DailyMed Label: Daytrana

DailyMed Label: Daytrana

2024

DailyMed Prescription

Daytrana

methylphenidate

Noven Therapeutics, LLC

NDC: 68968-5552

NDC: 68968-5553

NDC: 68968-5554

NDC: 68968-5555

NDC: 68968-5552

NDC: 68968-5553

NDC: 68968-5554

NDC: 68968-5555

NDC: 68968-5552

NDC: 68968-5552

NDC: 68968-5553

NDC: 68968-5553

NDC: 68968-5554

NDC: 68968-5554

NDC: 68968-5555

NDC: 68968-5555

DAYTRANA is an adhesive-based matrix transdermal system containing methylphenidate that is applied to intact skin. The chemical name for methylphenidate is α-phenyl-2-piperidineacetic acid methyl ester. It is a white to off-white powder and is soluble in alcohol, ethyl acetate, and ether. Methylphenidate is practically insoluble in water and petrol ether. Its molecular weight is 233.31. Its empirical formula is C 14 H 19 NO 2 . The structural formula of methylphenidate is: Transdermal System Components DAYTRANA contains methylphenidate in a multipolymeric adhesive. The methylphenidate is dispersed in acrylic adhesive that is dispersed in a silicone adhesive. The composition per unit area of all dosage strengths is identical, and the total dose delivered is dependent on the transdermal system size and wear time. DAYTRANA consists of three layers, as seen in the figure below (cross-section of the transdermal system). Proceeding from the outer surface toward the surface adhering to the skin, the layers are (1) a polyester/ethylene vinyl acetate laminate film backing, (2) a proprietary adhesive formulation incorporating Noven Pharmaceuticals, Inc.'s DOT Matrix™ transdermal technology consisting of an acrylic adhesive, a silicone adhesive, and methylphenidate, and (3) a fluoropolymer-coated polyester protective liner, which is attached to the adhesive surface and must be removed before the transdermal system can be used. The active component of the transdermal system is methylphenidate. The remaining components are pharmacologically inactive. daytrana-structure daytrana-figure-cross-section

DAYTRANA (methylphenidate transdermal system) is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 17 years of age. DAYTRANA 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 )

The recommended starting dose for patients new to or converting from another formulation of methylphenidate is 10 mg. ( 2.2 ) DAYTRANA should be applied to the hip area (using alternating sites) 2 hours before an effect is needed and should be removed 9 hours after application. DAYTRANA may be removed earlier than 9 hours if a shorter duration of effect is desired or late day side effects appear. ( 2.2 , 2.3 ) Dosage should be titrated to effect. Dose titration, final dosage, and wear time should be individualized according to the needs and response of the patient. ( 2.2 ) Prior to treating patients with DAYTRANA, 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 DAYTRANA [see Warnings and Precautions ( 5.15 )] . It is recommended that DAYTRANA 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. *Nominal in vivo delivery rate in children and adolescents when applied to the hip, based on a 9-hour wear period. Table 1      DAYTRANA - Recommended Titration Schedule (Patients New to Methylphenidate) Upward Titration, if Response is Not Maximized Week 1 Week 2 Week 3 Week 4 Transdermal System Size 12.5 cm 2 18.75 cm 2 25 cm 2 37.5 cm 2 Nominal Delivered Dose* (mg/9 hours) 10 mg 15 mg 20 mg 30 mg Delivery Rate* (1.1 mg/hr)* (1.6 mg/hr)* (2.2 mg/hr)* (3.3 mg/hr)* Patients converting from another formulation of methylphenidate should follow the above titration schedule due to differences in bioavailability of DAYTRANA compared to other products. The parent or caregiver should be encouraged to use the administration chart included with each carton of DAYTRANA 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 tray, 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 DAYTRANA, based on the 9-hour application time. The adhesive side of DAYTRANA should be placed on a clean, dry area of the hip. The area selected should not be oily, damaged, or irritated. Apply DAYTRANA 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 DAYTRANA. DAYTRANA 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. DAYTRANA 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 DAYTRANA 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 DAYTRANA 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 )] . DAYTRANA should not be stored in refrigerators or freezers. DAYTRANA 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 DAYTRANA or adhesive. DAYTRANA 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.

