Melatonin Noxarem 5 Mg 10 Tablets

1. NAME OF THE MEDICINE

Melatonin Noxarem 5 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

5 mg: each tablet contains 5 mg of melatonin.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Compressed.

5 mg: white capsule-shaped tablet with a score on one side, dimensions 10 mm x 5 mm. The tablet can be divided into equal doses.

4. CLINICAL DATA
4.1. Therapeutic indications

Melatonin Noxarem is used for the short-term treatment of jet lag in adults (see section 5.1).
4.2. Dosage and method of administration

Posology

The standard dose is one 3 mg tablet daily at local bedtime upon arrival at your destination for up to 4 days. If the standard 3 mg dose does not adequately relieve your symptoms, you can take a 5 mg tablet instead of the 3 mg tablet at your local bedtime. You should not take the 5 mg tablet in addition to the 3 mg tablet, but you can take the higher dose on subsequent days. The maximum daily dose is 5 mg once a day.

You should take the dose that adequately relieves your symptoms for the shortest period. Due to the possibility of melatonin not having an effect or causing an adverse effect on resynchronization after jet lag due to taking it at the wrong time, melatonin should not be taken before 8:00 p.m. or after 4:00 a.m. in the destination place.

Elderly patients

As the pharmacokinetics of exogenous (immediate-release) melatonin are comparable in young adults and older people in general, no dosing recommendation is provided for older people (see section 5.2).

Renal insufficiency

Only limited data are available regarding the use of melatonin in patients with kidney failure. Patients with kidney failure should be careful when using melatonin. Melatonin is not recommended for patients with chronic renal failure (see sections 4.4 and 5.2).

Liver failure

There are no data available regarding the use of melatonin in patients with hepatic impairment. Limited data indicate that plasma melatonin clearance is significantly decreased in patients with cirrhosis. Melatonin is not recommended for patients with hepatic impairment (see sections 4.4 and 5.2).

Pediatric population

The safety and effectiveness of melatonin in children and adolescents aged 0 to 18 years has not been established.

There is no available data.

Administration method

Orally. The tablets should be taken with a glass of water. Eating food at or near the time of taking melatonin is not expected to affect the effectiveness or safety of melatonin. However, it is recommended not to consume food approximately 2 hours before or 2 hours after taking melatonin (see sections 4.4 and 5.2).
4.3. Contraindications

Hypersensitivity to the active ingredient or to any of the excipients included in section 6.1.
4.4. Special warnings and precautions for use

Drowsiness

Melatonin can cause drowsiness. Therefore, the product should be used with caution if the effects of drowsiness are likely to constitute a safety risk (see section 4.7).

Autoimmune diseases

There are no clinical data on the use of melatonin in individuals with autoimmune diseases. Therefore, the use of Melatonin Noxarem is not recommended in patients with autoimmune diseases.

Liver and kidney failure

Only limited data are available on the safety and effectiveness of melatonin use in patients with hepatic or renal impairment. Melatonin is not recommended for patients with hepatic insufficiency or chronic renal insufficiency (see sections 4.2 and 5.2).

Cardiovascular conditions

There are limited data regarding the potential for melatonin to produce adverse effects on blood pressure and heart rate in populations with cardiovascular conditions taking concurrent antihypertensive medication. It is not clear whether these adverse effects can be attributed to melatonin itself or to interactions of melatonin with other drugs. The use of melatonin is not recommended in patients with cardiovascular conditions and concurrent antihypertensive medication.

Concomitant use of anticoagulants

Care should be taken when taking melatonin together with anticoagulant drugs, including warfarin and the newer direct-acting anticoagulants, as melatonin may increase the effect of these drugs, increasing the risk of bleeding (see section 4.5).

Glycemic control

Limited data suggest that taking melatonin close to the time of eating carbohydrate-rich meals may impair blood glucose control for several hours. Melatonin should be taken at least 2 hours before and 2 hours after a meal. Ideally, people with diabetes or significantly impaired glucose tolerance should take melatonin at least 3 hours after a meal (see sections 4.2 and 5.2). Unnecessary long-term use of melatonin should be avoided due to its effects on glucose metabolism and increased risk of type 2 diabetes.
4.5. Interaction with other medicinal products and other forms of interaction

Interaction studies have been carried out only with adults.

Concomitant use not recommended:

Patients taking fluvoxamine should be cautious as it increases melatonin levels [17-fold higher area under the curve (AUC) and 12-fold higher serum Cmax] by inhibiting its metabolism through hepatic isoenzymes CYP1A2 and CYP2C19. cytochrome P450 (CYP). The combination should be avoided.
You should not drink alcohol with melatonin, as it reduces its effectiveness on sleep. Alcohol can disrupt sleep and has the potential to worsen certain symptoms of jet lag (e.g., headache, morning fatigue, problems concentrating).

