Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: RAD Neurim Pharmaceuticals EEC SARL, 4 rue de Marivaux, 75002 Paris, France, e-mail: regulatory@neurim.com
Pharmacotherapeutic group: Psycholeptics, melatonin receptor agonists
ATC code: N05CH01
The activity of melatonin at the melatonin receptors (MT1, MT2 and MT3) is believed to contribute to its sleep-promoting properties, as these receptors (mainly MT1 and MT2) are involved in the regulation of circadian rhythms and sleep regulation.
Efficacy and safety have been assessed in a randomised, placebo-controlled study in children diagnosed with ASDs and neurodevelopmental disabilities caused by Smith-Magenis syndrome who had not shown improvement after standard sleep behavioural intervention. Treatment was administered for up to two years.
The study comprises 5 periods: 1) pre-study period (4 weeks), 2) baseline single-blind placebo period (2 weeks), 3) randomized placebo-controlled treatment period (13 weeks), 4) open label treatment period (91 weeks), and 5) single blind run-out period (2 weeks placebo).
A total of 125 children (2-17.0 years of age, mean age 8.7 +/- 4.15; 96.8% ASD, 3.2% Smith-Magenis syndrome [SMS]) whose sleep failed to improve on behavioural intervention alone were randomized and 112 weeks' results are available. 28.8% patients were diagnosed with ADHD before study initiation and 77% had abnormal SDQ hyperactivity/inattention score (>=7) at baseline.
The study met the primary endpoint, demonstrating statistically significant effects of Slenyto 2/5 mg versus placebo on change from baseline in mean Sleep and Nap Diary (SND)-assessed Total Sleep Time (TST) after 13 weeks of double-blind treatment. At baseline, mean TST was 457.2 minutes in the Slenyto and 459.9 minutes in the placebo group. After 13 weeks of double-blind treatment, participants slept on average 57.5 minutes longer at night with Slenyto compared to 9.1 minutes with placebo adjusted mean treatment difference Slenyto–placebo 33.1 minutes in the all Randomized Set; Multiple Imputation (MI) (p=0 .026).
At baseline, mean Sleep Latency (SL) was 95.2 minutes in the Slenyto and 98.8 minutes in the placebo group. By the end of the 13-week treatment period, children fell asleep on average 39.6 minutes faster with Slenyto and 12.5 minutes faster with placebo adjusted mean treatment difference -25.3 minutes in the all Randomized Set; MI (p=0.012) without causing earlier wakeup time. The rate of participants attaining clinically meaningful responses in TST (increase of 45 minutes from baseline) and/or SL (decrease of 15 minutes from baseline) was significantly higher with Slenyto than with placebo (68.9% versus 39.3% respectively; p=0 .001).
Besides shortening of SL, increase in the longest sleep episode (LSE) = uninterrupted sleep duration compared to placebo was observed. By the end of the 13-week double-blind period, the mean LSE increased on average by 77.9 minutes in the Slenyto treated group, compared to 25.5 minutes in the placebo-treated group. The adjusted estimated treatment differences were 43.2 minutes in the all Randomized Set (MI, p=0.039). Wake up time was unaffected; after 13 weeks, patients' wake up time was delayed insignificantly by 0.09 hour (0.215) (5.4 minutes) with Slenyto compared to placebo treatment.
Slenyto 2 mg/5 mg treatment resulted in a significant improvement over placebo in the child’s externalizing behaviours (hyperactivity/inattention+ conduct scores) as assessed by the Strength and Difficulties Questionnaire (SDQ) after 13 weeks of double-blind treatment (p=0.021). For the total SDQ score after 13 weeks of double blind treatment, there was a trend to benefit in favour of Slenyto (p=0.077). For social functioning (CGAS), the differences between Slenyto and placebo were small and not statistically significant (Table 1).
