methylphenidate
Dosage Form: patch
FULL PRESCRIBING INFORMATION
WARNING: DRUG DEPENDENCE
Daytrana should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.
Indications and Usage for Daytrana
Daytrana (methylphenidate transdermal system) is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).
The efficacy of Daytrana in patients diagnosed with ADHD was established in two 7-week controlled clinical trials in children (ages 6-12) and one 7-week, controlled clinical trial in adolescents (ages 13-17).
A diagnosis of ADHD (DSM-IV-TR®) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; "on the go;" excessive talking; blurting answers; can't wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met.
Special Diagnostic Considerations
The specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV-TR® characteristics.
Need for Comprehensive Treatment Program
Daytrana is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Stimulants are not intended for use in the patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms.
Daytrana Dosage and Administration
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.
| Upward Titration, if Response is Not Maximized | ||||
|---|---|---|---|---|
| *Nominal in vivo delivery rate in children and adolescents when applied to the hip, based on a 9-hour wear period. | ||||
| Week 1 | Week 2 | Week 3 | Week 4 | |
| Patch Size | 12.5 cm2 | 18.75 cm2 | 25 cm2 | 37.5 cm2 |
| 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.
Application
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 patch for children; responsible adolescents may apply or remove the patch themselves if appropriate. The Medication Guide included at the end of this insert also 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 patch to the hip area avoiding the waistline, since clothing may cause the patch to rub off. When applying the patch the next morning, place on the opposite hip at a new site if possible.
If patients or caregivers experience difficulty separating the patch from the release liner or observe transfer of adhesive to the liner, tearing and/or other damage to the patch during removal from the liner, the patch should be discarded according to the directions provided below, and a new patch 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 patch should be discarded.
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 patch appears to be damaged. Do not cut patches. Only intact patches should be applied. The patch 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 patch with the skin, especially around the edges. Exposure to water during bathing, swimming, or showering can affect patch adherence. Patches should not be applied or re-applied with dressings, tape, or other common adhesives. In the event that a patch does not fully adhere to the skin upon application, or becomes partially or fully detached during wear time, the patch should be discarded according to the directions provided in this label [see Dosage and Administration (2.3)] and a new patch may be applied at a different site. The total recommended wear time for that day should remain 9 hours regardless of the number of patches used [see Patient Counseling Information (17.1)].
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 patch [see Warnings and Precautions (5.7)]. When heat is applied to Daytrana after patch 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: Pharmacokinetics/Absorption). This increased absorption can be clinically significant and result in overdose of methylphenidate (see OVERDOSAGE).
Patches should not be stored in refrigerators or freezers.
Removal of Daytrana
Daytrana patches should be peeled off slowly. If necessary, patch removal may be facilitated by gently applying an oil-based product (i.e., petroleum jelly, olive oil, or mineral oil) to the patch edges, gently working the oil underneath the patch edges. If any adhesive remains on the skin following patch removal, an oil-based product may be applied to patch sites in an effort to gently loosen and remove any residual adhesive that remains following patch removal.
In the unlikely event that a patch 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 patches or adhesive.
Disposal of Daytrana
Upon removal of Daytrana, used patches should be folded so that the adhesive side of the patch adheres to itself and should be flushed down the toilet or disposed of in an appropriate lidded container. If the patient stops using the prescription, each unused patch should be removed from its individual pouch, separated from the protective liner, folded onto itself, and disposed of in the same manner as used patches.
The parent or caregiver should be encouraged to record on the administration chart included with each carton the time that each patch was applied and removed. If a patch was removed without the parent or caregiver's knowledge, or if a patch is missing from the tray or outer pouch, the parent or caregiver should be encouraged to ask the child when and how the patch was removed.
Maintenance/Extended Treatment
There is no body of evidence available from controlled clinical trials to indicate how long the patient with ADHD should be treated with Daytrana. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. The effectiveness of Daytrana for long-term use, i.e., for more than 7 weeks, has not been systematically evaluated in controlled trials. The physician who elects to use Daytrana for extended periods should periodically re-evaluate the long-term usefulness of Daytrana for the individual patient with periods off medication to assess the patient's functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued.
Dose/Wear Time Reduction and Discontinuation
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 patch 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 patches when worn as recommended.
Dosage Form and strengths
Four dosage strengths are available:
| Nominal Dose Delivered (mg) Over 9 Hours* | Dosage Rate* (mg/hr) | Patch Size (cm2) | Methylphenidate Content per Patch (mg) |
|---|---|---|---|
| *Nominal in vivo delivery rate in children and adolescents when applied to the hip, based on a 9-hour wear period. | |||
| 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 |
Contraindications
Hypersensitivity to Methylphenidate
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 (11.1)].
Agitation
Daytrana is contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.
Glaucoma
Daytrana is contraindicated in patients with glaucoma.