Concomitant use with caution:

Patients taking 5- or 8-methoxypsoralen (5 and 8 MOP) should use caution as it increases melatonin levels by inhibiting its metabolism.
Patients taking cimetidine should use caution as, by inhibiting its metabolism through CYP1A2, this agent increases plasma melatonin levels.
Patients taking estrogens (e.g., contraceptives or hormone replacement therapy) should use caution as they increase melatonin levels by inhibiting its metabolism through CYP1A1 and CYP1A2.
Patients taking nifedipine should use caution as concurrent use of melatonin and nifedipine may increase blood pressure.

Concomitant use leading to precautions and dosage adjustments:

The effects of other medications and extrinsic factors on melatonin:

CYP1A2 inhibitors, such as quinolones, may result in increased melatonin exposure.
CYP1A2 inducers such as carbamazepine and rifampicin may reduce plasma melatonin concentrations.
Cigarette smoking can reduce melatonin levels due to the induction of CYP1A2.
By inhibiting the metabolism of melatonin by the catalytic enzyme CYP1A2, caffeine increases the concentration of both endogenous melatonin and orally administered melatonin.
There is a large amount of data in the available information on the effect of adrenergic agonists/antagonists, opiate agonists/antagonists, antidepressant medications, prostaglandin inhibitors, benzodiazepines, tryptophan, and alcohol on blood secretion. endogenous melatonin. It has not been studied whether or not these active ingredients interfere with the dynamics or kinetic effects of melatonin or vice versa.
Food can affect plasma melatonin concentration (particularly Cmax) (see sections 4.2 and 5.2).

Effects of melatonin on other medicines:

Melatonin metabolism is primarily mediated by CYP1A enzymes. Therefore, it is possible that there are interactions between melatonin and other active ingredients as a consequence of its effect on CYP1A enzymes.
Melatonin may increase the sedative properties of benzodiazepines and non-benzodiazepine hypnotics, such as zaleplon, zolpidem, and zopiclone. In a clinical trial, clear evidence of a transient pharmacodynamic interaction between melatonin and zolpidem was obtained one hour after co-dosing. Coadministration resulted in increased attention, memory, and coordination problems compared to administration of zolpidem alone.
Melatonin has been co-administered in studies with thioridazine and imipramine, which are active ingredients that affect the central nervous system. No clinically significant pharmacokinetic interactions were found in each case. However, co-administration of melatonin resulted in a greater sense of calmness and difficulty performing tasks compared to taking imipramine alone, as well as a greater feeling of "foggy head" compared to thioridazine alone.
Concomitant use of melatonin and warfarin may result in increased anticoagulation, the INR should be reviewed when using them together. Melatonin may also increase the effect of direct-acting anticoagulants (e.g., dabigatran, rivaroxaban, apixaban, edoxaban).

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no clinical data available on pregnancies exposed to melatonin. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development (see section 5.3). Exogenous melatonin easily crosses the human placenta. In view of the absence of clinical data, use in pregnant women and women intending to become pregnant is not recommended.

Lactation

Endogenous melatonin was detected in human breast milk, meaning that exogenous melatonin is likely secreted into human breast milk. There is data in animal models, including rodents, sheep, cows, and primates, indicating maternal transfer of melatonin to the fetus via the placenta or milk. Therefore, melatonin should not be taken during pregnancy and breastfeeding.

Fertility

There are no data on the possible adverse effects of short-term use of melatonin on human fertility.
4.7. Effects on ability to drive and use machines

The influence of Melatonin Noxarem on the ability to drive and use machines is moderate. Melatonin Noxarem can cause drowsiness and alter alertness (vigilance) for hours; therefore, the product should be used with caution if the effects of drowsiness are likely to constitute a safety risk.

4.8. Adverse reactions

Security Profile Summary

Drowsiness/drowsiness, headache, and dizziness/disorientation are the most frequently reported adverse effects when taking melatonin short-term to treat jet lag. Drowsiness, headache, dizziness and nausea are the most common adverse effects in healthy people and patients who have taken typical clinical doses of melatonin over periods of several days to several weeks.

Tabulated list of adverse reactions

The following adverse reactions to melatonin have been reported in clinical trials or spontaneous case reports. In each frequency group, unwanted effects are presented in order of decreasing severity.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions to the medication after authorization. This allows for continued monitoring of the benefit/risk ratio of the medication. Healthcare professionals are invited to report suspected adverse reactions through the Spanish Pharmacovigilance System for Medicines for Human Use: www.notificaRAM.es.

4.9. Overdose

The administration of daily doses of up to 300 mg of melatonin has been reported without causing significant adverse reactions.

If an overdose occurs, drowsiness is expected. Clearance of the active ingredient is expected during the 12 hours after ingestion. Treatment in accordance with local emergency practices and contacting the Poison Information Service is recommended.

5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Psycholeptics, melatonin receptor agonists, ATC code: N05CH01

Melatonin is a natural hormone produced by the pineal gland that is structurally related to serotonin. Physiologically, melatonin secretion increases shortly after it begins to get dark, peaks between 2 and 4 am, and decreases during the second part of the night. Melatonin is associated with the control of circadian rhythms and incorporation into the light-dark cycle. It is also associated with a hypnotic effect and a greater tendency to sleep. Melatonin administered before or after the nocturnal peak in melatonin secretion can, respectively, advance or delay the circadian rhythm of melatonin secretion.

