Ritalin/Ritalin LA

Ritalin/Ritalin LA Mechanism of Action





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Pharmacology: Ritalin is a racemate consisting of a 1:1 mixture of d-threo methylphenidate (d-MPH) and l-threo methylphenidate (l-MPH).
Methylphenidate is a central nervous system (CNS) stimulant. Its mode of action in humans is not completely understood but methylphenidate presumably exerts its stimulant effect by an inhibition of dopamine reuptake in the striatum, without triggering the release of dopamine. There is neither specific evidence which clearly establishes the mechanism whereby methylphenidate produces its mental and behavioural effects in children, nor conclusive evidence as to how these effects relate to the condition of the central nervous system.
The l-enantiomer is thought to be pharmacologically inactive.
Repeated oral administration of methylphenidate to young rats was associated with decreased spontaneous locomotor activity at systemic exposures (plasma AUC) about 3-fold that at the maximum clinical dose, due to an exaggerated pharmacological activity of methylphenidate. A deficit in the acquisition of a specific learning task was also observed, only in females, at systemic exposures (plasma AUC) 8-fold that at the maximum clinical dose. The clinical relevance of these findings is unknown.
The effect of treatment with 40 mg dexmethylphenidate hydrochloride, the pharmacologically active d-enantiomer of Ritalin, on QT/QTc interval was evaluated in a study in 75 healthy volunteers. The maximum mean prolongation of QTcF intervals was <5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time matched comparisons versus placebo. This was below the threshold of clinical concern and no exposure response relationship was evident.
Clinical Trials: Studies in published literature have shown that Ritalin significantly improves daytime sleepiness and cataplexy.
ADHD in Children: Ritalin LA was demonstrated to be effective in the treatment of ADHD in two placebo-controlled clinical studies in children aged 6-12 years with a DSM-IV diagnosis of ADHD (n=195 exposed to study medicine).
The results of the first study (Protocol 02), a randomised, double-blind, placebo controlled, crossover clinical study conducted in a laboratory classroom setting, demonstrated that a single dose of 20 mg Ritalin LA had a rapid onset of effect and was statistically superior to placebo in improving classroom behaviour and cognitive responses. After administration of Ritalin LA, the improvement relative to placebo was statistically significant during both the morning (0-4 hours) and the afternoon (4-9 hours).
The second study (Protocol 07) was a randomised, double-blind, placebo controlled, parallel group clinical study conducted in normal school and home settings, in which Ritalin LA was administered once daily at individually titrated doses in the range of 10-40 mg/day for up to two weeks. The primary efficacy variable was the change from baseline to final score in the Connors ADHD/DSM-IV Scale for Teachers (CADS-T). CADS-T assesses symptoms of hyperactivity and inattention. The results of the analysis demonstrate that Ritalin LA was statistically superior to placebo (p<0.0001). The efficacy of Ritalin LA in controlling symptoms of ADHD was consistently reflected in the assessments of teachers, parents and investigators. The results of the primary efficacy analysis  is summarised in Table 1. (See Table 1.)

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ADHD in Adults: Ritalin LA was evaluated in a randomized, double-blind, placebo-controlled, multicentre study in the treatment of 725 adult patients (395 male and 330 female) diagnosed with ADHD according to DSM-IV ADHD criteria. The study was designed to: Confirm the clinically effective and safe dose range of Ritalin LA for adults (18 to 60 years old) in a 9-week, double-blind, randomized, placebo-controlled, parallel group period (Period 1) consisting of a 3-week titration stage followed by a 6-week fixed dose stage (40, 60, 80 mg/day or placebo). Subsequently patients were re-titrated to their optimal dose of Ritalin LA (40, 60 or 80 mg/day) over a 5 week period (Period 2). Evaluate the maintenance of effect of Ritalin LA in adults with ADHD in a 6 month, double-blind, randomized, withdrawal study (Period 3).
Efficacy was assessed using the DSM-IV ADHD rating scale (DSM-IV ADHD RS) for symptomatic control and Sheehan Disability Score (SDS) for functional improvement as change in respective total scores from baseline to the end of the first period. All dose levels of Ritalin LA showed significantly greater symptom control (p<0.0001 for all dose levels) compared to placebo as measured by a reduction in DSM-IV ADHD RS total score. All doses of Ritalin LA showed significantly greater functional improvement (p=0.0003 at 40 mg, p=0.0176 at 60 mg, p<0.0001 at 80 mg) compared to placebo as measured by reduction in SDS total score (see Table 2).