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 ) DAYTRANA 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 )] . DAYTRANA 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 DAYTRANA, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing DAYTRANA. ( 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 DAYTRANA 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: DAYTRANA 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 DAYTRANA if it occurs. ( 5.9 ) Contact Sensitization: Use of DAYTRANA may lead to contact sensitization. Treatment should be discontinued if contact sensitization is suspected. Erythema is commonly seen with use of DAYTRANA 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 DAYTRANA application site to direct external heat sources. When heat is applied to DAYTRANA 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: DAYTRANA-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 DAYTRANA 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 DAYTRANA, 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 ) DAYTRANA has a high potential for abuse and misuse. The use of DAYTRANA exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. DAYTRANA 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 DAYTRANA, 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 DAYTRANA, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their caregivers or families about these risks. Advise patients to store DAYTRANA in a safe place, preferably locked, and instruct patients to not give DAYTRANA to anyone else. Throughout DAYTRANA treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. DAYTRANA has special disposal instructions. Instruct patients to find a take back location to dispose of unused or expired DAYTRANA. If a take back program is unavailable, instruct them to: Remove DAYTRANA 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). 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 DAYTRANA use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. 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 DAYTRANA-treated patients for hypertension and tachycardia. 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 DAYTRANA 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 DAYTRANA. 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. 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). DAYTRANA-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. Stimulant medications, including DAYTRANA, 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 DAYTRANA treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for DAYTRANA-treated patients who develop signs or symptoms of peripheral vasculopathy. 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 DAYTRANA-treated pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. DAYTRANA 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 DAYTRANA 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 DAYTRANA in patients with chemical leukoderma. In an open-label study of 305 subjects conducted to characterize dermal reactions in children with ADHD treated with DAYTRANA using a 9-hour wear time, one subject (0.3%) was confirmed by patch testing to be sensitized to methylphenidate (allergic contact dermatitis). This subject experienced erythema and edema at DAYTRANA 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 DAYTRANA may lead to contact sensitization. DAYTRANA should be discontinued if contact sensitization is suspected. Erythema is commonly seen with use of DAYTRANA 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 DAYTRANA, 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 patch-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 DAYTRANA. Patients who develop contact sensitization to DAYTRANA 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 DAYTRANA may not be able to take methylphenidate in any form. Patients should be advised to avoid exposing the DAYTRANA 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 DAYTRANA 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 )] . Periodic CBC, differential, and platelet counts are advised during prolonged therapy. There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, DAYTRANA-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions ( 6.2 )] . Prescribe DAYTRANA to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor DAYTRANA-treated patients with a history of abnormally increased IOP or open angle glaucoma. 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 DAYTRANA, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor DAYTRANA-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

Detailed information on serious and adverse reactions of particular importance is provided in the

Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. ( 7.2 ) Concomitant use of MAOIs and CNS stimulants, including DAYTRANA, 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 DAYTRANA with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. DAYTRANA 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 )] . 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. Concomitant use of halogenated anesthetics and methylphenidate may increase the risk of sudden blood pressure and heart rate increase during surgery. Avoid use of DAYTRANA in patients being treated with anesthetics on the day of surgery. 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.

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including DAYTRANA, 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 DAYTRANA, 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. 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 DAYTRANA and any potential adverse effects on the breastfed infant from DAYTRANA or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. The safety and effectiveness of DAYTRANA 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 DAYTRANA 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 DAYTRANA. 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. DAYTRANA has not been studied in patients greater than 65 years of age.

DAYTRANA is supplied in a sealed tray containing 30 individually pouched transdermal systems. See the chart below for information regarding available strengths. *Nominal in vivo delivery rate per hour in children and adolescents when applied to the hip, based on a 9-hour wear period. **Methylphenidate content in each transdermal system. Nominal Dose Delivered (mg) Over 9 Hours Dosage Rate* (mg/hr) Transdermal System Size (cm 2 ) Methylphenidate Content per Transdermal System** (mg) Transdermal Systems Per Carton NDC Number 10 1.1 12.5 27.5 30 68968-5552-3 15 1.6 18.75 41.3 30 68968-5553-3 20 2.2 25 55 30 68968-5554-3 30 3.3 37.5 82.5 30 68968-5555-3 Store at 25° C (77° F); excursions permitted to 15-30° C (59-86° F) [see USP Controlled Room Temperature]. Do not store transdermal systems unpouched. Do not store transdermal systems in refrigerators or freezers. Once the sealed tray is opened, use contents within 2 months. Apply the transdermal system immediately upon removal from the individual protective pouch. For transdermal use only. See the Patient Counseling Information ( 17 ) for specific disposal instructions for unused or expired DAYTRANA.