Table 1. CHILD BEHAVIOUR (13 weeks Double-blind):
| Variable | Group | Adjusted treatment means (SE) [95% CI] | Treatment difference (SE) | 95% CI | p-value* |
|---|---|---|---|---|---|
| SDQ | |||||
| Externalizing behaviours | Slenyto | -0.70 (0.244) [-1.19;-0.22] | 2<> -0.83 (0.355) | 2<> -1.54,-0.13 | 2<>0.021 |
| Placebo | 0.13 (0.258) [-0.38; 0.64] | ||||
| Total score | Slenyto | -0.84 (0.387) [-1.61, -0.07] | 2<> -1.01 (0.563) | 2<> -2.12, 0.11 | 2<>0.077 |
| Placebo | 0.17 (0.409) [-0.64, 0.98] | ||||
| CGAS | |||||
| Slenyto Placebo | 1.96 (1.328) (-0.67,4.60) 1.84 (1.355) (-0.84,4.52) | 0.13 (1.901) | -3.64,3.89 | ns | |
* MMRM analysis CI = confidence interval; SDQ = Strength and Difficulties Questionnaire; CGAS = the Children’s Global Assessment Scale; SE = standard error
The treatment effects on sleep variables were associated with improved parents' well-being. There was a significant improvement with Slenyto over placebo in Composite Sleep Disturbance Index (CSDI) - assessed parent satisfaction in child sleep pattern (p=0.005) and in caregivers' well-being as assessed by the WHO-5 after 13 weeks of double-blind treatment (p=0.01) (Table 2).
Table 2. PARENTS WELL BEING (13 weeks Double-blind):
| Variable | Group | Adjusted treatment means (SE) [95% CI] | Treatment difference (SE) | 95% CI | p-value* |
|---|---|---|---|---|---|
| WHO-5 | Slenyto | 1.43 (0.565) (0.31,2.55) | 2.17 (0.831) | 0.53,3.82 | 0.01 |
| Placebo | -0.75 (0.608) (-1.95,0.46) | ||||
| CSDI satisfaction | Slenyto | 1.43 (0.175) (1.08,1.78) | 0.72 (0.254) | 0.22,1.23 | 0.005 |
| Placebo | 0.71 (0.184) (0.34,1.07) |
* MMRM analysis CI = confidence interval; WHO-5= the World Health Organization Well-Being Index; CSDI = Composite Sleep Disturbance Index; SE = standard error
Patients (51 from the Slenyto group and 44 from the placebo group, mean age 9 ± 4.24 years, range 2-17.0 years) received open-label Slenyto 2/5 mg according to the double-blind phase dose, for 91 weeks with optional dose adjustment to 2, 5 or 10 mg/day after the first 13 weeks of follow-up period. 74 patients completed 104 weeks of treatment, 39 completed 2 years and 35 completed 21 months of Slenyto treatment. The improvements in total sleep time (TST), sleep latency (SL) and duration of uninterrupted sleep (LSE; longest sleep episode) seen in the double blind-phase were maintained throughout the 39 weeks' follow up period.
After 2 weeks withdrawal on placebo, a descriptive reduction in most scores was seen but levels were still significantly better than baseline levels with no signs of rebound effects.
In the Slenyto study described above, 36 participants in addition to ASD had an ADHD diagnosed in their medical history. Analysis of the effects of Slenyto on the primary endpoint, TST, demonstrated the same level of improvement in participants with and without ADHD comorbidity.
Melatonin treatment has been studied in a 4-week randomized, double-blind, placebo- controlled study conducted in 105 children between 6-12 years of age, with ADHD and chronic sleep onset insomnia who did not receive ADHD medications or behavioural intervention (van der Heijden KB et al. 2007). In this study, immediate release melatonin supplementation was used at a dose of 3 mg or 6 mg for 4 weeks. Melatonin treatment advanced circadian rhythms of sleep-wake and shortened sleep latency in children with ADHD and chronic sleep onset insomnia. Mean sleep latency decreased by 21.3 minutes in the melatonin group and increased by 3 minutes in the placebo group. Total time asleep increased by 19.8 minutes in the melatonin group and decreased by 13.6 minutes in the placebo group. Immediate release melatonin had no effect on problem behaviour, cognitive performance, or quality of life.
