Daytrana

Daytrana is a transdermal patch developed and marketed by Noven Pharmaceuticals, Inc. that was approved in April 2006. In the literature, Daytrana is most commonly referred to as methylphenidate transdermal system (MTS).

Daytrana is approved by the Food and Drug Administration (FDA) as a once daily treatment of pediatric patients—ages 6 to 17—with attention deficit hyperactivity disorder (ADHD). However, off-label prescriptions in older patients are not uncommon. It is mainly prescribed as a second-line treatment for ADHD when traditional oral forms are not well-tolerated or if patients have difficulty with compliance.

Noven's original FDA submission indicated that it should be used for 12 hours; when the FDA rejected the submission they requested evidence that a shorter time period was safe and effective; Noven provided such evidence and Daytrana was approved for the aforementioned indication over a 9-hour period.^[1]

Transdermal versus oral administration

Orally administered methylphenidate is subject to first-pass metabolism, by which the levo-isomer is extensively metabolized. By circumventing this first-pass metabolism, the relative concentrations of l-threo-methylphenidate are much higher, with transdermal administration (50-60% of those of dexmethylphenidate instead of about 14-27%).^[2][3]

Contraindications

Methylphenidate is contraindicated for individuals using monoamine oxidase inhibitors (e.g., phenelzine and tranylcypromine), or individuals with agitation, tics, or glaucoma, or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.^[4]

The US FDA gives methylphenidate a pregnancy category of C, and women are advised to only use the drug if the benefits outweigh the potential risks.^[5] Not enough animal and human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development. In 2007, empirical literature included 63 cases of prenatal exposure to methylphenidate across three empirical studies.^[6]

Adverse effects

Daytrana has a side effect profile comparable to other medications containing methylphenidate. The patch should not be worn for longer than 9 hours, even if a new patch was placed due to the previous patch falling off.

Methylphenidate is generally well tolerated.^[7][8] The most commonly observed adverse effects with a frequency greater than placebo include appetite loss, dry mouth, anxiety/nervousness, nausea, and insomnia. Gastrointestinal adverse effects may include abdominal pain and weight loss. Nervous system adverse effects may include akathisia (agitation/restlessness), irritability, dyskinesia (tics), lethargy (drowsiness/fatigue), and dizziness. Cardiac adverse effects may include palpitations, changes in blood pressure and heart rate (typically mild), and tachycardia (rapid resting heart rate). Ophthalmologic adverse effects may include blurred vision and dry eyes, with less frequent reports of diplopia and mydriasis.^[9] Other adverse effects may include depression, emotional lability, confusion, and bruxism. Hyperhidrosis (increased sweating) is common. Chest pain is rarely observed.^[10]

There is some evidence of mild reductions in growth rate with prolonged treatment in children, but no causal relationship has been established and reductions do not appear to persist long-term.^[11] Hypersensitivity (including skin rash, urticaria, and fever) is sometimes reported. The Daytrana patch has a much higher rate of dermal reactions than oral methylphenidate.^[12]

Methylphenidate can worsen psychosis in psychotic patients, and in very rare cases it has been associated with the emergence of new psychotic symptoms.^[13] It should be used with extreme caution in patients with bipolar disorder due to the potential induction of mania or hypomania.^[14] There have been very rare reports of suicidal ideation, but evidence does not support a link.^[11] Logorrhea is occasionally reported. Libido disorders, disorientation, and hallucinations are very rarely reported. Priapism is a very rare adverse event that can be potentially serious.^[15]

USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of methylphenidate or other ADHD stimulants.^[16]

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.^[17]

Interactions

Methylphenidate may inhibit the metabolism of coumarin anticoagulants, certain anticonvulsants, and some antidepressants (tricyclic antidepressants and selective serotonin reuptake inhibitors). Concomitant administration may require dose adjustments, possibly assisted by monitoring of plasma drug concentrations.^[8] There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.^{[18][19][20][21]}

When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification,^[22][23] not unlike the hepatic formation of cocaethylene from cocaine and alcohol. The reduced potency of ethylyphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible.^[24][25]

Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.^[26]

Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of β-adrenergic agonists with methylphenidate may increase the risk of liver toxicity.^[27]

Mechanism of action

Methylphenidate is a central nervous system stimulant and Daytrana is the long acting transdermal patch formulation. Methylphenidate works in the CNS to selectively inhibit the presynaptic reuptake of dopamine and norepinephrine. It has been demonstrated to block dopamine transporter molecules and increase extracellular levels of dopamine in the striatum of healthy adults.^[28]

Pharmacokinetics

In patients using Daytrana a 39 nanograms/mL peak serum concentration of methylphenidate be has been found to occur between 7.5 and 10.5 hours after administration.^[29] However the onset to peak effect is 2 hours and the clinical effects remain up to 2 hours after patch has been removed. The absorption of Daytrana is increased when the transdermal patch is applied onto inflamed skin or skin that has been exposed to heat. The absorption lasts for approximately 9 hours after application (onto normal, unexposed to heat, and uninflammed skin). 90% of the medication is excreted in the urine as metabolites and unchanged drug.^[29]

In pregnancy

The Food and Drug Administration has labeled Daytrana as a Category C medication in pregnancy,^[30] and so it was found to have adverse effects in the fetus when studied in animals. However, there have not been enough studies performed in humans that show that the benefits of using Daytrana are outweighed by potential adverse effects.

Footnotes

External links

• Official Daytrana website