Slenyto · 4.6 Fertility, pregnancy and lactation · 1

HOS-098231 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The most frequently reported adverse reactions with Slenyto in clinical studies were somnolence, fatigue, mood swings, headache, irritability, aggression and hangover occurring in 1:100-1:10 children. Tabulated list of adverse reactions Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 6  System Organ Class Common Psychiatric disorders Mood swings, Aggression, Irritability Nervous system disorders Somnolence, Headache, Sudden onset of sleep Respiratory, thoracic and Sinusitis mediastinal disorders General disorders and Fatigue, Hangover administration site conditions The following adverse reactions (frequency unknown) have been reported with off-label use of the adult formulation, 2 mg prolonged-release melatonin tablets: epilepsy, visual impairment, dyspnoea, epistaxis, constipation, decreased appetite, swelling face, skin lesion, feeling abnormal, abnormal behaviour and neutropenia. Furthermore, in ASD and neurogenetic children treated with 2-6 mg of the adult formulation under a Temporary Recommendation for Use (RTU) program in France (N=926), the following additional adverse reactions (frequency uncommon) have been reported: depression, nightmares, agitation and abdominal pain. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

HOS-098227 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-098226 · has-indication-information · PDF-Seite 2

Slenyto is indicated for: - treatment of insomnia in children and adolescents aged 2-18 years with Autism Spectrum Disorder (ASD), and / or neurogenetic disorders with aberrant diurnal melatonin secretion and /or nocturnal awakenings, where sleep hygiene measures have been insufficient. - treatment of insomnia in children and adolescents aged 6-17 years with attention-deficit hyperactivity disorder (ADHD) where sleep hygiene measures have been insufficient. 2

HOS-098229 · has-interaction-information · PDF-Seite 4

Interaction studies have only been performed in adults. In the absence of specific studies in children, the drug interactions with melatonin are those known in adults. Melatonin’s metabolism is mainly mediated by CYP1A enzymes. Therefore, interactions between melatonin and other active substances as a consequence of their effect on CYP1A enzymes is possible. Concomitant use not recommended Concomitant use of the following medicinal products and alcohol is not recommended (see section 4.4): Fluvoxamine Fluvoxamine increases melatonin levels (by 17-fold higher AUC and a 12-fold higher serum Cmax) by inhibiting its metabolism by hepatic cytochrome P450 (CYP) isozymes CYP1A2 and CYP2C19. The combination should be avoided. Alcohol Alcohol should not be taken with melatonin, because it reduces the effectiveness of melatonin on sleep. 4 Benzodiazepines/non-benzodiazepine hypnotics Melatonin may enhance the sedative properties of benzodiazepines and non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone. In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between melatonin and zolpidem one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and co-ordination compared to zolpidem alone. Combination with benzodiazepines and non-benzodiazepine hypnotics should be avoided. Thioridazine and imipramine Melatonin has been co-administered in studies with thioridazine and imipramine, active substances which affect the central nervous system. No clinically significant pharmacokinetic interactions were found in each case. However, melatonin co-administration resulted in increased feelings of tranquility and difficulty in performing tasks compared to imipramine alone, and increased feelings of “muzzy- headedness” compared to thioridazine alone. Combination with thioridazine and imipramine should be avoided. Concomitant use to be considered with caution Concomitant use of the following medicinal products should be considered with caution: 5- or 8-methoxypsoralen Caution should be exercised in patients on 5- or 8-methoxypsoralen (5 or 8-MOP), which increases melatonin levels by inhibiting its metabolism. Cimetidine Caution should be exercised in patients on cimetidine which is a potent inhibitor of certain cytochrome P450 (CYP450) enzymes, mainly CYP1A2 and thereby increases plasma melatonin levels, by inhi

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HOS-098230 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no data from the use of melatonin in pregnant women. Animal studies do not indicate reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of melatonin during pregnancy. Breastfeeding Endogenous melatonin was measured in human breast milk thus exogenous melatonin is probably secreted into human milk. Data in animals indicate maternal transfer of melatonin to the foetus via the placenta or in the milk. The effect of melatonin on newborns/infants is unknown. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from melatonin therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Fertility In studies performed in both adult and juvenile animals, melatonin had no effect on male or female fertility (see section 5.3).

HOS-098228 · has-warning-information · PDF-Seite 4

Drowsiness Melatonin may cause drowsiness and residual effects such as daytime fatigue may occur. These effects should be considered, particularly in children and adolescents with ADHD, as they may exacerbate daytime symptoms like inattention, hyperactivity, or behavioural disturbances. Caregivers and healthcare professionals should monitor patients for signs of daytime fatigue and adjust the dosing schedule or discontinue treatment if such effects impair daily functioning. Therefore, the medicinal product should be used with caution if the effects of drowsiness are likely to be associated with a risk to safety (see section 4.7). Autoimmune diseases No clinical data exist concerning the use of melatonin in individuals with autoimmune diseases. Therefore, melatonin is not recommended for use in patients with autoimmune diseases. Interactions with other medicines and alcohol Concomitant use with fluvoxamine, alcohol, benzodiazepines/non-benzodiazepines hypnotics, thioridazine and imipramine is not recommended (see section 4.5). Lactose Slenyto contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.