Melatonin Other names: N-acetyl-5-methoxytryptamine Pineal Hormone

Prostaglandin synthesis inhibitors (NSAIDs) such as acetylsalicylic acid and ibuprofen, given in the evening may suppress endogenous melatonin levels in the early part of the night by up to 75%. If possible, administration of NSAIDs should be avoided in the evening.

CYP1A2 inducers such as carbamazepine and rifampicin may reduce plasma concentrations of melatonin. Therefore, when CYP1A2 inducers and melatonin are both given, dose adjustment may be required.

CYP1A2 inhibitors such as quinolones (ciprofloxacin and norfloxacin) may give rise to increased melatonin exposure.

There is no experience of the use of melatonin in patients with liver impairment. Published data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment. Therefore, melatonin is not recommended for use in patients with hepatic 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.

Alcohol should not be taken with melatonin, because it reduces the effectiveness of melatonin on sleep.

Beta-blockers may supress the night-time release of endogenous melatonin and thus should be administered in the morning.

Caution should be exercised in patients on oestrogens (e.g. contraceptive or hormone replacement therapy), which increase melatonin levels by inhibiting its metabolism by CYP1A1 and CYP1A2.

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.

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 inhibiting its metabolism.

Fluvoxamine increases melatonin levels (by 17-fold higher AUC and a 12-fold higher serum C_max) by inhibiting its metabolism by hepatic cytochrome P450 (CYP) isozymes CYP1A2 and CYP2C19. The combination should be avoided.

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.

Smoking is known to induce CYP1A2 metabolism, therefore if patients stop or start smoking during treatment with melatonin, dose adjustment may be required.

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.

Caution should be exercised in patients on 5- or 8-methoxypsoralen (5 or 8-MOP), which increases melatonin levels by inhibiting its metabolism.

There are no data from the use of melatonin in pregnant women. Animal studies do not indicate reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of melatonin during pregnancy.

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.

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

Summary of the safety profile

In clinical trials (in which a total of 1,931 patients were taking melatonin and 1,642 patients were taking placebo), 48.8% of patients receiving melatonin reported an adverse reaction compared with 37.8% taking placebo. Comparing the rate of patients with adverse reactions per 100 patient weeks, the rate was higher for placebo than melatonin (5.743 – placebo vs. 3.013 – melatonin). The most common adverse reactions were headache, nasopharyngitis, back pain, and arthralgia, which were common, by MedDRA definition, in both the melatonin and placebo treated groups.

Tabulated list of adverse reactions

The following adverse reactions were reported in clinical trials and from post-marketing spontaneous reporting. In clinical trials a total of 9.5% of patients receiving melatonin reported an adverse reaction compared with 7.4% of patients taking placebo. Only those adverse reactions reported during clinical trials occurring in patients at an equivalent or greater rate than placebo have been included below.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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 established from the available data).

Paediatric population

The most frequently reported adverse reactions with melatonin 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.

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.