July 26, 2016
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Mechanism Of Action

Methylphenidate HCl is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate 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.


Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer.



Methylphenidate is readily absorbed. Following oral administration of CONCERTAR®, plasma methylphenidate concentrations increase rapidly, reaching an initial maximum 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 CONCERTAR® occurred between 6 and 10 hours.

CONCERTA® once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily (see Figure 1). The relative bioavailability of CONCERTAR® once daily and methylphenidate three times daily in adults is comparable.

Figure 1: Mean methylphenidate plasma concentrations in 36 adults, following a single dose of CONCERTAR® 18 mg once daily and immediate-release methylphenidate 5 mg three times daily administered every 4 hours.

Mean methylphenidate plasma concentrations - Illustration

The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of CONCERTAR® 18 mg once daily and methylphenidate 5 mg three times daily are summarized in Table 6.

Table 6: Pharmacokinetic Parameters (Mean ± SD) After Single Dose in Healthy Adults

Parameters CONCERTA® (18 mg once daily)
Methylphenidate (5 mg three times daily)
Cmax (ng/mL) 3.7 ± 1.0 4.2 ± 1.0
Tmax (h) 6.8 ± 1.8 6.5 ± 1.8
AUCinf (ng•h/mL) 41.8 ± 13.9 38.0 ± 11.0
t½ (h) 3.5 ± 0.4 3.0 ± 0.5

The pharmacokinetics of CONCERTAR® were evaluated in healthy adults following single- and multiple-dose administration (steady state) of doses up to 144 mg/day. The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of CONCERTAR® were noted following single and repeated once-daily dosing, indicating no significant drug accumulation. The AUC and t½ following repeated once-daily dosing are similar to those following the first dose of CONCERTAR® in a dose range of 18 to 144 mg.

Dose Proportionality

Following administration of CONCERTAR® in single doses of 18, 36, and 54 mg/day to healthy adults, Cmax and AUC(0-inf) of d-methylphenidate were proportional to dose, whereas l-methylphenidate Cmax and AUC(0-inf) increased disproportionately with respect to dose. Following administration of CONCERTAR®, plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer.

In healthy adults, single and multiple dosing of once-daily CONCERTAR® doses from 54 to 144 mg/day resulted in linear and dose-proportional increases in Cmax and AUCinf for total methylphenidate (MPH) and its major metabolite, α-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 in adolescent ADHD patients aged 13 to 16 administered their prescribed dose (18 to 72 mg/day) of CONCERTAR®, mean Cmax and AUCTAU of d- and total methylphenidate increased proportionally with respect to dose.


Plasma methylphenidate concentrations in adults and adolescents decline biexponentially following oral administration. The half-life of methylphenidate in adults and adolescents following oral administration of CONCERTAR® was approximately 3.5 hours.

Metabolism and Excretion

In humans, methylphenidate is metabolized primarily by de-esterification to PPAA, which has little or no pharmacologic activity. In adults the metabolism of CONCERTAR® once daily as evaluated by metabolism to PPAA is similar to that of methylphenidate three times daily. The metabolism of single and repeated oncedaily doses of CONCERTAR® is similar.

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.

Food Effects

In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of CONCERTAR® when administered after a highfat breakfast. There is no evidence of dose dumping in the presence or absence of food.

Alcohol Effect

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

Special Populations


In healthy adults, the mean dose-adjusted AUC(0-inf) values for CONCERTAR® were 36.7 ng•h/mL in men and 37.1 ng•h/mL in women, with no differences noted between the two groups.


In adults receiving CONCERTAR®, dose-adjusted AUC(0-inf) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics.


Increase in age resulted in increased apparent oral clearance (CL/F) (58% increase in adolescents compared to children). Some of these differences could be explained by body-weight differences among these populations. This suggests that subjects with higher body weight may have lower exposures of total methylphenidate at similar doses.

The pharmacokinetics of CONCERTAR® have not been studied in children less than 6 years of age.

Renal Insufficiency

There is no experience with the use of CONCERTAR® in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of PPAA. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of CONCERTAR®.

Hepatic Insufficiency

There is no experience with the use of CONCERTAR® in patients with hepatic insufficiency.

Clinical Studies

CONCERTA® was demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in 4 randomized, double-blind, placebo-controlled studies in children and adolescents and 2 double-blind placebo-controlled studies in adults who met the Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria for ADHD.


