Methylphenidate

Methylphenidate Transdermal System (methylphenidate transdermal system) is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 17 years of age. Limitations of Use The use of Methylphenidate Transdermal System is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions ( 5.8 ), Use in Specific Populations ( 8.4 )] . Methylphenidate Transdermal System is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 17 years of age. ( 1 ) Limitations of Use The use of Methylphenidate Transdermal System is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage ( 5.8 , 8.4 ).

Four dosage strengths are available: *Nominal in vivo delivery rate in children and adolescents when applied to the hip, based on a 9-hour wear period. Nominal Dose Delivered (mg) Over 9 Hours* Dosage Rate* (mg/hr) Transdermal System Size (cm 2 ) Methylphenidate Content per Transdermal System (mg) 10 1.1 12.5 27.5 15 1.6 18.75 41.3 20 2.2 25 55 30 3.3 37.5 82.5 ​Transdermal system: 10mg/9 hours (1.1 mg/hr), 15mg/9 hours (1.6 mg/hr), 20mg/9 hours (2.2 mg/hr), 30mg/9 hours (3.3 mg/hr) ( 3 )

Known hypersensitivity to methylphenidate ( 4.1 ) Patients currently using or within 2 weeks of using an MAO inhibitor ( 4.2 )

4.1 Hypersensitivity to Methylphenidate Methylphenidate Transdermal System is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product (polyester/ethylene vinyl acetate laminate film backing, acrylic adhesive, silicone adhesive, and fluoropolymer-coated polyester) [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).

Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. ( 5.2 ) Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. ( 5.3 ) Psychiatric Adverse Reactions: Prior to initiating Methylphenidate Transdermal System, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing Methylphenidate Transdermal System. ( 5.4 ) Seizures: Stimulants may lower the convulsive threshold. Discontinue in the presence of seizures. ( 5.5 ) Priapism: If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention. ( 5.6 ) Peripheral Vasculopathy, including Raynaud’s phenomenon: Careful observation for digital changes is necessary during Methylphenidate Transdermal System treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. ( 5.7 ) Long-Term Suppression of Growth in Pediatric Patients: Closely monitor (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. ( 5.8 ) 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. Monitor for signs of skin depigmentation. Discontinue Methylphenidate Transdermal System if it occurs. ( 5.9 ) Contact Sensitization: Use of Methylphenidate Transdermal System may lead to contact sensitization. Treatment 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. ( 5.10 ) External Heat: Patients should be advised to avoid exposing the Methylphenidate Transdermal System application site to direct external heat sources. When heat is applied to Methylphenidate Transdermal System after application, both the rate and extent of absorption are significantly increased. ( 5.11 ) Hematologic monitoring: Periodic CBC, differential, and platelet counts are advised during prolonged therapy. ( 5.12 ) Acute Angle Closure Glaucoma: 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. ( 5.13 ) Increased Intraocular Pressure (IOP) and Glaucoma: 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 patients with a history of increased IOP or open angle glaucoma. ( 5.14 ) Motor and Verbal Tics and Worsening of Tourette’s Syndrome: Before initiating Methylphenidate Transdermal System, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate. ( 5.15 )

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 Transdermal System 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: 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 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 Exacerbation of Pre-Existing Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disease CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating Methylphenidate Transdermal System treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms CNS stimulants, at the recommended dosages, may cause psychotic or manic symptoms, (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients compared with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing Methylphenidate Transdermal System.

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. […]

