Methylphenidate 10 mg (ER) · Tablets

Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action of methylphenidate in the treatment of ADHD is not known. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.

Absorption — Following oral administration of methylphenidate hydrochloride extended-release tablets, plasma methylphenidate concentrations reached an initial maximum concentration at about 1 hour, followed by gradual ascending concentrations over the next 5 to 9 hours, after which a gradual decrease begins. Mean times to reach peak plasma concentrations across all doses of methylphenidate hydrochloride extended-release tablets occurred between 6 and 10 hours.

Methylphenidate hydrochloride extended-release tablets once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily [see Figure 1]. No clinically significant difference in methylphenidate exposures was observed following the administration of either methylphenidate hydrochloride extended-release tablets once daily and immediate-release methylphenidate three times daily in adults.

The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of one 18 mg methylphenidate hydrochloride extended-release tablet dose and three 5 mg methylphenidate doses every four hours are summarized in Table 7.

The methylphenidate pharmacokinetics were evaluated in healthy adults following single- and multiple-doses (steady state) of methylphenidate hydrochloride extended-release tablets (up to 144 mg/day (up to 2 times the maximum recommended dose)). The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of methylphenidate hydrochloride extended-release tablets were noted following single and repeated once-daily methylphenidate hydrochloride extended-release tablet dosing, indicating no significant drug accumulation. The AUC and t½ following repeated once-daily dosing are similar to those following a single 18 to 144 mg dose of methylphenidate hydrochloride extended-release tablets.

Dose Proportionality — Following administration of methylphenidate hydrochloride extended-release tablets in single doses of 18, 36, and 54 mg/day to healthy adults, C maxand AUC (0-inf)of d-methylphenidate were dose proportional, whereas l-methylphenidate C maxand AUC (0-inf)increased disproportionately with respect to dose. Following administration of methylphenidate hydrochloride extended-release tablets, plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer.

In healthy adults, single and multiple doses (once-daily) methylphenidate hydrochloride extended-release tablets doses from 54 to 144 mg/day resulted in linear and dose-proportional increases in C maxand AUC inffor total methylphenidate (MPH) and its major metabolite, a-phenyl-piperidine acetic acid (PPAA). There was no time dependency in the pharmacokinetics of methylphenidate. The ratio of metabolite (PPAA) to parent drug (MPH) was constant across doses from 54 to 144 mg/day, both after single dose and upon multiple dosing.

In a multiple-dose study, after patients aged 13 to 16 with ADHD were administered their prescribed methylphenidate hydrochloride extended-release tablet dose (18 to 72 mg/day), mean C maxand AUC TAUof d- and total methylphenidate increased proportionally with respect to dose.

Food Effects: In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of methylphenidate hydrochloride extended-release tablets when administered after a high-fat breakfast.

Distribution — Plasma methylphenidate concentrations in adults and adolescents decline biexponentially following oral administration. The half-life of methylphenidate in adults and adolescents following oral methylphenidate hydrochloride extended-release tablets administration was approximately 3.5 hours.

Elimination — Metabolism: In humans, methylphenidate is metabolized primarily by de-esterification to PPAA, which has little or no pharmacologic activity. In adults the metabolism of methylphenidate hydrochloride extended-release tablets once daily as evaluated by metabolism to PPAA was similar to that of immediate-release methylphenidate three times daily. The metabolism of single and repeated once-daily doses of methylphenidate hydrochloride extended-release tablets was similar.

Excretion: After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose.

Alcohol Effect on Methylphenidate Release in Methylphenidate Hydrochloride Extended-Release Tablets

An in vitrostudy was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the methylphenidate extended-release 18 mg extended-release tablets. At an alcohol concentration up to 40% there was no increased release of methylphenidate in the first hour. The results with the 18 mg extended-release tablet strength are considered representative of the other available tablet strengths.