RUBIFEN Immediate release tablet, Sustained release tablet Ref.[50684] Active ingredients: Methylphenidate

Absorption

Immediate release tablets: After oral administration the active substance (methylphenidate hydrochloride) is rapidly and almost completely absorbed. Owing to extensive first-pass metabolism its systemic availability is only 30% (11-51%) of the dose. Ingestion with food accelerates absorption, but has no effect on the amount absorbed.

Peak plasma concentrations of about 40 nmol/L (11 ng/mL) are reached on average 1-2 hours after administration of 0.30 mg/kg. Peak plasma concentrations vary markedly between patients. The area under the concentration-time curve (AUC) and the peak plasma concentration (_Cmax) are proportional to the dose.

SR Tablets: in the fasted state, absorption of methylphenidate from Rubifen 20 mg SR tablets is 37% slower than with the conventional tablets and results in a smaller fluctuation of plasma concentration. C_max is lower (by 40%) and is attained later (at 3 hours) but the total amount absorbed (AUC) is the same.

After a high-fat meal, both AUC (by 25%) and C_max (by 27%) are significantly higher, although the rate of absorption (C_max/AUC ratio) remains the same. Time to C_max (T_max) is also slightly faster after a high-fat meal (median T_max = 2.5 hrs.) as compared to without food (median T_max = 3 hrs.). As with immediate release tablets, there is considerable variation in plasma methylphenidate concentrations between patients.

Distribution

In blood, methylphenidate and its metabolites are distributed between plasma (57%) and erythrocytes (43%). Binding to plasma proteins is low (10-33%). The apparent distribution volume is about 13.1 L/kg.

Methylphenidate excretion into breast milk has been noted in two case reports, where the calculated relative infant dose was ≤0.2% of the weight adjusted maternal dose. Adverse events were not noted in either infant (6 months of age and 11 months of age).

Biotransformation

Biotransformation of methylphenidate is rapid and extensive. Peak plasma concentrations of the main, de-esterified metabolite α-phenyl-2-piperidine acetic acid are attained about 2 hours after administration and are 30-50 times higher than those of the unchanged substance. The half-life of α-phenyl-2- piperidine acetic acid is about twice that of methylphenidate, and its mean systemic clearance is 0.17 L/h/kg. Only small amounts of hydroxylated metabolites (e.g. hydroxymethylphenidate and hydroxyritalinic acid) are detectable. Therapeutic activity seems to be principally due to the parent compound.

Elimination

Methylphenidate is eliminated from the plasma with a mean half-life of 2 hours. The apparent mean systemic clearance is 10 L/h/kg. After oral administration, 78-97% of the dose is excreted in the urine and 1-3% in the faeces in the form of metabolites within 48-96 hours. Only small quantities (<1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as α-phenyl2-piperidine acetic acid (60-86%).

The elimination half-life and the cumulative urinary excretion of α-phenyl-2-piperidine acetic acid are not significantly different for SR tablets. Hence, in the fasted state, the total amount absorbed from one SR tablet and 20 mg in conventional tablet form is equal.

Special Populations

There are no apparent differences in the pharmacokinetics of methylphenidate between hyperactive children and healthy adult volunteers.

Elimination data from patients with normal renal function suggest that renal excretion of unchanged methylphenidate would hardly be diminished in the presence of impaired renal function. However, renal excretion of the metabolite α-phenyl-2-piperidine acetic acid may be reduced.

Not applicable.