Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2022 Publisher: Janssen-Cilag (New Zealand) Ltd, Auckland, NEW ZEALAND
Pharmacotherapeutic group: centrally acting sympathomimetics
ACT code: N06BA04
Methylphenidate is a central nervous system stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of noradrenaline and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.
Methylphenidate hydrochloride is the racemic mixture of d,l methyl α-phenyl-2-piperidineacetate hydrochloride. The d-isomer is pharmacologically more active than the l-isomer.
CONCERTA was demonstrated to be effective in the treatment of ADHD, in children aged 6 to 12 years, in three pivotal studies. Studies 1 and 2 were single-centre, double-blind, double-dummy, randomised, placebo and active-controlled, crossover comparisons (n = 64 and 70). Study 3 was a multicentre, 4 week, double-blind, double-dummy, randomised, placebo and active-controlled, parallel study (n = 282). The primary comparison of interest in all three trials was CONCERTA versus placebo.
The primary efficacy parameter for CONCERTA was the Inattention/Overactivity with Aggression (IOWA) Conners I/O subscale rated by the community school teacher. Statistically significant (p <0.001) reduction in the Inattention/Overactivity subscale versus placebo was shown consistently across all three controlled studies for CONCERTA once daily.
Onset and duration of efficacy were assessed by the laboratory school teacher using the SKAMP (Swanson, Kotkin, Agler, M-Fynn and Pelham) combined attention ratings for studies 1 and 2. The onset of efficacy was estimated to be 1.5 hours and duration continued through to 12 hours. Patients demonstrated higher productivity and greater accuracy during CONCERTA treatment.
Two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to 65 years. The controlled studies compared CONCERTA administered once daily and placebo in a multi-centre, parallel group, 5-week, fixed-dose study (Study 4) (18, 36, and 72 mg/day) and in a multi-centre, parallel group, 7-week dose-titration study (Study 5) (36 to 108 mg/day).
Study 4 was a multi-centre, double-blind, randomized, placebo-controlled, parallel group, dose-response study (5-week duration) with 3 fixed dose groups (18, 36, and 72 mg). Patients were randomized to receive CONCERTA administered at doses of 18 mg (n=101), 36 mg (n=102), 72 mg/day (n=102), or placebo (n=96). All three doses of CONCERTA were 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.
Study 5 demonstrated the effectiveness of CONCERTA 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 CONCERTA 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 CONCERTA was significantly superior to placebo.
Methylphenidate is readily absorbed. Following oral administration of CONCERTA to adults, the drug overcoat dissolves and plasma methylphenidate concentrations increase rapidly reaching an initial maximum at about 1 to 2 hours. The methylphenidate contained in two internal drug layers is gradually released over the next few hours. Peak plasma concentrations are achieved at about 6 to 8 hours after which plasma levels of methylphenidate gradually decrease. CONCERTA once daily minimises the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily. The extent of absorption of CONCERTA once daily is generally comparable to conventional immediate release preparations given three times daily.
Following the administration of CONCERTA 18 mg once daily in 36 adults, the mean pharmacokinetic parameters were Cmax 3.7 ± 1.0 ng/mL, Tmax 6.8 ± 1.8 h, AUC∞ 41.8 ± 13.9 ngh/mL and t1/2 3.5 ± 0.4 h. No differences in the pharmacokinetics of CONCERTA were noted following single and repeated once daily dosing indicating no significant drug accumulation. The AUC and t1/2 following repeated once daily dosing are similar to those following the first dose of CONCERTA 18 mg.
Following administration of CONCERTA in single doses of 18, 36 and 54 mg/day to adults, Cmax and AUC0-∞ of d-methylphenidate were proportional to dose, whereas l-methylphenidate Cmax and AUC0-∞ increased disproportionately with respect to dose. Following administration of CONCERTA, plasma concentrations of the l-isomer were approximately 1/40th the plasma concentrations of the d-isomer.
In healthy adults, single and multiple dosing of once daily CONCERTA 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, (alpha)-phenyl-piperidine acetic acid (PPAA). The single dose and steady state (Day 4) clearance and half-life parameters were similar, indicating that 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.
Pharmacokinetic equivalence has been demonstrated for two 27-mg CONCERTA tablets with three 18-mg CONCERTA tablets. The mean values of the treatment ratio (2 × 27 mg fasted/3 × 18 mg fasted) of the logtransformed pharmacokinetic values for Cmax, Tmax and AUCinf were 101.1%, 104.3% and 100.3% respectively. The 90% CIs for the treatment ratios were within the pre-specified 80%-125% range.
In a multiple dose study in adolescent ADHD patients aged 13 to 16 administered their prescribed dose (18 to 72 mg/day) of CONCERTA, mean Cmax and AUCTAU of methylphenidate increased proportionally with respect to dose.
Studies on the effects of dosing after overnight fasting, after consumption of a normal breakfast and a high-fat breakfast showed no differences in pharmacokinetics or pharmacodynamics of CONCERTA. There is no evidence of dose dumping in the presence or absence of food.
Plasma methylphenidate concentrations in adults decline biexponentially following oral administration. The terminal plasma half-life of methylphenidate in adults following oral administration of CONCERTA was approximately 3.5 hours.
In humans, methylphenidate is metabolised primarily by de-esterification to α-phenyl-piperidine acetic acid (PPAA) which has little or no pharmacologic activity. In adults the metabolism of CONCERTA once daily, as evaluated by metabolism to PPAA, is similar to that of methylphenidate three times daily. The metabolism of single and repeated once daily doses of CONCERTA is similar.
After oral dosing of radiolabelled 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. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is not expected to have a significant effect on the pharmacokinetics of CONCERTA.
In a lifetime dietary carcinogenicity study carried out in mice, methylphenidate caused an increase in hepatocellular adenomas at a dose of 60–80 mg/kg/day, and in males only, an increase in hepatoblastomas (a relatively rare rodent malignant tumour type) at 60 mg/kg/day. These dose levels are approximately 3–8 fold the maximal recommended clinical dose on a mg/m² basis. There was no increase in tumours at 30-40 mg/kg/day (approximately 1-4 fold the maximal recommended clinical dose on a mg/m² basis). The mouse strain used is sensitive to the development of hepatic tumours, and the significance of these results to humans is not known. There was no evidence of carcinogenicity in two strains of transgenic mice administered methylphenidate in the diet for 24 weeks at doses up to 60–74 mg/kg/day (approximately 3–8 fold the maximal recommended clinical dose on a mg/m² basis) or in a lifetime dietary study in rats at doses up to 50 mg/kg/day (approximately 4–10 fold the maximal recommended clinical dose on a mg/m² basis).
Methylphenidate was not mutagenic in the in vitro assays (Ames reverse mutation assay, mouse lymphoma cell forward mutation assay). Methylphenidate was weakly clastogenic in vitro (Chinese Hamster ovary cells) but was negative in vivo (mouse bone marrow micronucleus assay). Sister chromatid exchange assay results were positive only at high (cytotoxic) concentrations.
Dietary administration of methylphenidate to male and female mice at doses up to 150–160 mg/kg/day did not impair fertility in an 18–week continuous breeding study in which both parents and offspring were treated. This dose was approximately 7–16 fold the maximal recommended human dose on a mg/m² basis.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
