Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1. Pharmacodynamic properties
Ritalin is a racemate consisting of a 1:1 mixture of d-methylphenidate (d-MPH) and l- methylphenidate (l-MPH).
Ritalin is a mild CNS stimulant with more prominent effects on mental than on motor activities. Its mode of action in humans is not completely understood, but its stimulant effects are thought to be due to an inhibition of dopamine and norepinephrine reuptake into presynaptic neurons and thereby increasing these neurotransmitters in the extraneuronal space.
The mechanism by which Ritalin exerts its mental and behavioural effects in children is not clearly established, nor is there conclusive evidence showing how these effects relate to the condition of the central nervous system.
The l-enantiomer is thought to be pharmacologically inactive.
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 efficacy and safety
Ritalin has been used for over 50 years in the treatment of ADHD. Its effectiveness in the treatment of ADHD is well established. In addition to improving core symptoms of ADHD, methylphenidate also improves behaviours associated with ADHD such as impaired academic performance and social function.
Studies in the published literature have shown Ritalin to significantly improve daytime sleepiness and cataplexy.

Children with ADHD
Ritalin LA was evaluated in a randomized, double-blind, placebo-controlled, parallel group clinical study in which 134 children, ages 6 to 12, with DSM-IV diagnoses of Attention Deficit Hyperactivity Disorder (ADHD) received a single morning dose of Ritalin LA in the range of 10-40 mg/day, or placebo, for up to 2 weeks. The optimal dose for each patient was determined in a dose titration phase of the study prior to randomization.
The primary efficacy variable was the change from baseline to the final rating in the ADHD/DSM-IV Scale for Teachers (CADS-T) total subscale score. The CADS-T assesses symptoms of hyperactivity and inattention. The analysis of the primary efficacy variable showed a significant treatment difference in favour of Ritalin LA (p < 0.0001). A statistically significant treatment effect for Ritalin LA relative to placebo was also found in all analyses of the secondary CADS efficacy variables, as well as in two post-hoc analyses for the ADHD diagnostic subtypes (combined type, inattentive type). The results of the primary and secondary efficacy analyses are summarized in Table 5.


RIT API 04APR24 V13           Page 17 of 22           reference: New Zealand Data Sheet Jan.2024 Table 5 ADHD/DSM-IV Subscales for teachers and parents, change from baseline (ITT population, LOCF analysis)
Ritalin LA              Placebo                                   p-value n          Mean change1 n                     Mean     change1
(SD2)                              (SD2)
CADS-T subscale
Total                       623          10.7 (15.7)        703           -2.8 (10.6)         < 0.0001 Inattentive                 62           5.3 (8.25)         70            -1.5 (5.67)         < 0.0001 Hyperactive-Impulsive       62           5.4 (7.95)         70            -1.3 (5.93)         < 0.0001 CADS-P subscale
Total                       63           6.3 (13.5)         70            0.5 (13.55)         0.0043 Inattentive                 63           2.8 (7.28)         70            0.2 (6.4)           0.0213 Hyperactive-Impulsive       63           3.5 (6.87)         70            0.3 (7.66)          0.0015 1 score at end of placebo-washout period minus final score
2 standard deviation
3 two patients (one in each treatment group) had no CADS-T baseline values but had post-randomization values.
They are, therefore, not included in the descriptive statistics.


Adults with ADHD
Ritalin LA was evaluated in a randomized, double-blind, placebo-controlled, multicentre study (RIT124D2302) 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: 1) 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).
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 6).
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.

Table 6 Analysis of improvement from baseline 1 to end of Period 1 in DSM IV ADHD RS total score and SDS total score by treatment / (LOCF*) for Period 1 Ritalin LA          Ritalin LA             Ritalin LA           Placebo 40 mg               60 mg                  80 mg n                  160                 155                    156                  161 

RIT API 04APR24 V13                Page 18 of 22             reference: New Zealand Data Sheet Jan.2024 Ritalin LA             Ritalin LA                 Ritalin LA              Placebo 40 mg                  60 mg                      80 mg
Change in DSM-        LS mean**             15.45                  14.71                      16.36                   9.35 IV ADHD RS from baseline         p-value               <0.0001                <0.0001                    <0.0001 
Significance          0.0167                 0.0208                     0.0313 level
Change in SDS         n                     151                    146                        148                     152 total score from
LS mean               5.89                   4.9                        6.47                    3.03 baseline p-value               0.0003                 0.0176                     <0.0001 Significance          0.0167                 0.0208                     0.0313 level***
* LOCF:      Last Observation Carried Forward using the final visit for each patient with data in the 6-week fixed- dose phase of Period 1
**LS mean: Least Square mean changes from Analysis of Covariance (ANCOVA) model with treatment group & centre as factors and baseline DSM-IV ADHD RS total score and SDS total score as covariate ***Significance level:      the final two-sided level of significance (alpha) for the test following the extended gatekeeping procedure

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 7). 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 (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.

Table 7 Percentage of treatment failures during Period 3
All Ritalin LA vs placebo
All Ritalin LA          Placebo                                P-value* N=352                   N=115              Odds ratio          (significance n (%)                   n (%)              (95% CI)            level**) Treatment failure                    75 (21.3)               57 (49.6)          0.3 (0.2, 0.4)          <0.0001 (0.0500) Not treatment failure                277 (78.7)              58 (50.4) * Two-sided p-value based on comparison between each Ritalin LA group and placebo using the logistic regression model.
**Significance level = the final two-sided level of significance (alpha) for the test following the extended gatekeeping procedure 
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 section 4.2 Posology and method of administration).
The long term efficacy and safety of Ritalin LA in adult patients was further evaluated in a 26-week open label extension study of Ritalin LA in 298 adult patients with ADHD
(RIT124D2302E1). Combining all patients in both studies, a total of 354 patients continuously received Ritalin LA for > 6 months and 136 patients for > 12 months.
The safety profile of Ritalin LA did not change with the longer duration of treatment of adult ADHD patients. The safety profile seen in study RIT124D2302E1 was similar to that observed in study RIT124D2302. No unexpected serious adverse events or adverse events were observed in this extension study and the commonly observed adverse events were expected and driven by the pharmacologic activity.
Furthermore, Ritalin LA treatment during the study consistently demonstrated clinical efficacy when using self-rated scales (SDS) and physician-rated scales (ie, DSM-IV ADHD RS, CGI-I, and CGI-S). The results were consistently in favor of Ritalin LA treatment across RIT API 04APR24 V13                      Page 19 of 22                    reference: New Zealand Data Sheet Jan.2024 all assessments. Patients continued to show symptomatic improvement and a reduction in functional impairment throughout the study as shown by the mean change in DSM-IV ADHD total score by -7.2 points and the mean change in SDS total score by 4.8 points when assessed against the extension baseline.

Pharmacokinetic Properties