Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: MYLAN (PTY) LTD, 4 Brewery Street, Isando, 1600, Republic of South Africa
A.1.2 Psychoanaleptics (antidepressants)
Pharmacotherapeutic group: Centrally Acting Sympathomimetics
ATC code: N06BA04
Methylphenidate HCI 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 well absorbed. Following oral administration of prolonged release methylphenidate to adults, plasma methylphenidate concentrations increase reaching an initial maximum at about 1 to 2 hours, then increase gradually over the next several hours.
Peak plasma concentrations are achieved at about 6 to 8 hours after which a gradual decrease in plasma levels of methylphenidate begins. Extended release methylphenidate once daily reduces the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily.
The mean pharmacokinetic parameters in 36 adults following the administration of extended release methylphenidate 18 mg once daily are summarised in Table 1 below.
Table 1. Mean ± SD pharmacokinetic parameters:
| Parameters | Extended release methylphenidate (18 mg once daily) (n=36) |
|---|---|
| Cmax (ng/ml) | 3,7 ± 1,0 |
| Tmax (h) | 6,8 ± 1,8 |
| AUCinf (ng-h/ml) | 41,8 ± 13,9 |
| t½ (h) | 3,5 ± 0,4 |
No differences in the pharmacokinetics of extended release methylphenidate were noted following single and repeated once daily dosing indicating no significant accumulation. The AUC and t½ following repeated once daily dosing are similar to those following the first dose of extended release methylphenidate.
Following administration of extended release methylphenidate in single doses of 18, 36 and 54 mg/day to healthy adults, Cmax and AUC(0-∞) of d-methylphenidate were proportional to dose, whereas l-methylphenidate Cmax and AUC(0-∞) increased disproportionately with respect to dose. Following administration of extended release methylphenidate, plasma concentrations of the l-isomer were approximately 1/40th the plasma concentrations of the disomer.
In healthy adults, single and multiple dosing of once daily extended release methylphenidate 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 compound (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 adolescents ADHD patients aged 13 – 16 administered their prescribed dose (18 to 72 mg/day) of extended release methylphenidate, mean Cmax and AUCTAU of methylphenidate increased proportionally with respect to the dose.
Plasma methylphenidate concentrations in adults decline bi-exponentially following oral administration. The half-life of methylphenidate in adults following oral administration of extended release methylphenidate was approximately 3,5 hours.
In humans, methylphenidate is metabolised primarily by de-esterification to (alpha)-phenylpiperidine acetic acid (PPAA) which has little or no pharmacologic activity. In adults, the metabolism of extended release methylphenidate 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 extended release methylphenidate 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.
In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of extended release methylphenidate when administered after a high fat breakfast. There is no evidence of dose dumping in the presence or absence of food.
The pharmacokinetics of extended release methylphenidate has not been studied in children less than 6 years of age.
There is no experience with the use of extended release methylphenidate in patients with renal insufficiency. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of extended release methylphenidate.
There is no experience with the use of extended release methylphenidate in patients with hepatic insufficiency.
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