"The US Food and Drug Administration (FDA) has approved the amphetamine Dyanavel XR (Tris Pharma Inc), a once-daily extended-release oral liquid, for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children aged 6 years "...
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.
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].
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
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.
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.
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.
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 products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.
Peripheral Vasculopathy, Including Raynaud's phenomenon
Stimulants, including Daytrana, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients
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.
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 beyond 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 the Daytrana patch 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 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.
Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
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]. This increased absorption can be clinically significant and can result in overdose of methylphenidate [see OVERDOSAGE].
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
Patient Counseling Information
Advise patients to read the FDA-approved patient labeling (Medication Guide).
Information for Patients
Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to s eek immediate medical attention in the event of priapism [see WARNINGS AND PRECAUTIONS]
Circulation Problems In Fingers And Toes [Peripheral Vasculopathy, Including Raynaud’S Phenomenon]
- Instruct patients beginning treatment with Daytrana about the risk of peripheral vasculopathy, including Raynaud's Phenomenon, and in associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red
- Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.
- Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking Daytrana
- Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.
Advise patients of the possibility of a persistent loss of skin pigmentation at, around and distant from the application site. Loss of pigmentation has also been reported, in some cases, beyond the application site. Advise patients to immediately inform their healthcare provider if changes in skin pigmentation occur [see WARNINGS AND PRECAUTIONS].
Parents and 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, and a new patch should be applied [see DOSAGE AND ADMINISTRATION]. 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. Daytrana may be removed earlier than 9 hours if a shorter duration of effect is desired or late day side effects appear.
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, and a new patch should be applied [see DOSAGE AND ADMINISTRATION]. 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.
Stimulants may impair the ability of the patient to operate potentially hazardous machinery or vehicles. Patients should be cautioned accordingly until they are reasonably certain that Daytrana does not adversely affect their ability to engage in such activities.
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/Storage and Handling]. 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 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.
Carcinogenes Is /Mutagenes Is 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.
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.
Use In Specific Populations
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.
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.
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.
Daytrana has not been studied in patients greater than 65 years of age.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 11/23/2015
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