.

Immune System Disorders: hypersensitivity reactions including generalized erythematous and urticarial rashes, allergic contact dermatitis, angioedema, and anaphylaxis.

Investigations: blood pressure increased.

Nervous System Disorders: convulsion, dyskinesia, lethargy, somnolence, serotonin syndrome in combination with serotonergic drugs, and extrapyramidal disorder, motor and verbal tics.

Psychiatric Disorders: depression, hallucination, nervousness, and libido changes.

Skin and Subcutaneous Tissue Disorders: alopecia.

Adverse Reactions with Oral Methylphenidate Products: Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed below may also occur.

Other reactions include:

Cardiac Disorders: angina, arrhythmia, and pulse increased or decreased.

Immune System Disorders: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura.

Metabolism and Nutrition Disorders: anorexia and weight loss during prolonged therapy.

Nervous System Disorders: drowsiness, rare reports of Tourette’s syndrome and toxic psychosis.

Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause.

Vascular Disorders: blood pressure increased or decreased and cerebral arteritis and/or occlusion.

Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate:

Blood and Lymphatic System Disorders: leukopenia and/or anemia.

Hepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury.

Psychiatric Disorders: transient depressed mood.

Skin and Subcutaneous Tissue Disorders: scalp hair loss.

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis.

7.1 Monoamine Oxidase Inhibitors (MAOI)

Concomitant use of MAOIs and CNS stimulants, including methylphenidate transdermal system, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications (4.2)]. Concomitant use of methylphenidate transdermal system with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated.

7.2 Antihypertensive Drugs

Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed [see Warnings and Precautions (5.2)].

7.3 Coumarin Anticoagulants, Antidepressants, and Selective Serotonin Reuptake Inhibitors

Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and some tricyclic drugs (e.g., imipramine, clomipramine, desipramine) and selective serotonin reuptake inhibitors. Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing methylphenidate.

7.4 Halogenated Anesthetics

Concomitant use of halogenated anesthetics and methylphenidate may increase the risk of sudden blood pressure and heart rate increase during surgery. Avoid use of methylphenidate transdermal system in patients being treated with anesthetics on the day of surgery.

7.5 Risperidone

Combined use of methylphenidate with risperidone when there is a change in dosage, whether an increase or decrease, of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of methylphenidate transdermal system in pediatric patients less than 6 years have not been established. Long-term effects of methylphenidate in children have not been well established.

The safety and effectiveness of methylphenidate transdermal system for the treatment of ADHD have been established in pediatric patients 6 to 17 years.

8.5 Geriatric Use

Methylphenidate transdermal system has not been studied in patients greater than 65 years of age.

9.1 Controlled Substance

Methylphenidate transdermal system contains methylphenidate, a Schedule II controlled substance.

9.2 Abuse

Methylphenidate transdermal system has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1)]. Methylphenidate transdermal system can be diverted for non-medical use into illicit channels or distribution.

Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including methylphenidate transdermal system, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

9.3 Dependence

12.1 Mechanism of Action

Methylphenidate is a CNS stimulant. Its mode of therapeutic action in ADHD is not known.

12.2 Pharmacodynamics

Methylphenidate is a racemic mixture comprised of the d- and l-enantiomers. The d-enantiomer is more pharmacologically active than the l-enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.

12.3 Pharmacokinetics

The pharmacokinetics of methylphenidate transdermal system when applied to the hip for 9 hours have been studied in ADHD patients 6 to 17 years old.

Absorption

The amount of methylphenidate absorbed systemically is a function of both wear time and transdermal system size. In patients with ADHD, peak plasma levels of methylphenidate are reached at about 10 hours after single application and 8 hours after repeat transdermal system applications (12.5 cm2 to 37.5 cm2) when worn up to 9 hours.

On single dosing of children or adolescents with methylphenidate transdermal system, there was a delay of, on average, 2 hours before d-methylphenidate was detectable in the circulation. On repeat dosing, low concentrations (1.2-3.0 ng/mL in children and 0.5-1.7 ng/mL in adolescents, on average across the dose range) were observed earlier in the profile, due to carry-over effect. Following the application of methylphenidate transdermal system 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.

Following administration of methylphenidate transdermal system 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 methylphenidate transdermal system 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 methylphenidate transdermal system; 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 (12.2)].

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 (14)].

When methylphenidate transdermal system 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 methylphenidate transdermal system after 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.

Dose Proportionality

Following a single 9-hour application of methylphenidate transdermal system doses of 10 mg/9 hours to 30 mg/9 hours transdermal systems to 34 children with ADHD, Cmax and AUC0-t of d-methylphenidate were proportional to the transdermal system dose. Mean plasma concentration-time plots are shown in Figure 1. Cmax of l-methylphenidate was also proportional to the transdermal system dose. AUC0-t of l-methylphenidate was only slightly greater than proportional to transdermal system 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 Methylphenidate Transdermal System 10 mg (□), 20 mg (◊) and 30 mg (Δ) per 9-Hour Transdermal System

 

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility