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) (see ADVERSE REACTIONS), 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.

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.

Contact Sensitization

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.

A study designed to provoke skin sensitization revealed a signal for Daytrana™ to be an irritant and also a contact sensitizer. This study involved an induction phase consisting of continuous exposure to the same skin site for 3 weeks, followed by a 2 week rest period, and then challenge/rechallenge. Under conditions of the study, Daytrana™ was more irritating than both the placebo patch control and the negative control (saline). Of 133 adult subjects who participated in the challenge phase of the sensitization study, at least 18 (13.5%) were confirmed to have been sensitized to Daytrana™ based on the results of the challenge and/or rechallenge phases of the study. This evaluation methodology employed continuous irritant induction exposure. This evaluation methodology may not be predictive of dermal sensitization in actual clinical use with recommended 9-hour wear times and alternating application sites on the hip.

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 0 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.

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.

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.

Visual Disturbance

Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.

Use in Children Under Six Years of Age

Daytrana™ should not be used in children under six years of age, since safety and efficacy in this age group have not been established.

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: Pharmacokinetics/Absorption). This increased absorption can be clinically significant and can result in overdose of methylphenidate (see OVERDOSAGE).

Hematologic Monitoring

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

Information For Patients

Patients should be informed to apply Daytrana™ to a clean, dry site on the hip, which is not oily, damaged, or irritated. The site of application must be alternated daily. The patch should not be applied to the waistline, or where tight clothing may rub it.

If patients or caregivers experience difficulty separating the patch from the release liner or observe tearing and/or other damage to the patch during removal from the liner, the patch should be discarded according to the directions provided in this label (see DOSAGE AND ADMINISTRATION: Disposal of Daytrana™), 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 2 hours before the desired effect. Daytrana™ should be removed approximately 9 hours after it is applied, although the effects from the patch will last for several more hours.

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. 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.

Patients or caregivers should avoid touching the adhesive side of the patch during application, in order to avoid absorption of methylphenidate. If they do touch the adhesive side of the patch, they should immediately wash their hands after application.

In the event that a patch does not fully adhere to the skin upon application, or is partially or fully detached during wear time, the patch should be discarded according to the directions provided in this label (see DOSAGE AND ADMINISTRATION: Disposal of Daytrana™), and a new patch should be applied. If a patch is replaced, the total recommended wear time for that day should remain 9 hours, regardless of the number of patches used.

Patches should not be applied or re-applied with dressings, tape, or other common adhesives.

Exposure to water during bathing, swimming, or showering can affect patch adherence.

Do not cut patches. Only intact patches should be applied.

If there is an unacceptable duration of appetite loss or insomnia in the evening, taking the patch off earlier may be attempted before decreasing the patch dose.

Skin redness or itching is common with Daytrana™, and small bumps on the skin may also occur in some patients. If any swelling or blistering occurs the patch should not be worn and the patient should be seen by the prescriber. Patients or caregivers should not apply hydrocortisone or other solutions, creams, ointments, or emollients immediately prior to patch application, since the effect on patch adhesion and methylphenidate absorption has not been established. The potential adverse effects of topical corticosteroid use during treatment with Daytrana™ are unknown.

Patches should be stored at 25 degrees Celsius (77 degrees Fahrenheit) with excursions permitted that do not exceed 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit). (see HOW SUPPLIED). Patients or caregivers should be advised not to store Daytrana™ in the refrigerator or freezer.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Daytrana™ (methylphenidate transdermal system) and should counsel them in its appropriate use. A patient Medication Guide is available for Daytrana™. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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.

Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay, and was negative in vivo in the mouse bone marrow micronucleus 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 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.

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.

Nursing Mothers

It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Daytrana™ is administered to a nursing woman.

Pediatric Use

The safety and efficacy of Daytrana™ in children under 6 years old have not been established. Long-term effects of methylphenidate in children have not been well established (see WARNINGS).

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.

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