Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

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 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.

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 inhibiting its metabolism.

Oestrogens
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.

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

CYP1A2 inducers
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.

Smoking

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

NSAIDs

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.

Beta-blockers

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