Mellozzan 3 mg Tablet

Mellozzan is indicated for

- short term treatment of jet lag in adults (see 5.1)

- insomnia in children and adolescents aged 6-17 years with Attention-Deficit Hyperactivity Disorder (ADHD), where sleep hygiene measures have been insufficient

Posology

Adults with jet lag

The recommended dose is 0.5 - 5 mg for a maximum of 5 days.

The dose should be taken at the time of destination bedtime for journeys of 5 time zones or longer, especially when traveling in the easterly direction.

Due to the potential for incorrectly timed intake of melatonin to have no effect, or an adverse effect, on resynchronisation following jet lag, Mellozzan tablets should not be taken before 20:00 hr or after 04:00 hr at destination.

As alcohol can impair sleep and potentially worsen certain symptoms of jet lag (e.g. headache, morning fatigue, concentration) it is recommended that alcohol is not consumed when taking Mellozzan (see section 4.5).

A maximum of 16 treatment cycles may occur per year.

Insomnia in children and adolescents with ADHD

Treatment should be initiated by physicians experienced in ADHD and/or paediatric sleep medicine.

Recommended starting dose of Mellozzan tablets: 0.5 - 2 mg to be taken 30 - 60 minutes before bedtime.

The dose of melatonin can be increased by 1 mg every week until effect up to a maximum 5 mg per day, independent of age. The lowest effective dose should be sought.

Limited data are available for up to 3 years of treatment. After at least 3 months of treatment, the physician should evaluate the treatment effect and consider stopping treatment if no clinically relevant treatment effect is seen. The patient should be monitored at regular intervals (at least every 6 months) to check that Mellozzan is still the most appropriate treatment. During ongoing treatment, especially if the treatment effect is uncertain, discontinuation attempts should be done regularly, e.g. once per year.

If the sleep disorder has started during treatment with medicinal products for ADHD, dose adjustment or switching to another product should be considered.

Special populations

Elderly

As the pharmacokinetics of melatonin (immediate release) is comparable in young adults and elderly persons in general, no specific dosage recommendations for elderly persons are provided (see sections 4.4 and 5.2).

Renal impairment

The effect of any stage of renal impairment on melatonin pharmacokinetics has not been studied. Caution should be used when melatonin is administered to patients with renal impairment.

Hepatic impairment

Limited data indicate that plasma clearance of melatonin is significantly reduced in patients with liver cirrhosis. Mellozzan tablets are not recommended in patients with moderate or severe hepatic impairment (see section 5.2)

Children below 6 years of age

Mellozzan tablets are not recommended for children below 6 years with ADHD.

Method of administration

Oral use.

The tablets can be crushed and mixed with water directly before the administration.

Food can enhance the increase in plasma melatonin concentration (see section 5.2). Intake of melatonin with carbohydrate-rich meals may impair blood glucose control for several hours (see section 4.4). It is recommended that food is not consumed 2 hours before and 2 hours after intake of Mellozzan tablets.

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

Melatonin may cause drowsiness. Melatonin tablets should be used with caution if the effects of drowsiness are likely to be associated with a risk to patient safety.

Elderly

Exposure levels to melatonin after oral administration in young and moderately older adults are comparable. It is unclear if significantly older persons are especially sensitive to exogenous melatonin. Caution should therefore be exercised in treatment of this age group and individual dosage is recommended.

Immunological disease

Occasional case reports have described exacerbation of an autoimmune disease in patients taking melatonin. There are no data regarding use of melatonin tablets in patients with autoimmune diseases. Melatonin tablets are not recommended in patients with autoimmune diseases.

Epilepsy

Melatonin has been reported to increase, decrease and have no effect on seizure frequency. Because of the uncertainty of the effect of melatonin on epileptic seizures, caution should be exercised for use in people with epilepsy.

Diabetes

Limited data suggest that melatonin taken in close proximity to ingestion of carbohydrate-rich meals may impair blood glucose control for several hours. Melatonin tablets should be taken at least 2 hours before and at least 2 hours after a meal, ideally at least 3 hours after meal by persons with significantly impaired glucose tolerance or diabetes.

