Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Accord-UK Ltd (Trading style: Accord), Whiddon Valley, Barnstaple, Devon, EX32 8NS
Pharmacotherapeutic group: Psychoanaleptics; centrally acting sympathomimetics
ATC code: N06BA04
Methylphenidate HCl is a mild 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 noradrenaline and dopamine into the presynaptic neurone 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.
In the pivotal clinical studies, methylphenidate prolonged-release tablets were assessed in 321 patients already stabilised with immediate release preparations (IR) of methylphenidate and in 95 patients not previously treated with IR preparations of methylphenidate.
Clinical studies showed that the effects of methylphenidate prolonged-release tablets were maintained until 12 hours after dosing when the product was taken once daily in the morning.
Eight hundred ninety-nine (899) adults with ADHD aged 18 to 65 years were evaluated in three double-blind, placebo- controlled studies of 5 to 13 weeks duration. Some short-term efficacy has been demonstrated for methylphenidate prolonged-release tablets in a dosage range of 18 to 72 mg/day, but this has not been consistently shown beyond 5 weeks. In one study, in which response was defined as at least a 30% reduction from baseline in Conners' Adult ADHD Rating Scales (CAARS) ADHD Symptoms total score at Week 5 (endpoint) and analysed assuming subjects with missing data at their final visit were non-responders, a significantly higher proportion of patients responded to treatment with methylphenidate prolonged-release tablets at doses of 18, 36, or 72 mg/day compared to placebo. In the two other studies, when analysed assuming subjects with missing data at their final visit were non-responders, there were numerical advantages for methylphenidate prolonged-release tablets compared to placebo but a statistically significant difference in the proportion of patients meeting predefined response criteria was not demonstrated between methylphenidate prolonged-release tablets and placebo.
Methylphenidate is readily absorbed. Following oral administration of methylphenidate prolonged-release tablets in adults the tablet coating dissolves, providing an initial maximum methylphenidate concentration at about 1 to 2 hours. The methylphenidate contained in the tablet core is gradually released over the next several hours. Peak plasma concentrations are achieved at about 6 to 8 hours, after which plasma levels of methylphenidate gradually decrease. Methylphenidate prolonged-release tablets taken once daily minimises the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily. The extent of absorption of methylphenidate prolonged-release tablets once daily is generally comparable to conventional immediate release preparations.
Following the administration of methylphenidate prolonged-release tablets 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), AUCinf 41.8 ± 13.9 (ng.h/mL), and t½ 3.5 ± 0.4 (h).
No differences in the pharmacokinetics of methylphenidate prolonged-release tablets were noted following single and repeated once daily dosing, indicating no significant methylphenidate accumulation. The AUC and t1/2 following repeated once daily dosing are similar to those following the first dose of methylphenidate prolonged-release tablets 18 mg.
Following administration of methylphenidate prolonged-release tablets in single doses of 18, 36, and 54 mg/day to adults, Cmax and AUC(0-inf) of methylphenidate were proportional to dose.
Plasma methylphenidate concentrations in adults decline biexponentially following oral administration. The half-life of methylphenidate in adults following oral administration of methylphenidate prolonged-release tablets was approximately 3.5 h. The rate of protein binding of methylphenidate and of its metabolites is approximately 15%. The apparent volume of distribution of methylphenidate is approximately 13 litres/kg.
In humans, methylphenidate is metabolised primarily by de-esterification to alpha-phenyl-piperidine acetic acid (PPA, approximately 50 fold the level of the unchanged substance) which has little or no pharmacologic activity. In adults the metabolism of methylphenidate prolonged-release tablets once daily as evaluated by metabolism to PPA is similar to that of methylphenidate three times daily. The metabolism of single and repeated once daily doses of methylphenidate prolonged-release tablets is similar.
The elimination half-life of methylphenidate in adults following administration of methylphenidate prolonged-release tablets was approximately 3.5 hours. After oral administration, about 90% of the dose is excreted in urine and 1 to 3% in faeces, as metabolites within 48 to 96 hours. Small quantities of unchanged methylphenidate are recovered in urine (less than 1%). The main urinary metabolite is alpha-phenyl-piperidine acetic acid (60-90%).
After oral dosing of radiolabelled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPA, accounting for approximately 80% of the dose.
In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of methylphenidate prolonged-release tablets when administered after a high fat breakfast on an empty stomach.
In healthy adults, the mean dose-adjusted AUC values for methylphenidate prolonged-release tablets 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 healthy adults receiving methylphenidate prolonged-release tablets, dose-adjusted AUC was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics.
The pharmacokinetics of methylphenidate prolonged-release tablets has not been studied in children younger than 6 years of age. In children 7-12 years of age, the pharmacokinetics of methylphenidate prolonged-release tablets after 18, 36 and 54 mg were (mean±SD): Cmax 6.0 ± 1.3, 11.3 ± 2.6, and 15.0 ± 3.8 ng/mL, respectively, Tmax 9.4 ± 0.02, 8.1 ± 1.1, 9.1 ± 2.5 h, respectively, and AUC0-11.5 50.4 ± 7.8, 87.7 ± 18.2, 121.5 ± 37.3 ng.h/mL, respectively.
There is no experience with the use of methylphenidate prolonged-release tablets in patients with renal insufficiency. After oral administration of radiolabelled methylphenidate in humans, methylphenidate was extensively metabolised and approximately 80% of the radioactivity was excreted in the urine in the form of PPA. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of methylphenidate prolonged-release tablets.
There is no experience with the use of methylphenidate prolonged-release tablets in patients with hepatic insufficiency.
In life-time rat and mouse carcinogenicity studies, increased numbers of malignant liver tumours were noted in male mice only. The significance of this finding to humans is unknown.
Methylphenidate did not affect reproductive performance or fertility at low multiples of the clinical dose.
Methylphenidate is not considered to be teratogenic in rats and rabbits. Foetal toxicity (i.e. total litter loss) and maternal toxicity was noted in rats at maternally toxic doses.
© 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.