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Significant clinical efficacy was demonstrated in all three Ritalin LA dose levels using physician rated scales [Clinical Global Impression- Improvement (CGI-I) and Clinical Global Improvement- Severity (CGI-S)], self-rated scales [Adult Self-Rating Scale (ASRS)] and observer-rated scales [Conners' Adult ADHD Rating Scale Observer Short Version (CAARS O:S)]. The results were consistently in favour of Ritalin LA over placebo across all assessments in Period 1.
Maintenance of effect of Ritalin LA was evaluated by measuring the percentage of treatment failure in Ritalin LA compared to the placebo group at the end of a 6-month maintenance period (see Table 3). Completion rates varied across the treatment groups, with the lowest rate in the placebo group (34.1%) and rates between 47.7% and 58.3% across the Ritalin LA dose group. Once the Ritalin LA dose was optimized in Period 2, approximately 79% of patients continued to maintain disease control for a period of at least 6 months compared with approximately 50% given placebo (p<0.0001 vs placebo). An odds ratio of 0.3 suggested that patients treated with placebo had a 3 times higher chance of becoming a treatment failure compared to Ritalin LA (see Table 3).

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Patients who entered Period 3 had completed a total of between 5-14 weeks of Ritalin LA treatment in Periods 1 and 2. Patients then assigned to placebo in Period 3 did not experience increased signs of withdrawal and rebound compared to patients who continued on Ritalin LA treatment. The study performed in adults did not suggest any difference in efficacy or safety amongst gender subgroups (see Dosage & Administration).Efficacy was maintained or improved in the majority of subjects who elected to continue open-label treatment with Ritalin LA for up a further 26 weeks. Symptomatic improvement and a reduction in functional impairment was maintained or improved throughout the 26 week extension study period in the patients who elected to continue open label treatment with Ritalin LA.
Pharmacokinetics: Absorption: Ritalin: Following oral administration of Ritalin tablets, the active substance, methylphenidate hydrochloride, is rapidly and almost completely absorbed from the tablets. Owing to extensive first-pass metabolism, the absolute bioavailability was 22 ± 8% for the d-enantiomer and 5 ± 3% for the l-enantiomer. Ingestion with food increased both the Cmax (23%) and the AUC (15%) of methylphenidate, but had no effect on the rate of absorption. Peak plasma concentrations of approx. 40 nmol/L (11 ng/mL) are attained, on the average, 2 hours after administration.  The peak plasma concentrations, however, vary markedly from one person to another. The area under the plasma concentration curve (AUC), as well as the peak plasma concentration, is proportional to the size of the dose administered.
Ritalin LA: Following oral administration of Ritalin LA capsules to children diagnosed with Attention-Deficit Hyperactivity Disorder (ADHD) and adults, methylphenidate is rapidly absorbed and produces a bimodal plasma concentration-time profile (i.e. two distinct peaks approximately four hours apart). The relative bioavailability of Ritalin LA capsules administered once daily is comparable to the same total dose of immediate release methylphenidate HCl tablets administered twice daily in children and in adults.
The fluctuations between peak and trough plasma methylphenidate concentrations are smaller for Ritalin LA capsules administered once daily compared to methylphenidate HCl tablets administered twice daily.
Mean pharmacokinetic parameters for Ritalin LA 40 mg capsules administered as a single dose once daily compared to methylphenidate HCl 20 mg immediate-release tablets administered twice daily four hours apart are summarised in Table 4. (See Table 4.)

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Food Effects: Ritalin LA may be administered with or without food. There were no significant differences in AUC when Ritalin LA was administered with either a high fat breakfast or applesauce, compared to administration in the fasting condition, although a high fat meal and applesauce reduced Cmax2 by 25% and 13% respectively. There is no evidence of dose dumping in the presence or absence of food.
For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered (see Dosage & Administration).
Distribution: In the blood, methylphenidate and its metabolites become distributed in the plasma (57%) and the erythrocytes (43%). Methylphenidate and its metabolites have low plasma protein-binding (approximately 15%). The apparent volume of distribution (Vd) has been calculated at 13.1 L/kg after an oral dose. The volume of distribution was 2.65 ± 1.11 L/kg for d-MPH and 1.80 ± 0.91 L/kg for l-MPH, following intravenous administration of 10 mg MPH.
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 (see Precautions). Adverse events were not noted in either infant (6 months and 11 months of age).
Metabolism: Biotransformation of methylphenidate, primarily by the carboxyl esterase CES1A1, is rapid and extensive. Peak plasma concentrations of the main, deesterified, metabolite, α-phenyl-2-piperidine acetic-acid (ritalinic acid), are attained about 2 hours after administration and are 30 to 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. 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 to 3 hours, and the calculated mean systemic clearance is 4 to 10 L/h/kg after an oral dose. The systemic clearance is 0.40±0.12 L/h/kg for d-MPH and 0.73±0.28 L/h/kg for l-MPH. Within 48 to 96 hours, 78 to 97% of the dose administered is excreted in the urine and 1 to 3% in the faeces in the form of metabolites. Unchanged methylphenidate appears in the urine only in small quantities (<1%). Most of the dose is excreted in the urine as α-phenyl-2-piperidine acetic acid (60-86%).
Special Populations: Effects of Age: There are no apparent differences in the pharmacokinetic behaviour of methylphenidate in hyperactive children and healthy adult volunteers.
Renal Impairment: 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.
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