Mechanism of action

Melatonin's activity at MT1, MT2, and MT3 receptors is thought 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.

Clinical efficacy and safety

Typical symptoms of jet lag are sleep disorders, as well as tiredness and fatigue during the day, although mild cognitive problems, irritability and gastrointestinal disorders may also occur. Jet lag worsens depending on the number of time zones you cross, and is typically worse on eastbound trips, as people find it harder to advance their circadian rhythm (body clock) than to slow it down, which happens on westbound trips.

Adverse reactions reported in jet lag studies with melatonin doses between 0.5 and 8 mg were typically mild and often difficult to distinguish from jet lag symptoms.

Pediatric population

The safety and effectiveness of melatonin in children and adolescents aged 0 to 18 years has not been determined.
5.2. Pharmacokinetic properties

Absorption

In adults, the absorption of orally ingested melatonin is complete.

Bioavailability is around 15%. There is a significant first pass effect with a first pass metabolism of around 80 - 90%. The Tmax usually occurs approximately 50 minutes (normal range 15 to 90 minutes) after administration.

Data on the effect of eating food at or around the time of taking melatonin are limited. It appears that food has a negligible effect on Tmax. for immediate-release melatonin, but which considerably increases the variability in Cmax. The latter is not expected to affect the effectiveness or safety of melatonin. However, it is recommended not to consume food approximately 2 hours before or 2 hours after taking melatonin (see section 4.4).

Melatonin easily crosses the placenta. The cord blood level of full-term babies correlates with that of the mother, and is only slightly lower (~ 15 – 35%) after ingestion of a 3 mg dose.

Distribution

The in vitro plasma protein binding of melatonin is approximately 60%. Melatonin binds mainly to albumin, although it also binds to alpha1-acid glycoprotein; Binding to other plasma proteins is limited. Melatonin distributes rapidly from plasma to most tissues and organs and easily crosses the barrier between the brain and blood.

Biotransformation

Melatonin is primarily metabolized in the liver. Experimental data suggest that CYP1A1 and CYP1A2 of the cytochrome P450 isoenzyme system are primarily responsible for melatonin metabolism with CYP2C19 of minor importance. The main metabolite is inactive 6-sulfatoxy-melatonin. The metabolism is very fast, the metabolite level increases in a few minutes.

Elimination

The metabolites are excreted through the kidneys, 80% in the form of 6-sulfatoxy-melatonin.

The elimination half-life (t½) is approximately 45 minutes.

There are large differences in the pharmacokinetics of melatonin between individuals.

Linearity

The kinetics of oral melatonin are linear in a range of 0.1 - 8 mg.

Sex

Limited data suggest that Cmax. and the AUC after ingestion of immediate-release melatonin could be higher (potentially almost double) in women, compared to men, but also that the difference between the sexes is smaller than the variation between members of the same sex, particularly women in which the Cmax. seems to multiply several times. Plasma half-life does not appear to be significantly different in men and women.

Special populations

Elderly patients

Melatonin metabolism decreases with age. The concentration of plasma with nocturnal endogenous melatonin is lower in older people compared to young adults. Limited data on Tmax, plasma/serum Cmax, elimination half-life (T½) and AUC after ingestion of immediate-release melatonin do not indicate significant differences between younger adults and older people in general, although the range of values ​​(variability interindividual) of each parameter (particularly Tmax and AUC) is usually higher in older people.

Renal insufficiency

Published data indicate that there is no accumulation of melatonin after repeated dosing in patients on stable hemodialysis. As melatonin is mainly excreted as metabolites in the urine, serum/plasma levels of melatonin metabolites are expected to increase in patients with more advanced renal impairment.

Liver failure

Limited data indicate that daytime serum/plasma endogenous melatonin concentration is considerably elevated in patients with cirrhosis, probably due to reduced melatonin clearance; Serum T½ in patients with cirrhosis was twice that of study controls. As the liver is the primary organ for melatonin metabolism, liver failure is expected to result in increased exposure to exogenous melatonin.
5.3. Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

Reactions were only observed at exposures considered higher than the maximum human limit, indicating little relevance for clinical use.

Following intraperitoneal administration of a single high dose of melatonin to pregnant mice, fetal length and body weight tended to be smaller, possibly due to maternal toxicity. Delayed sexual maturation in male and female rat offspring, as well as ground squirrels, occurred following exposure to melatonin during pregnancy and postpartum. These data indicate that exogenous melatonin crosses the placenta and is secreted into milk, and that this may have an influence on ontogeny and activation of the hypothalamic-pituitary-gonadal axis. Because rats and ground squirrels breed seasonally, the implications of these findings for humans are uncertain.

6. PHARMACEUTICAL DATA

6.1. List of excipients

Calcium hydrogen phosphate dihydrate

Microcrystalline cellulose

Magnesium stearate

Colloidal anhydrous silica

Pregelatinized starch

Leaflet Melatonin Noxarem 5 Mg 10 Tablets