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Pharmacotherapeutic group: psychoanaleptics, psychostimulants, agents used for ADHD and nootropics; centrally acting sympathomimetics. ATC Code: N06BA04.
Pharmacology: Pharmacodynamics: Mechanism of action: MEDIKINET MR is a mild CNS stimulant with more prominent effects on mental than on motor activities. Its mode of action in man is not completely understood but its effects are thought to be due to cortical stimulation and possibly to stimulation of the reticular activating system.
The mechanism by which MEDIKINET MR exerts its mental and behavioural effects in patients is not clearly established, nor is there conclusive evidence showing how these effects relate to the condition of the central nervous system. It is thought to block the re-uptake of norepinephrine and dopamine into the presynaptic neurone and increase the release of these monoamines into the extraneuronal space. MEDIKINET MR is a racemic mixture of the d- and l-threo enantiomers of methylphenidate. The d-enantiomer is more pharmacologically active than the l-enantiomer.
Clinical efficacy and safety: After approval for the treatment of ADHD in children MEDIKINET MR has been investigated in two randomised, double-blind, placebo-controlled clinical studies on adult patients. 363 patients were investigated in the EMMA study (1) during a treatment period lasting 24 weeks. In the QUMEA study (2) 162 patients were treated for a total of 20 weeks. After the 8-week-double-blind-phase of this, all patients were treated in the open phase for further 12 weeks with MEDIKINET MR. The main target parameter in both studies was WRI score reduction (Wender-Reimherr-Interview = WRAADS). The measurement time point was week 24 (study 1) or week 8 (study 2).
The daily dose was individually titrated in weekly stages starting with 10 mg a day depending on efficacy and tolerability (study 1) or starting with a dose of 0.5 mg/kg body weight (study 2). A dose of 60 mg a day (study 1) or 1 mg/kg body weight (study 2) should not be exceeded. In the first study, the average dose of methylphenidate at end point was lower, 0.55 mg/kg body weight (administered daily dose min. 10 mg, max. 60 mg) compared with the second study, on average 0.9 mg/kg body weight (administered daily dose min. 20 mg, max. 120 mg). A greater effect size for the whole study population was calculated when administering a higher average dose (0.9 mg/kg body weight), as was the case in the QUMEA study. The clinical studies yielded only limited experience with daily doses of over 80 mg, since only 2 patients were treated with 120 mg/day.
Dose/Gender effects: The results of the first study (EMMA) reveal that gender-specific differences in the response to methylphenidate and the possibility that women could benefit from lower doses cannot be ruled out.
This study demonstrated efficacy in men solely in the highest dose range with MPH > 0.7 mg/kg body weight. In women, however, efficacy was demonstrated even in the low (< 0.3 mg/kg body weight) and mid dose range (0.3-0.7 mg/kg body weight). With respect to reduction in symptoms, women in the high dose group showed no significant effect and, with respect to response rate, efficacy was comparable with that in lower dose groups.
In the second study (QUMEA) these gender-specific effects could not be confirmed reliably. This was because the low dose range was not administered and only a few patients were treated in the mid dose range. In the high dose group, the response rate in women was significantly higher in the comparison between verum and placebo. For men, a non-significant result was obtained. With respect to the main target parameter (WRI reduction in week 8), a significant score reduction when compared to placebo was obtained in both men and women.
The following data was obtained for the study population as a whole: With respect to reduction in the total WRI score in the EMMA study the change from baseline to week 24 was -18.88 on verum compared to -13.99 on placebo, giving an effect size of 0.39, 95% CI (0.18, 0.63, for effect size) p=0.002. (ANOVA using LOCF for missing values). In the QUMEA the change from baseline to week 8 was -13.2 on verum compared to -6.2 on placebo, giving an effect size of 0.54, 95% CI (0.22, 0.85, for effect size) p=0.0001. (ANOVA using LOCF for missing values).
The recalculated responder rate was determined as: Responder: Patients with WRAADDS Score 30% reduction or more and without trial discontinuation, Non-Responder: Patients with less reduction in WRAADDS score or early trial discontinuation for every reason, which lead to missing values in week 24 or 8). In the EMMA trial the recalculated responder rate was 128 (53%) in the verum group vs. 44 (37%) in the placebo group (Week 24, fisher's exact test, two-sided, 0.0051). The recalculated responder rate in the QUMEA study in week 8 was 41 (49%) vs. 14 (18%) (verum versus placebo, fisher's exact test, two-sided, p< 0.0001).
Medikinet XL was also studied in a further randomized, double-blind, placebo-controlled clinical trial (Comparison of Methylphenidate and Psychotherapy Study - COMPAS trial) in 433 adult patients. This study was conducted with Medikinet XL licensed nationally in Germany as "Medikinet adult".
The participants receive either cognitive behavioral group psychotherapy or individual clinical management with the offer for counseling in individual sessions in addition to daily doses of placebo or Medikinet XL. Treatment was conducted for 52 weeks.
The primary outcome of the study was reduction in ADHD symptoms, assessed by a decrease in the CAARS-O: L score from baseline to the end of the first 12-weeks of treatment.