Tics
Daytrana is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette's syndrome [see Adverse Reactions (6.1)].
Monoamine Oxidase Inhibitors
Daytrana is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result).
WARNINGS and PRECAUTIONS
Serious Cardiovascular Events
Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems
Children and Adolescents
Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug.
Adults
Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs.
Hypertension and Other Cardiovascular Conditions
Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia [see Adverse Reactions (6.1)].
Assessing Cardiovascular Status in Patients Being Treated With Stimulant Medications
Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.
Psychiatric Adverse Events
Pre-Existing Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.
Bipolar Illness
Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
Emergence of New Psychotic or Manic Symptoms
Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to none in placebo-treated patients.
Aggression
Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility.
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.
Long-Term Suppression of Growth
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 consistently medicated children (i.e., treatment for 7 days per week throughout the year) have 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 period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.
Visual Disturbance
Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
Contact Sensitization
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 patch 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 Using External Heat
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 patch. When heat is applied to Daytrana after patch 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)].
Hematologic Monitoring
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
Adverse Reactions
Detailed information on serious and adverse reactions of particular importance is provided in the BoxedWarning and Warnings and Precautions (5) sections:
- Drug dependence [see box Warning]
- Hypersensitivity to Methylphenidate [see Contraindications (4.1)]
- Marked anxiety, tension, or agitation [see Contraindications (4.2)]
- Glaucoma [see Contraindications (4.3)]
- Tics or a family history of Tourette's syndrome [see Contraindications (4.4)]
- Monoamine Oxidase Inhibitors [see Contraindications (4.5) and Drug Interactions (7.1)]
- Serious Cardiovascular Events [see Warnings and Precautions (5.1)]
- Increase in Blood Pressure [see Warnings and Precautions (5.2)]
- Psychiatric Adverse Events [see Warnings and Precautions (5.2)]
- Seizures [see Warnings and Precautions (5.3)]
- Long-Term Suppression of Growth [see Warnings and Precautions (5.4)]
- Visual Disturbance [see Warnings and Precautions (5.5)]
- Contact Sensitization [see Warnings and Precautions (5.6)]
- External Heat [see Warnings and Precautions (5.7)]
- Hematologic Monitoring [see Warnings and Precautions (5.8)]
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 AdverseReactions (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 (6.3)].
The overall Daytrana development program included exposure to Daytrana 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 Daytrana with a wear time of 9 hours, 212 subjects were exposed for ≥ 6 months and 115 were exposed for ≥ 1 year; 85 adolescents have been exposed for ≥ 6 months. Most patients studied were exposed to Daytrana patch 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.
Throughout this section adverse reactions reported are events that were considered to be reasonably associated with the use of Daytrana based on comprehensive assessment of the available adverse event information. A causal association for Daytrana often cannot be reliably established in individual cases. Further, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.
Clinical Trials Experience
Adverse Reactions Associated 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 Daytrana 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 Daytrana 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 Daytrana discontinued due to adverse reactions compared with 2.8% (2/72) receiving placebo. The most commonly reported adverse reactions leading to discontinuation in the Daytrana 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
Daytrana 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 patch 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 patch site [see Warnings and Precautions (5.6)].
Most Commonly Reported Adverse Reactions
Table 2 lists treatment-emergent adverse reactions reported in ≥ 1% Daytrana-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.
| Adolescents | Children | |||
|---|---|---|---|---|
| * Six subjects had affect lability, all judged as mild and described as increased emotionally sensitive, emotionality, emotional instability, emotional lability, and intermittent emotional | ||||
| System Organ Class Preferred term | Placebo N = 72 | Daytrana N = 145 | Placebo N = 85 | Daytrana N = 98 |
| Cardiac Disorders | ||||
| Tachycardia | 0 (0) | 1 (0.7) | 0 (0) | 1 (1.0) |
| Gastrointestinal disorders | ||||
| Abdominal pain | 0 (0) | 7 (4.8) | 5 (5.9) | 7 (7.1) |
| Nausea | 2 (2.8) | 14 (9.7) | 2 (2.4) | 12 (12.2) |
| Vomiting | 1 (1.4) | 5 (3.4) | 4 (4.7) | 10 (10.2) |
| Investigations | ||||
| Weight decreased | 1 (1.4) | 8 (5.5) | 0 (0) | 9 (9.2) |
| Metabolism and nutrition disorders | ||||
| Anorexia | 1 (1.4) | 7 (4.8) | 1 (1.2) | 5 (5.1) |
| Decreased appetite | 1 (1.4) | 37 (25.5) | 4 (4.7) | 25 (25.5) |
| Nervous system disorders | ||||
| Dizziness | 1 (1.4) | 8 (5.5) | 1 (1.2) | 0 (0) |
| Headache | 9 (12.5) | 18 (12.4) | 10 (11.8) | 15 (15.3) |
| Psychiatric disorders | ||||
| Affect lability | 1 (1.4) | 0 (0) | 0 (0) | 6 (6.1)* |
| Insomnia | 2 (2.8) | 9 (6.2) | 4 (4.7) | 13 (13.3) |
| Irritability | 5 (6.9) | 16 (11) | 4 (4.7) | 7 (7.1) |
| Tic | 0 (0) | 0 (0) | 0 (0) | 7 (7.1) |
Adverse Reactions With the Long-Term Use of Daytrana
In a long-term open-label study of up to 12 months duration in 326 children wearing Daytrana 9 hours daily, the most common (≥ 10%) adverse reactions were decreased appetite, headache, and weight decreased. A total of 30 subjects (9.2%) were withdrawn from the study due to adverse events and 22 additional subjects (6.7%) discontinued treatment as the result of an application site reaction. Other than application site reactions, affect lability (5 subjects, 1.5%) was the only additional adverse reaction leading to discontinuation reported with a frequency of greater than 1%.