Three double-blind, active- and placebo-controlled studies were conducted in 416 children aged 6 to 12 years. The controlled studies compared CONCERTAR® given once daily (18, 36, or 54 mg), methylphenidate given three times daily over 12 hours (15, 30, or 45 mg total daily dose), and placebo in two single-center, 3-week crossover studies (Studies 1 and 2) and in a multicenter, 4-week, parallel-group comparison (Study 3). The primary comparison of interest in all three trials was CONCERTAR® versus placebo.

Symptoms of ADHD were evaluated by community schoolteachers using the Inattention/Overactivity with Aggression (IOWA) Conners scale. Statistically significant reduction in the Inattention/Overactivity subscale versus placebo was shown consistently across all three controlled studies for CONCERTAR®. The scores for CONCERTAR® and placebo for the three studies are presented in Figure 2.

Figure 2: Mean Community School Teacher IOWA Conners Inattention/Overactivity Scores with CONCERTA® once daily (18, 36, or 54 mg) and placebo. Studies 1 and 2 involved a 3-way crossover of 1 week per treatment arm. Study 3 involved 4 weeks of parallel-group treatments with a Last Observation Carried Forward analysis at week 4. Error bars represent the mean plus standard error of the mean

Mean Community School Teacher IOWA Conners Inattention/Overactivity Scores - Illustration

In Studies 1 and 2, symptoms of ADHD were evaluated by laboratory schoolteachers using the SKAMP* laboratory school rating scale. The combined results from these two studies demonstrated statistically significant improvements in attention and behavior in patients treated with CONCERTAR® versus placebo that were maintained through 12 hours after dosing. Figure 3 presents the laboratory schoolteacher SKAMP ratings for CONCERTAR® and placebo.

*Swanson, Kotkin, Agler, M-Fynn, and Pelham

Figure 3: Laboratory School Teacher SKAMP Ratings: Mean (SEM) of Combined Attention (Studies 1 and 2)

CONCERTA® (methylphenidate HCl) Figure 3 Illustration


In a randomized, double-blind, multicenter, placebo-controlled trial (Study 4) involving 177 patients, CONCERTAR® was demonstrated to be effective in the treatment of ADHD in adolescents aged 13 to 18 years at doses up to 72 mg/day (1.4 mg/kg/day). Of 220 patients who entered an open 4-week titration phase, 177 were titrated to an individualized dose (maximum of 72 mg/day) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness with acceptable tolerability. Patients who met these criteria were then randomized to receive either their individualized dose of CONCERTAR® (18 – 72 mg/day, n=87) or placebo (n=90) during a two-week doubleblind phase. At the end of this phase, mean scores for the investigator rating on the ADHD Rating Scale demonstrated that CONCERTAR® was statistically significantly superior to placebo.


Two double-blind, placebo-controlled studies were conducted in 627 adults aged18 to 65 years. The controlled studies compared CONCERTAR® administered once daily and placebo in a multicenter, parallel-group, 7-week dose-titration study (Study 5) (36 to 108 mg/day) and in a multicenter, parallel-group, 5-week, fixeddose study (Study 6) (18, 36, and 72 mg/day).

Study 5 demonstrated the effectiveness of CONCERTAR® in the treatment of ADHD in adults aged 18 to 65 years at doses from 36 mg/day to 108 mg/day based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS). Of 226 patients who entered the 7-week trial, 110 were randomized to CONCERTAR® and 116 were randomized to placebo. Treatment was initiated at 36 mg/day and patients continued with incremental increases of 18 mg/day (36 to 108 mg/day) based on meeting specific improvement criteria with acceptable tolerability. At the final study visit, mean change scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated that CONCERTAR® was statistically significantly superior to placebo.

Study 6 was a multicenter, double-blind, randomized, placebo-controlled, parallelgroup,dose-response study (5-week duration) with 3 fixed-dose groups (18, 36, and 72 mg). Patients were randomized to receive CONCERTAR® administered atdoses of 18 mg (n=101), 36 mg (n=102), 72 mg/day (n=102), or placebo (n=96). All three doses of CONCERTAR® were statistically significantly more effective than placebo in improving CAARS (Conners' Adult ADHD Rating Scale) total scores at double-blind end point in adult subjects with ADHD.


American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994.

Last reviewed on RxList: 1/6/2016
This monograph has been modified to include the generic and brand name in many instances.

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