As a result, a combination of group therapy or clinical management with Medikinet XL was superior to the same combination with placebo with respect to an improvement of ADHD symptoms. ADHD symptoms markedly improved during treatment with Medikinet XL (n = 210; adjusted mean ADHD index score, 16.2; ES = -0.81), as compared to placebo (n = 209; adjusted mean ADHD index score, 17.9; ES = -0.50). The difference was statistically significant (difference in ADHD index score values of Medikinet XL vs. Placebo -1.7; 97.5% CI, -3.0 vs. -0.4; 95% CI, -2..8 vs. -0..6; P = ..003).
The average daily dose (SD) in the 179 patients treated with Medikinet XL was 48.8 (20.2) mg.
The COMPAS trial showed that in adults, psychological interventions under controlled conditions rendered a superior treatment outcome (over 52 weeks) when combined with Medikinet XL, as compared to a combination with placebo.
Pharmacokinetics: Absorption: MEDIKINET MR has a plasma profile showing two phases of active substance release, with a sharp, initial, upward slope similar to a methylphenidate hydrochloride immediate-release tablet, and a second rising portion approximately three hours later, followed by a gradual decline.
When taken by adults in the morning after breakfast, the immediate-release portion of the hard capsule dissolves rapidly and results in an initial peak plasma concentration. After passing through the stomach and into the small intestine, the sustained-release portion of the hard capsule releases its methylphenidate hydrochloride. This results in the formation of a 3-4 hour plateau phase during which concentrations do not sink below 75% of the peak plasma concentration. The amount of methylphenidate hydrochloride absorbed when administered once daily is comparable with conventional immediate-release formulations administered twice daily.
MEDIKINET MR combines the advantages of a fast onset of action with the build-up of an extended duration plateau phase.
The following pharmacokinetic parameters were measured following a single daily dose of MEDIKINET MR 20 mg administered after breakfast: Cmax = 6.4 ng/ml, tmax = 2.75 h, AUCinf = 48.9 ng.h.ml-1 and t½ = 3.2 h.
The area under the plasma concentration curve (AUC), as well as the peak plasma concentration, is proportional to the dose.
Food Effects: Ingestion together with food with a high fat content delays its absorption (tmax) by approximately 1.5 hour. There is no difference in bioavailability of MEDIKINET MR given either a normal or high calorie breakfast. The plasma curves show similar exposure regarding rate and extend of absorption.
It is necessary to take MEDIKINET MR with or after breakfast. The food influence takes effect and shows a significant and relevant retardation. This justifies the posology to be taken with food. A recommendation in relation of type of food is not necessary. Administration without food can have a risk of dose dumping.
Sprinkle Administration: The Cmax, tmax, and AUC of the sprinkled contents of the MEDIKINET MR hard capsule are similar (bioequivalent) to the intact hard capsule. MEDIKINET MR may, therefore, be administered either as an intact hard capsule, or the hard capsule may be opened and the contents swallowed, without chewing, immediately after sprinkling onto applesauce or other similar soft food.
Availability, systemic: Owing to extensive first-pass metabolism, its systemic availability amounts to approximately 30% (11-51%) of the dose.
Distribution: In the blood, methylphenidate and its metabolites become distributed in plasma (57%) and erythrocytes (43%). Methylphenidate and its metabolites have a low plasma protein-binding (10-33%). The volume of distribution after a single intravenous dose is 2.2 l/kg (2.65±1.1 l/kg for d-methylphenidate and 1.8±0.9 L/kg for l-methylphenidate).
Elimination: Methylphenidate is eliminated from the plasma with an average half-life of approximately 2 hours.
The mean clearance after an intravenous single dose is 0.565 l/h/kg (0.40±0.12 l/h/kg for d-methylphenidate and 0.73±0.28 l/h/kg for l-methylphenidate). After oral administration, approximately 78-97% of the dose is excreted within 48 to 96 h via the urine and 1 to 3% via the faeces in the form of metabolites. Only small amounts (< 1%) of unchanged methylphenidate appear in the urine. A large proportion of an intravenous dose (89%) is eliminated in the urine within 16 hours, presumably regardless of the pH value, as ritalinic acid.
The renal elimination of ritalinic acid may decrease in the case of impaired renal function.
The bulk of the dose is excreted in the urine as 2-phenyl-2-piperidyl acetic acid (PPAA, 60-86%).
Pharmacokinetics in special patient groups: Paediatric population: The pharmacokinetics of Medikinet MR in children younger 6 years of age have not been studied.
There are apparently no differences in the pharmacokinetics of methylphenidate between children with hyperkinetic disorder/ADHD and healthy adult subjects.
Elderly: The pharmacokinetics of Medikinet MR in patients aged 65 years and over have not been studied.
Renal impairment: Elimination data from patients with normal renal function suggest that renal excretion of the unchanged methylphenidate would hardly be diminished at all in the presence of impaired renal function. However, renal excretion of PPAA may be reduced.
Toxicology: Preclinical safety data: Carcinogenicity: 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.
Pregnancy-embryonal/foetal development: 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.