In the paediatric population comprising 16 ASD children ages 7-15 years old suffering from insomnia, following Slenyto 2 mg (2 × 1 mg mini-tablets) administration after a standardized breakfast, melatonin concentrations peaked within 2 hours after administration and remained elevated for 6 hours thereafter with a Cmax (SD) of 410 pg/ml (210) in the saliva.
In adults, following Slenyto 5 mg (1 × 5 mg mini-tablet) administered after food, melatonin concentrations peaked within 3 hours after administration; Cmax (SD) was 3.57 ng/ml (3.64) in plasma. Under fasted conditions Cmax was lower (1.73 ng/ml) and tmax was earlier (within 2 hours) with a minor effect on AUC-∞ that was slightly reduced (-14%) as compared to fed state.
The absorption of orally ingested melatonin is complete in adults and may be decreased by up to 50% in the elderly. The kinetics of melatonin are linear over the range of 2-8 mg.
Data with 2 mg prolonged release melatonin tablets and data with 1 mg and 5 mg mini-tablets indicate that there is no accumulation of melatonin after repeated dosing. This finding is compatible with the short half-life of melatonin in humans.
Bioavailability is in the order of 15%. There is a significant first pass effect with an estimated first pass metabolism of 85%.
The in vitro plasma protein binding of melatonin is approximately 60%. Melatonin is mainly bound to albumin, alpha1-acid glycoprotein and high density lipoprotein.
Melatonin undergoes a fast first hepatic pass metabolism and is metabolised predominantly by CYP1A enzymes, and possibly CYP2C19 of the cytochrome P450 system with elimination half life of ca 40 minutes. Prepubertal children and young adults metabolize melatonin faster than adults. Altogether, melatonin metabolism declines with age, with pre-pubertal and pubertal metabolism faster than at older age. The principal metabolite is 6-sulfatoxy-melatonin (6-S-MT), which is inactive. The site of biotransformation is the liver. The excretion of the metabolite is completed within 12 hours after ingestion.
Melatonin does not induce CYP1A2 or CYP3A enzymes in vitro at supra-therapeutic concentrations.
Terminal half life (t½) is 3.5-4 hours. Two liver-mediated metabolic pathways account for around 90% of melatonin metabolism. The predominant metabolic flux is through hydroxylation at C6 via the hepatic microsome P-450 system to yield 6-hydroxymelatonin. The second, less significant, pathway is 5-demethylation to yield a physiological melatonin precursor, N-acetylserotonin. Both 6-hydroxymelatonin and N-acetylserotonin are ultimately conjugated to sulfate and glucoronic acid, and excreted in the urine as their corresponding 6-sulfatoxy and 6-glucoronide derivatives.
Elimination is by renal excretion of metabolites, 89% as sulfated and glucoronide conjugates of 6-hydroxymelatonin (over 80% as 6-sulfatoxy melatonin) and 2% is excreted as melatonin (unchanged active substance).
A 3-4-fold increase in Cmax is apparent for women compared to men. A five-fold variability in Cmax between different members of the same sex has also been observed. However, no pharmacodynamic differences between males and females were found despite differences in blood levels.
There is no experience of the use of melatonin in paediatric patients with renal impairment (see Section 4.2). However as melatonin is mainly eliminated via liver metabolism, and the metabolite 6-SMT is inactive, renal impairment is not expected to influence clearance of melatonin.
The liver is the primary site of melatonin metabolism and therefore, hepatic impairment results in higher endogenous melatonin levels.
Plasma melatonin levels in patients with cirrhosis were significantly increased during daylight hours. Patients had a significantly decreased total excretion of 6-sulfatoxymelatonin compared with controls. There is no experience of the use of melatonin in paediatric patients with liver impairment. Published data demonstrate markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment (see Section 4.2).
Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
A slight effect on post-natal growth and viability was found in rats only at very high doses, equivalent to approximately 2000 mg/day in humans.
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