Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Shire Pharmaceuticals Ireland Limited, Block 2 & 3, Miesian Plaza, 50-58 Baggot Street Lower, Dublin 2, Ireland
Pharmacotherapeutic group: Psychoanaleptics, Psychostimulants and agents used for ADHD and nootropics, Centrally acting Sympathomimetics
ATC code: N06BA04
Equasym XL 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.
In a pivotal study 318 subjects aged between 6 and 12 years received at least one dose of study medication out of 327 subjects randomized. Scores for the IOWA Conner’s rating, the primary efficacy endpoint assessed by teachers during the school day, showed the following results for the per protocol population (279 patients treated for 21 days):
| Placebo (N=39)a | Immediate Release Methylphenidate (N=120)b | Equasym XL (N=120) | |
|---|---|---|---|
| Baseline Mean (SD) | 6.0 (3.64) | 6.1 (3.74) | 5.8 (3.59) |
| Day 21/Withdrawal | |||
| LS Mean (SE) | 7.7 (0.50) | 4.3 (0.29) | 4.5 (0.29) |
| 95% CI | 6.69, 8.66 | 3.71, 4.84 | 3.98, 51.0 |
| Difference from Placebo | - | -3.4 | -3.1 |
| 95% CI for the difference | - | -4.53, -2.26 | -4.26, -2.00 |
| P-valuec | - | <0.001 | <0.001 |
| Difference from MIR | - | - | -0.3 |
| 97.5% lower CI bound for the difference | - | - | -1.06 |
a N=38 at Day 7
b N=118 at Day 7
c Treatment groups have been compared using ANCOVA, with effects for treatment and baseline as covariates
In contrast to these results for the primary efficacy measure, differences between the Equasym XL and immediate release methylphenidate groups were observed for the Parent IOWA Conner’s secondary efficacy variable. This was based on assessments later in the evening, suggesting that there is some loss of efficacy of Equasym XL late in the day relative to twice daily immediate release methylphenidate. See also section 5.2. (Pharmacokinetic properties) and section 4.2 (Posology and method of administration).
The mechanism by which Equasym XL 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. It is thought to block the re-uptake of noradrenaline and dopamine into the presynaptic neurone and increase the release of these monoamines into the extraneuronal space. Equasym XL is a racemic mixture of the d- and l-threo enantiomers of methylphenidate. The d-enantiomer is more pharmacologically active than the l-enantiomer.
Equasym XL has a plasma profile showing two phases of active substance release, with a sharp, initial, upward slope similar to a methylphenidate immediate-release tablet, and a second rising portion approximately three hours later, followed by a gradual decline.
Peak plasma concentrations of approximately 40 nmol/litre (11 ng/ml) are attained, on average, 1-2 hours after administration of 0.30 mg/kg. The peak plasma concentrations, however, show considerable intersubject variability.
The range of concentrations at 1.5 hours was 3.2–13.3 ng/ml with a mean of 7.7 ng/ml. The second phase of release resulted in a second maximum observed concentration in most subjects at 4.5 hours after dosing, with the observed concentrations ranging from 4.9–15.5 ng/ml with a mean of 8.2 ng/ml. Administration of an extended release formulation at breakfast instead of two immediate release formulation tablets (breakfast and lunch) may reduce the pre-lunch trough and post lunch peak of methylphenidate, and plasma levels may be lower after the end of the school day. Clinical trial data suggest that the different pharmacokinetic profiles may result in a different pattern of behaviour and symptom control during the day for some patients compared with a conventional immediate release methylphenidate regimen. In particular there may be some reduction of symptom control in the late afternoon and early evening (see section 5.1 Pharmacodynamic properties). These differences should be taken into consideration when assessing their individual requirements.
The area under the plasma concentration curve (AUC), as well as the peak plasma concentration, is proportional to the dose.
Ingestion together with food with a high fat content delays its absorption (Tmax) by approximately one hour and increases the maximum concentration (Cmax) by approximately 30% and the amount absorbed (AUC) by approximately 17%.
The Cmax Tmax and AUC of the sprinkled contents of the Equasym XL capsule are similar (bioequivalent) to the intact capsule. Equasym XL may, therefore, be administered either as an intact capsule, or the capsule may be opened and the contents swallowed, without chewing, immediately after sprinkling onto applesauce or other similar soft food.
The Pharmacokinetics of Equasym XL have not been studied in children younger than 7 years of age.
Owing to extensive first-pass metabolism its systemic availability amounts to approximately 30% (11-51%) of the dose.
In the blood, methylphenidate and its metabolites become distributed in the plasma (57%) and the erythrocytes (43%). Methylphenidate and its metabolites have a low plasma protein-building rate (10-33%). The apparent distribution has been calculated as 13.1 litres/kg.
Methylphenidate is eliminated from the plasma with a mean half-life 2 hours, and the calculated mean systemic clearance is 10 litres/h/kg.
Within 48-96 hours 78-97% of the dose administered is excreted in the urine and 1-3% in the faeces in the form of metabolites.
The bulk of the dose is excreted in the urine as 2-phenyl-2-piperidyl acetic acid (PPAA, 60-86%).
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.
Methylphenidate is not considered to be a teratogenic in rats and rabbits. Foetal toxicity (i.e. total litter loss) and maternal toxicity was noted in rats at maternally toxic doses.
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