Pharmacokinetic interactions

Melatonin is mainly metabolised via CYP1A enzymes. Interactions between melatonin and other active substances affecting CYP1A enzymes are therefore possible.

CYP1A2 inhibitors

CYP1A2 inhibitors may increase the plasma concentrations of melatonin considerably. Concomitant treatment with melatonin and the CYP1A2 inhibitor fluvoxamine (also CYP2C19 inhibitor) should be avoided. Caution should be exercised when melatonin is used concomitantly with the following CYP1A2 inhibitors, ciprofloxacin, norfloxacin and verapamil.

Combined hormonal contraception: Contraceptives containing ethinylestradiol and gestagen can inhibit CYP1A2 and lead to a 4-5 times increase of melatonin concentration. The dose of melatonin may need to be reduced.

Hormonal substitution therapy: In post-menopausal women, hormonal substitution therapy has been reported to delay melatonin T_max without other effects on the melatonin concentration or melatonin rhythm.

Through interaction with moderately pronounced inhibitors of CYP1A2, increase of the plasma concentration of melatonin is expected. Caution is therefore indicated in patients taking 5- or 8-methoxypsoralen (5 or 8-MOP), cimetidine or caffeine.

CYP1A2 inducers

CYP1A2 inducers may decrease the plasma concentrations of melatonin.

Dose adjustment of melatonin may be needed if given concomitantly with the following CYP1A2 inducers: carbamazepine, phenytoin, rifampicin, omeprazole and cigarette smoking (halved exposure compared to after 7 days of smoking abstinence).

Pharmacodynamic interactions

Adrenergic agonists/antagonists, opiate agonists/antagonists, antidepressants, prostaglandin inhibitors, tryptophan and alcohol affect the endogenous secretion of melatonin in the epiphysis, but do not affect the metabolism of melatonin. It is not known if these interactions are of clinical significance.

Alcohol

Alcohol should not be used concomitantly with melatonin since it may reduce the effect of melatonin on sleep.

Nifedipine

Melatonin may reduce the hypotensive effect of nifedipine. Caution must be taken during concomitant use of melatonin and adjustment of the nifedipine dose may be needed. As it is not known if this is a class effect, caution should be exercised when combining melatonin and other calcium antagonists.

Warfarin

It has been reported in case reports that concomitant use of melatonin and vitamin K antagonists such as warfarin can lead to either increased or decreased prothrombin levels, and a study has shown decreased levels of factor VIII:C and fibrinogen. The combination of warfarin or other vitamin K antagonists with melatonin may require dose adjustment of the anticoagulant drugs and should be avoided.

Benzodiazepine-related hypnotics

Melatonin may enhance the sedative properties of benzodiazepine-related hypnotics, e.g. zolpidem. Concomitant treatment with melatonin should be avoided.

NSAIDs.

Prostaglandin synthesis inhibitors (NSAIDs) such as acetylsalicylic acid and ibuprofen, taken in the evening, may suppress endogenous melatonin levels. If possible, administration of NSAIDs should be avoided in the evening.

Beta-blockers

Beta-blockers may suppress the endogenous melatonin and should therefore be administered in the morning

Pregnancy

There are no data from the use of melatonin in pregnant women. Animal studies are incomplete regarding effects on pregnancy, embryonic / foetal development, childbirth and postnatal development (see section 5.3). Exogenous melatonin readily crosses the human placenta. Considering the lack of clinical data, treatment with Mellozzan is not recommended during pregnancy or in women of childbearing potential not using contraceptives.

Breastfeeding

Data from animal studies indicate maternal transfer of melatonin to the foetus via the placenta or in the milk (see section 5.3). Endogenous melatonin has also been measured in breast milk from breast-feeding women, and therefore exogenous melatonin is most likely also excreted in human milk. Melatonin is therefore not recommended to breastfeeding women.

Fertility

No adequate data on the effect of melatonin on human fertility are available. Animal studies are incomplete in terms of effects on fertility (see section 5.3). High doses of melatonin and use for longer periods than indicated may compromise fertility in humans.

Melatonin has moderate effect on the ability to drive and use machines. Melatonin may cause dizziness and should therefore be used with caution if the effects of drowsiness are likely to be associated with a safety risk.