Methylphenidate is a CNS stimulant. Its mode of therapeutic action in ADHD is not known. 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. The pharmacokinetics of DAYTRANA 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 (12.5cm 2 to 37.5cm 2 ) when worn up to 9 hours. On single dosing of children or adolescents with DAYTRANA, 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 0.5-1.7ng/mL in adolescents, on average across the dose range) were observed earlier in the profile, due to carry-over effect. Following the application of DAYTRANA 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. 1 Dose maintained fixed for 28 days; 2 Dose escalated at 7 day intervals from 12.5 cm 2 through 18.75 cm 2 and 25 cm 2 to 37.5 cm 2 ; 3 Dose escalated at 7 day intervals from 18 mg through 27 mg and 36 mg to 54 mg; 4 Median (minimum - maximum); t lag = Last Sampling Time Prior to Time of First Quantifiable Plasma Concentration Table 3 Mean Plasma d-Methylphenidate Pharmacokinetic Parameters After Repeated 9-Hour Applications of DAYTRANA or Oral ER-MPH for up to 28 days to Pediatric ADHD Patients (Aged 6 - 17 years) Children Parameter DAYTRANA 1 12.5cm 2 (N=12) DAYTRANA 2 37.5cm 2 (N=10) Oral ER-MPH 3 18mg Oral ER-MPH 3 54mg C ssmax (ng/mL) 15.7 ± 9.39 42.9 ± 22.4 8.37 ± 4.14 26.1 ± 11.2 C ssmin (ng/mL) 1.04 ± 1.17 1.96 ± 1.73 0.708 ± 1.08 1.19 ± 1.54 AUC ss (ng·hr/mL) 163 ± 101 447 ± 230 97.7 ± 67.0 317 ± 160 t lag (h) 4 0 (0 - 2.0) 0 (0 - 1.0) 0 0 Adolescents C ssmax (ng/mL) 8.32 ± 4.60 16.5 ± 6.94 5.23 ± 1.72 18.0 ± 6.97 C ssmin (ng/mL) 0.544 ± 0.383 1.02 ± 0.629 0.360 ± 0.478 1.50 ± 0.937 AUC ss (ng·hr/mL) 85.7 ± 50.0 167 ± 66.0 59.7 ± 19.1 216 ± 80.8 t lag (h) 4 0 (0 - 2.0) 0 (0 - 2.0) 0 0 Following administration of DAYTRANA 12.5cm 2 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 (AUC ss ) relative to that anticipated on the basis of single dose pharmacokinetics (AUC0 -∞ ); after 28 days administration, these increments increased to 64% and 76%, respectively. C max 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 DAYTRANA 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 DAYTRANA; 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 DAYTRANA 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, T max is 4 hours, and both C max and AUC are approximately 3-fold higher. When heat is applied to DAYTRANA after application, both the rate and the extent of absorption are significantly increased. Median T lag occurs 1 hour earlier, T max occurs 0.5 hours earlier, and median C max and AUC are 2-fold and 2.5-fold higher, respectively. Application sites other than the hip can have different absorption characteristics and have not been adequately studied in safety or efficacy studies. Dose Proportionality Following a single 9-hour application of DAYTRANA doses of 10 mg / 9 hours to 30 mg / 9 hours transdermal systems to 34 children with ADHD, C max and AUC 0-t of d -methylphenidate were proportional to the transdermal system dose. Mean plasma concentration-time plots are shown in Figure 1. C max of l -methylphenidate was also proportional to the transdermal system dose. AUC 0-t of l -methylphenidate was only slightly greater than proportional to transdermal system dose. Distribution Upon removal of DAYTRANA, methylphenidate plasma concentrations in children with ADHD decline in a biexponential manner. This may be due to continued distribution of MPH from the skin after transdermal system removal. Metabolism and Excretion Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Transdermal administration of methylphenidate exhibits much less first pass effect than oral administration. Consequently, a much lower dose of DAYTRANA on a mg/kg basis compared to oral dosages may still produce higher exposures of d- MPH with transdermal administration compared to oral administration. In addition, very little, if any, l- methylphenidate is systemically available after oral administration due to first pass metabolism, whereas after transdermal administration of racemic methylphenidate exposure to l- methylphenidate is nearly as high as to d- methylphenidate. The mean elimination t 1/2 from plasma of d- methylphenidate after removal of DAYTRANA in children aged 6 to 12 years and adolescents aged 13-17 years was approximately 4 to 5 hours. The t 1/2 of l- methylphenidate was shorter than for d- methylphenidate and ranged from 1.4 to 2.9 hours, on average. The C max and AUC of d -methylphenidate were approximately 50% lower in adolescents, compared to children, following either a 1-day or 7-day administration of DAYTRANA (10mg/9hr). Multiple-dose administration of DAYTRANA did not result in significant accumulation of methylphenidate; following 7 days of DAYTRANA administration (10mg/9hr) in children and adolescents, the accumulation index of methylphenidate was 1.1, based on the mean steady state area under the plasma concentration-time curve (AUC ss ) relative to that anticipated on the basis of single dose pharmacokinetics (AUC 0-∞ ). Food Effects The pharmacokinetics or the pharmacodynamic food effect performance after application of DAYTRANA has not been studied, but because of the transdermal route of administration, no food effect is expected. Special Populations Gender The pharmacokinetics of methylphenidate after single and repeated doses of DAYTRANA were similar between boys and girls with ADHD, after allowance for differences in body weight. Race The influence of race on the pharmacokinetics of methylphenidate after administration of DAYTRANA has not been defined. Age The pharmacokinetics of methylphenidate after administration of DAYTRANA have not been studied in children less than 6 years of age. Renal Impairment There is no experience with the use of DAYTRANA in patients with renal insufficiency. Hepatic Impairment There is no experience with the use of DAYTRANA in patients with hepatic insufficiency. daytrana-03