Detailed information on serious and adverse reactions of particular importance is provided in the Boxed Warning and Warnings and Precautions ( 5 ) sections: Abuse, Misuse, and Addiction [see Boxed Warning ] Hypersensitivity to Methylphenidate [see Contraindications ( 4.1 )] Monoamine Oxidase Inhibitors [see Contraindications ( 4.2 ) and Drug Interactions ( 7.1 )] Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions ( 5.2 )] Increased Blood Pressure and Heart Rate [see Warnings and Precautions ( 5.3 )] Psychiatric Adverse Reactions [see Warnings and Precautions ( 5.4 )] Seizures [see Warnings and Precautions ( 5.5 )] Priapism [see Warnings and Precautions ( 5.6 )] Peripheral Vasculopathy [see Warnings and Precautions ( 5.7 )] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions ( 5.8 )] Chemical Leukoderma [see Warnings and Precautions ( 5.9 )] Contact Sensitization [see Warnings and Precautions ( 5.10 )] External Heat [see Warnings and Precautions ( 5.11 )] Hematologic Monitoring [see Warnings and Precautions ( 5.12 )] Acute Angle Closure Glaucoma [see Warnings and Precautions ( 5.13 )] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions ( 5.14 )] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions ( 5.15 )] Pediatric patients (ages 6 to 12 years): The most commonly (≥5% and twice the rate of placebo) reported adverse reactions in pediatric patients ages 6 to 12 years included appetite decreased, insomnia, nausea, vomiting, weight decreased, tic, affect lability, and anorexia. ( 6.1 ) Pediatric patients (ages 13 to 17 years): The most commonly (≥5% and twice the rate of placebo) reported adverse reactions in pediatric patients ages 13 to 17 years included appetite decreased, nausea, insomnia, weight decreased, dizziness, abdominal pain, and anorexia. The majority of subjects in these trials had erythema at the application site. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Padagis at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 transdermal system sizes of 12.5 cm 2 , 18.75 cm 2 , 25 cm 2 or 37.5 cm 2 , 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. Adverse Reactions in Clinical Studies with Discontinuation of Treatment In a 7-week double-blind, parallel-group, placebo-controlled study in children with ADHD conducted in the outpatient setting, 7.1% (7/98) of patients treated with Methylphenidate Transdermal System discontinued due to adverse events compared with 1.2% (1/85) receiving placebo. The most commonly reported (≥ 1% and twice the rate of placebo) adverse reactions leading to discontinuation in the Methylphenidate Transdermal System group were application site reaction (2%), tics (1%), headache (1%), and irritability (1%). In a 7-week double-blind, parallel-group, placebo-controlled study in adolescents with ADHD conducted in the outpatient setting, 5.5% (8/145) of patients treated with Methylphenidate Transdermal System discontinued due to adverse reactions compared with 2.8% (2/72) receiving placebo. The most commonly reported adverse reactions leading to discontinuation in the Methylphenidate Transdermal System group were application site reaction (2%) and decreased appetite/anorexia (1.4%). Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Trials Skin Irritation and Application Site Reactions Methylphenidate Transdermal System is a dermal irritant. In addition to the most commonly reported adverse reactions presented in Table 2, the majority of subjects in those studies had minimal to definite skin erythema at the Methylphenidate Transdermal System application site. This erythema generally caused no or minimal discomfort and did not usually interfere with therapy or result in discontinuation from treatment. Erythema is not by itself a manifestation of contact 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 [see Warnings and Precautions ( 5.10 )] . Most Commonly Reported Adverse Reactions Table 2 lists treatment-emergent adverse reactions reported in ≥ 1% Methylphenidate Transdermal System -treated children or adolescents with ADHD in two 7 week double-blind, parallel-group, placebo-controlled studies conducted in the outpatient setting. Overall, in these studies, 75.5% of children and 78.6% of adolescents experienced at least 1 adverse event. […]

Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. ( 7.2 )

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 Transdermal System 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 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including Methylphenidate Transdermal System, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visit https://womensmentalhealth.org/adhd-medications/. Risk Summary Published studies and post-marketing reports on methylphenidate use during pregnancy are insufficient to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the fetus associated with the use of CNS stimulants during pregnancy (see Clinical Considerations ). No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis. However, spina bifida was observed in rabbits when given oral doses of 200 mg/kg/day. When methylphenidate was administered orally to rats throughout pregnancy and lactation, offspring growth and survival were decreased at maternally toxic doses (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinical recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions CNS stimulants, such as Methylphenidate Transdermal System, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data Animal reproduction toxicity studies with transdermal methylphenidate have not been performed. In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally to pregnant animals during the period of organogenesis, at doses up to 100 and 200 mg/kg/day, respectively. No evidence of morphological development effects was found either of the species; however, increased incidences of fetal skeletal variations were observed in rats at 60 mg/kg or greater and an increase in fetal visceral variations was seen in rabbits at the highest dose. In a previous study, methylphenidate was shown to have malformations (increased incidence of fetal spina bifida) in rabbits when given oral doses of 200 mg/kg/day. When methylphenidate was administered orally to rats throughout pregnancy and lactation at doses of up to 60 mg/kg/day, offspring growth and survival were decreased at maternally toxic doses. In a study in which oral methylphenidate was given to rats throughout pregnancy and lactation at doses up to 60 mg/kg/day, offspring weights and survival were decreased at 40 mg/kg/day and above; these doses caused some maternal toxicity.

8.2 Lactation Risk Summary Limited published literature, based on breast milk sampling from five mothers, reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Methylphenidate Transdermal System and any potential adverse effects on the breastfed infant from Methylphenidate Transdermal System or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

8.4 Pediatric Use The safety and effectiveness of Methylphenidate Transdermal System have not been established in pediatric patients below the age of 6 years. In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss. The safety and effectiveness of Methylphenidate Transdermal System for the treatment of ADHD have been established in pediatric patients 6 to 17 years. Long Term Suppression of Growth Growth should be monitored during treatment with stimulants, including Methylphenidate Transdermal System. Children who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.8 )] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. Studies with transdermal methylphenidate have not been performed in juvenile animals. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose. The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day. The clinical significance of the long-term behavioral effects observed in rats is unknown.

8.5 Geriatric Use Methylphenidate Transdermal System has not been studied in patients greater than 65 years of age.

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