In a long-term open-label study of up to 6 months duration in 162 adolescents wearing Daytrana 9 hours daily, the most common (≥ 10%) adverse reactions were decreased appetite and headache. A total of 9 subjects (5.5%) were withdrawn from the study due to adverse events and 3 additional subjects (1.9%) discontinued treatment as the result of an application site reaction. Other adverse reactions leading to discontinuation that occurred with a frequency of greater than 1% included affect lability and irritability (2 subjects each, 1.2%).
Postmarketing Experience
In addition, the following adverse reactions have been identified during the postapproval use of Daytrana. 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 Daytrana exposure.
Cardiac Disorders: palpitation
Eye Disorders: visual disturbances, blurred vision, mydriasis, accommodation disorder
General Disorders and Administration Site Disorders: 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
Psychiatric Disorders: transient depressed mood, hallucination, nervousness
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: angina, arrhythmia, pulse increased or decreased
Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura
Metabolism/Nutrition: anorexia, weight loss during prolonged therapy
Nervous System: drowsiness, rare reports of Tourette's syndrome, toxic psychosis
Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion
Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate:
Blood/lymphatic: leukopenia and/or anemia
Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma
Psychiatric: transient depressed mood
Skin/Subcutaneous: scalp hair loss
Neuroleptic Malignant Syndrome: 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.
Drug Interactions
MAO Inhibitors
Daytrana should not be used in patients being treated (currently or within the preceding two weeks) with monoamine oxidase inhibitors [see Contraindications (4.5)].
Vasopressor Agents
Because of a possible effect on blood pressure, Daytrana should be used cautiously with pressor agents.
Hypotension Agents
Methylphenidate may decrease the effectiveness of drugs used to treat hypertension.
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.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C - Animal reproduction studies with transdermal methylphenidate have not been performed. In a study in which oral methylphenidate was given to pregnant rabbits during the period of organogenesis at doses up to 200 mg/kg/day no teratogenic effects were seen, although an increase in the incidence of a variation, dilation of the lateral ventricles, was seen at 200 mg/kg/day; this dose also produced maternal toxicity. A previously conducted study in rabbits showed teratogenic effects of methylphenidate at an oral dose of 200 mg/kg/day. In a study in which oral methylphenidate was given to pregnant rats during the period of organogenesis at doses up to 100 mg/kg/day, no teratogenic effects were seen although a slight delay in fetal skeletal ossification was seen at doses of 60 mg/kg/day and above; these doses caused some maternal toxicity.
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.
Adequate and well-controlled studies in pregnant women have not been conducted. Daytrana should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of Daytrana on labor and delivery in humans is unknown.
Nursing Mothers
It is not known whether methylphenidate is excreted in human milk. Daytrana should be administered to a nursing woman only if the potential benefit justifies the potential risk to the child.
Pediatric Use
Daytrana should not be used in children under six years of age, since safety and efficacy in this age group have not been established. Long-term effects of methylphenidate in children have not been well established.
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.
Geriatric Use
Daytrana has not been studied in patients greater than 65 years of age.
Drug Abuse and Dependence
Controlled Substance
Daytrana is classified as a Schedule II controlled substance by federal regulation.
Abuse
See warning containing drug abuse information [see Boxed Warning].
Dependence
See warning containing drug dependence information [see Boxed Warning].
Overdosage
Signs and Symptoms
Signs and symptoms of acute methylphenidate overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.
Recommended Treatment
Remove all patches immediately and cleanse the area(s) to remove any remaining adhesive. The continuing absorption of methylphenidate from the skin, even after removal of the patch, should be considered when treating patients with overdose. Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia.
Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Daytrana overdosage has not been established.
Poison Control Center
As with the management of all overdosages, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of overdosage with methylphenidate.
Daytrana Description
Daytrana is an adhesive-based matrix transdermal system (patch) 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 C14H19NO2. The structural formula of methylphenidate is:
Patch 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 deliver