Carcinogenesis Carcinogenicity studies of transdermal methylphenidate have not been performed. In a lifetime carcinogenicity study of oral methylphenidate carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown. Orally administered methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day. In a 24-week oral carcinogenicity study in the transgenic mouse strain p53 +/- , which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. In this study, male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese hamster ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day.

DAYTRANA was demonstrated to be effective in the treatment of ADHD in two (2) randomized double-blind, placebo-controlled studies in children aged 6 to 12 years and one (1) randomized, double-blind, placebo-controlled study in adolescents aged 13 to 17 years who met Diagnostic and Statistical Manual (DSM-IV-TR ® ) criteria for ADHD. DAYTRANA wear time was 9 hours in all three (3) studies. In Study 1, conducted in a classroom setting, symptoms of ADHD were evaluated by school teachers and observers using the Deportment Subscale from the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale which assesses behavior symptoms in the classroom setting. DAYTRANA was applied for 9 hours before removal. There was a 5-week open-label DAYTRANA dose optimization phase using dosages of 10, 15, 20, and 30 mg / 9 hours, followed by a 2-week randomized, double-blind, placebo-controlled crossover treatment phase using the optimal transdermal system dose for each patient or placebo. The mean differences between DAYTRANA and placebo in change from baseline in SKAMP Deportment Scores were statistically significant in favor of DAYTRANA beginning at 2 hours and remained statistically significant at all subsequent measured time points through 12 hours after application of DAYTRANA. In Study 2, conducted in the outpatient setting, DAYTRANA or placebo was blindly administered in a flexible-dose design using doses of 10, 15, 20, and 30 mg / 9 hours to achieve an optimal regimen over 5 weeks, followed by a 2-week maintenance period using the optimal transdermal system dose for each patient. Symptoms of ADHD were evaluated by the ADHD-Rating Scale (RS)-IV. DAYTRANA was statistically significantly superior to placebo as measured by the mean change from baseline for the ADHD-RS-IV total score. Although this study was not designed specifically to evaluate dose response, in general there did not appear to be any additional effectiveness accomplished by increasing the transdermal system dose from 20 mg / 9 hours to 30 mg / 9 hours. In Study 3, conducted in the outpatient setting, DAYTRANA or placebo was blindly administered in a flexible-dose design using doses of 10, 15, 20, and 30 mg / 9 hours during a 5-week dose-optimization phase, followed by a 2-week maintenance period using the optimal transdermal system dose for each patient. Symptoms of ADHD were evaluated using the ADHD-Rating Scale (RS)-IV. DAYTRANA was statistically significantly superior to placebo as measured by the mean change from baseline in the ADHD-RS-IV total score.

PRINCIPAL DISPLAY PANEL - NDC 68968-5552-3 - 10 mg 30 Count Carton NDC 68968-5552-3 Daytrana ® (methylphenidate transdermal system) Delivers 10 mg over 9 hours (1.1 mg/hr) Patch should be worn for approximately 9 hours Contains: 30 Patches CII Rx only Noven Therapeutics, LLC Once the tray is opened, use contents within 2 months. Manufactured for Noven Therapeutics, LLC, Miami, FL 33186 By Noven Pharmaceuticals, Inc. ©2007, 2010 Noven Pharmaceuticals, Inc. 1-877-567-7857 Pharmacists: Enclosed Medication Guide to be dispensed to each patient. 302188-8 Rev. 9/2016 Each patch contains 27.5 mg of methylphenidate. Active ingredient release is limited; please see recommended dosing in patient instructions. Inactive components: acrylic adhesive, coextruded backing film, polyester release liner and silicone adhesive. For transdermal use only (applied only to skin). Keep all patches within provided containers and dispense one patch daily. Apply immediately upon removal from pouch. Do not store unpouched. Do not store patches in refrigerators or freezers. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP controlled Room Temperature] Important: Keep out of the reach of children. It is important that this product be disposed of properly. See patient instructions for disposal information. Dosage and Administration: See package insert. Date of Patch Application MM/DD/YYYY Time Applied Time Removed Application Side Disposal Method Date of Patch Application MM/DD/YYYY Time Applied  Time Removed  Application Side  Disposal Method   _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash  _AM _PM  _AM _PM  _Right _Left _Fold & flush _ Fold & trash daytrana-10mg-30ct-carton