"The U.S. Food and Drug Administration today allowed marketing of the first medical device based on brain function to help assess attention-deficit/hyperactivity disorder (ADHD) in children and adolescents 6 to 17 years old. When used as part of "...
Dexmethylphenidate hydrochloride is a central nervous system stimulant. Focalin, the more pharmacologically active enantiomer of the d-and l-enantiomers, is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known.
Effects On QT Interval
The effect of Focalin® XR on the QT interval was evaluated in a double-blind, placebo-and open label active (moxifloxacin)-controlled study following single doses of Focalin® XR 40mg in 75 healthy volunteers. ECGs were collected up to 12 h post-dose. Frederica's method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was < 5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident-exposure response relationship.
Dexmethylphenidate hydrochloride is readily absorbed following oral administration of Focalin. In patients with ADHD, plasma dexmethylphenidate concentrations increase rapidly, reaching a maximum in the fasted state at about 1 to 1½ hours post-dose. No differences in the pharmacokinetics of Focalin were noted following single and repeated twice daily dosing, thus indicating no significant drug accumulation in children with ADHD.
When given to children as capsules in single doses of 2.5 mg, 5 mg, and 10 mg, Cmax and AUC0-inf of dexmethylphenidate were proportional to dose. In the same study, plasma dexmethylphenidate levels were comparable to those achieved following single dl-threo-methylphenidate HCl doses given as capsules in twice the total mg amount (equimolar with respect to Focalin).
In a single dose study conducted in adults, coadministration of 2 x 10 mg Focalin with a high fat breakfast resulted in a dexmethylphenidate tmax of 2.9 hours post-dose as compared to 1.5 hours post-dose when given in a fasting state. Cmax and AUC0-inf were comparable in both the fasted and non-fasted states.
Plasma dexmethylphenidate concentrations in children decline exponentially following oral administration of Focalin.
Metabolism and Excretion
In humans, dexmethylphenidate is metabolized primarily to d-α-phenyl-piperidine acetic acid (also known as d-ritalinic acid) by de-esterification. This metabolite has little or no pharmacological activity. There is little or no in vivo interconversion to the l-threo-enantiomer, based on a finding of minute levels of l-threo-methylphenidate being detectable in a few samples in only 2 of 58 children and adults. After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was ritalinic acid, accountable for approximately 80% of the dose.
In vitro studies showed that dexmethylphenidate did not inhibit cytochrome P450 isoenzymes.
The mean plasma elimination half-life of dexmethylphenidate is approximately 2.2 hours.
Pharmacokinetic parameters were similar for boys and girls (mean age 10 years).
In a single dose study conducted in adults, the mean dexmethylphenidate AUC0-inf values (adjusted for body weight) following single 2 x 10 mg doses of Focalin were 25%-35% higher in adult female volunteers (n=6) compared to male volunteers (n=9). Both tmax and t½ were comparable for males and females.
There is insufficient experience with the use of Focalin to detect ethnic variations in pharmacokinetics.
The pharmacokinetics of dexmethylphenidate after Focalin administration have not been studied in children less than 6 years of age. When single doses of Focalin were given to children between the ages of 6 to 12 years and healthy adult volunteers, Cmax of dexmethylphenidate was similar, however, children showed somewhat lower AUCs compared to the adults.
There is no experience with the use of Focalin in patients with renal insufficiency. After oral administration of radiolabeled racemic methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of ritalinic acid. Since very little unchanged drug is excreted in the urine, renal insufficiency is expected to have little effect on the pharmacokinetics of Focalin.
Focalin was evaluated in two double-blind, parallel-group, placebo-controlled trials in untreated or previously treated patients aged 6 to 17 years old with a DSM-IV diagnosis of Attention Deficit Hyperactivity Disorder (ADHD). Both studies included all three subtypes of ADHD, i.e., Combined Type, Predominantly Inattentive Type, or Predominantly Hyperactive-Impulsive Type. While both children and adolescents were included, the sample was predominantly children, thus, the findings are most pertinent to this age group. In both studies, the primary comparison of interest was Focalin versus placebo.
Focalin (5, 10, or 20 mg/day total dose), dl-threo-methylphenidate HCl (10, 20, or 40 mg/day total dose), and placebo were compared in a multicenter, 4-week, parallel group study in n=132 patients. Patients took the study medication twice daily, 3.5 to 5.5 hours between doses. Treatment was initiated with the lowest dose, and doses could be doubled at weekly intervals, depending on clinical response and tolerability, up to the maximum dose. The change from baseline to week 4 of the averaged score (an average of two ratings during the week) of the teacher's version of the SNAP-ADHD Rating Scale, a scale for assessing ADHD symptoms, was the primary outcome. Patients treated with Focalin showed a statistically significant improvement in symptom scores from baseline over patients who received placebo.
Figure 1 : Mean Change from Baseline in Teacher
SNAP-ADHD Scores in a 4-week Double-Blind Placebo-Controlled Study of Focalin®*
*Figure 1: Error bars represent the standard error of the mean.
The other study, involving n=75 patients, was a multicenter, placebo-controlled, double-blind, 2-week treatment withdrawal study in children who were responders during a 6-week, open label initial treatment period. Children took study medication twice a day separated by a 3.5 to 5.5 hour interval. The primary outcome was proportion of treatment failures at the end of the 2-week withdrawal phase, where treatment failure was defined as a rating of 6 (much worse) or 7 (very much worse) on the Investigator Clinical Global Impression -Improvement (CGI-I). Patients continued on Focalin showed a statistically significant lower rate of failure over patients who received placebo.
Figure 2 : Percent of
Treatment Failures following a 2-week Double-Blind Placebo-Controlled
Withdrawal of Focalin®
Last reviewed on RxList: 12/30/2013
This monograph has been modified to include the generic and brand name in many instances.
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