Summary of the safety profile

Melatonin causes few and no serious adverse reactions in the short term, up to three months. Long-term effects are poorly studied. Reported adverse reactions to melatonin are mainly headaches, nausea and fatigue in both adults and children.

However, these adverse reactions are also common for placebo-treated patients in reported clinical studies and no significant difference between patients receiving active substance and placebo is generally present in these studies.

No very common side effects have been reported.

Adverse reactions in adults are listed according to MedDRA system organ class and presented within each frequency category according to the following: 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).

Paediatric population

A low frequency of in general mild adverse reactions have been reported in the paediatric population.

The number of adverse reactions has not differed significantly between children who have received placebo compared to melatonin. The most common adverse reactions were headache, hyperactivity, dizziness and abdominal pain. No serious adverse reactions have been observed.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Drowsiness, headache, dizziness and nausea are the most commonly reported signs and symptoms of overdose with oral melatonin.

Daily doses of 20-50 mg as well as 300 mg in up to 2 years have been reported in the literature, without any clinically significant adverse reactions.

One dose of 250 mg taken 4 times daily during 25-30 days have only been reported to cause drowsiness/sleepiness. Also, in several cases of reported overdosing, mildly to moderately severe somnolence was the most commonly reported adverse reaction.

After doses of 3.0 -6.6 grams for 15-36 days, 6 of 11 patients reported somnolence during daytime and 4 of 11 patients reported stomach cramps, diarrhoea or migraine headaches.

Clearance of the active substance is expected within 12 hours of ingestion. A physician should assess if conventional overdose measures should be taken. No special treatment is required.

Pharmacotherapeutic group: Hypnotics and sedatives, melatonin receptor agonists, ATC code: N05CH01

Melatonin is a hormone produced by the pineal gland. It is structurally related to serotonin. Melatonin secretion increases shortly after dark, reaching its peak between 02:00 and 04:00 in the morning and decreases during the latter half of the night. Melatonin is involved in controlling the circadian rhythm and adaptation to the light-dark cycle. Melatonin is also associated with a sedative effect and an increased propensity for sleep.

Mechanism of action

The activity of melatonin on the MT1, MT2 and MT3 receptors is considered to contribute to its effect on sleep, as these receptors (especially MT1 and MT2) are involved in the regulation of circadian rhythm and sleep.

Pharmacodynamic effects

Melatonin has a hypnotic / sedative effect and increases propensity for sleep. Melatonin administered earlier or later than the nocturnal peak in melatonin secretion can, respectively, advance or delay the circadian rhythmicity of melatonin secretion. Administration of melatonin at bedtime (between 22:00 and 24:00 hr) at destination following rapid transmeridian travel (aircraft flight) hastens resynchronisation of circadian rhythmicity from 'departure time' to 'destination time' and ameliorates the collection of symptoms known as jet lag that are a consequence of such de-synchronisation.

Clinical efficacy

Typical symptoms of jet lag are sleep disturbances and daytime tiredness and fatigue, though mild cognitive impairment, irritability and gastrointestinal disturbances may also occur.

Jet lag is worse the more time-zones crossed, and is typically worse following eastward travel. Eight of ten clinical trials found that melatonin, taken close to the target bedtime at the destination (10 pm to midnight), decreased jet lag from flights crossing five or more time zones. The benefit is likely to be greater the more time zones are crossed and less for westward flights. Daily doses of melatonin between 0.5 mg and 5 mg are similarly effective, except that people fall asleep faster and sleep better after 5 mg than 0.5 mg.

Clinical trials have found melatonin to reduce patient-assessed overall symptoms of jet lag by ~44%, and to shorten the duration of jet lag. In 2 studies of flights over 12 time-zones melatonin effectively reduced the duration of jet lag by ~33%. Due to the potential for incorrectly timed intake of melatonin to have no effect, or to cause an adverse effect, on re-synchronisation of circadian rhythmicity/jet lag, melatonin should not be taken before 20:00 hr or after 04:00 hr at destination.

Paediatric population

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. Participants received melatonin (3 mg when body weight <40 kg [n = 44]; or 6 mg when body weight >40 kg [n = 9]) in fast-release tablets or placebo.

Mean actigraphic estimate of sleep onset advanced by 26.9 ± 47.8 minutes with melatonin, whereas there was a delay of 10.5 ± 37.4 minutes with placebo (p < 0.0001). 48.8% of children who received melatonin showed an advance of sleep onset >30 minutes compared to 12.8% with placebo (p = 0.001). There was an increase in mean total time asleep of 19.8 ± 61.9 minutes with melatonin and a decrease of 13.6 ± 50.6 minutes with placebo (p = 0.01). As compared with placebo, the melatonin group showed a decrease in sleep latency (p = 0.001) and increase in sleep efficiency (p = 0.01). The mean score on sleep log item difficulty falling asleep decreased by 1.2 ± 1.3 points (35.3% of baseline) with melatonin and by 0.1 ± 0.8 points (4.3% of baseline) with placebo (p < 0.0001).

Absorption

Absolute bioavailability of melatonin has been estimated in two studies to average 13% of the given dose via solution and 14–16% of the given dose via tablet.

Maximum concentration of orally administered melatonin occurs after 15–90 minutes (median T_max = 52 min).

Maximum concentration and exposure of melatonin after oral dosing of tablets increases proportionally to the dose from 0.25 up to 10 mg.

Data on the effect of intake of food at or around the time of intake of melatonin on its pharmacokinetics are limited, though suggest that concomitant food intake may increase the absorption almost 2-fold. Food appears to have a limited effect on T_max for immediate-release melatonin. This is not expected to affect the efficacy or safety of Mellozzan, however, it is recommended that food is not consumed approximately 2 hours before and 2 hours after intake of melatonin (see section 4.2).

Distribution

The plasma protein binding of melatonin in vitro is about 60%. Distribution volume during terminal elimination phase is proportional to body weight, averaging just over 1 L/kg.

Biotransformation

Melatonin is mainly eliminated by hydroxylation to 6-hydroxymelatonin in the liver, primarily mediated by CYP1A2 (to a lesser extent by CYP1A1). Quantitatively less important O-demethylation to N-acetyl-5-hydroxytryptamine mediated by CYP2C19 occurs. Melatonin metabolites are mainly eliminated by the urine, ~90% as sulphate and glucuronide conjugates of 6-hydroxymelatonin. Less than ~1% of a melatonin dose is excreted unchanged in urine.

Elimination and accumulation

Plasma elimination half-life (T½) is ~45 minutes (normal range ~30–60 minutes) in healthy adults. The half-life, on average, is comparable or slightly shorter in children compared to adults. Dosage once daily in combination with the short half-life means minimal accumulation of melatonin during regular treatment.

Special patient groups

Elderly

In a comparative study of serum melatonin with and without exogenous supplementation, lower concentrations were found in moderately older adults without treatment, while a trend toward higher concentrations was observed compared to healthy younger adults after treatment. The difference during treatment was not statistically significant; the same dosage may be recommended for moderately older as for younger adults.

Hepatic impairment

Limited data indicate that the daytime endogenous blood melatonin concentration is markedly elevated in patients with liver cirrhosis, probably due to reduced clearance (metabolism) of melatonin. Serum t½ for exogenous melatonin in cirrhosis patients was double that of controls in a small study.

As the liver is the primary site of melatonin metabolism, hepatic impairment can be expected to result in increased exposure to exogenous melatonin.

Renal impairment

The effect of any stage of renal impairment on melatonin pharmacokinetics has not been studied (see section 4.2).

Preclinical data reveal no special hazard for humans based on studies of repeated dose toxicity or genotoxicity.

The data regarding reproductive toxicology is limited. A study in pregnant rats did not show direct or indirect harmful effects with respect to pregnancy, foetal survival or foetal development.

Data from animal studies indicate that melatonin is transmitted to the foetus via the placenta and to breast milk.

There are no safety studies on juvenile animals.

Microcrystalline cellulose

Pregelatinized starch

Colloidal anhydrous silica

Magnesium stearate

Not applicable.

36 months

Store in the original container in order to protect from light.

HDPE bottle with polyethylene cap containing 30 or 100 tablets. Not all pack sizes may be marketed.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.