Miladean (Tablets) Instructions for Use

Marketing Authorization Holder

Valenta Pharm, JSC (Russia)

Contact Information

VALENTA PHARM JSC (Russia)

ATC Code

N06BX (Other psychostimulants and nootropic drugs)

Active Substances

Melatonin (BP British Pharmacopoeia)

Memantine (Rec.INN registered by WHO)

Dosage Form

Miladean

Tablets, orodispersible, 3 mg+5 mg: 10 or 30 pcs.

Dosage Form, Packaging, and Composition

Tablets, orodispersible, white or almost white, round, flat-cylindrical, with a bevel, with a characteristic mint odor.

Excipients: mannitol, crospovidone, polyvinyl acetate, povidone (K-30), colloidal silicon dioxide, sucralose, mint flavor, sodium stearyl fumarate (including sodium – 0.118 mg).

10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.

Clinical-Pharmacological Group

Nootropic drug

Pharmacotherapeutic Group

Psychoanaleptics; psychostimulants, agents used in attention deficit hyperactivity disorder, and nootropic agents; other psychostimulants and nootropic agents

Pharmacological Action

Mechanism of action

The drug Miladean contains two active substances – Melatonin and Memantine.

Melatonin is a synthetic analogue of the pineal gland hormone. The physiological action of melatonin is realized with the participation of the MT1, MT2, and MT3 receptor systems, as well as through a membrane-stabilizing effect. Melatonin exhibits pronounced antioxidant properties, anti-inflammatory and anti-apoptotic activity, and regulates the system of trophic factors in the neurovascular structures of the ischemic zone.

Memantine is a voltage-dependent, moderately affine, non-competitive antagonist of NMDA receptors. Impairment of glutamatergic neurotransmission, especially the function of NMDA receptors (excitotoxicity), contributes to both the manifestation of cognitive deficit symptoms and the progression of neurodegenerative processes in the CNS structures.

The synergistic effect of the combined administration of melatonin and memantine is realized through memantine reducing the hyperactivity of the glutamatergic system and protecting nerve cells from the toxic effects of excess glutamate, and protecting neuronal networks by reducing the severity of oxidative stress as a result of the antioxidant action of melatonin.

Pharmacodynamic effects

Melatonin normalizes circadian rhythms, regulates the sleep-wake cycle, and daily locomotor activity changes. It helps to normalize night sleep (accelerates falling asleep, improves sleep quality, reduces the number of nighttime awakenings, improves well-being after morning awakening, does not cause feelings of lethargy, fatigue, and tiredness upon awakening, dreams become more vivid and emotionally rich), helps to correct behavioral disorders, reduces stress reactions, exhibits an anxiolytic effect, stabilizes mood and motor activity, and has anti-inflammatory and neuroprotective effects. It does not cause habituation or dependence.

Memantine improves memory processes and other higher cortical functions, and increases daily activity.

As a result of the combined intake of memantine and melatonin, a unique therapeutic effect occurs, which manifests itself in improving the ability to assimilate new material and operate with existing knowledge and skills, and increasing confidence in the reliability of memory. Consequently, psycho-emotional tension associated with stressogenic situations of sudden loss of necessary information and skills is reduced.

The synergistic effect of the combined administration of melatonin and memantine regarding neuroprotection, reduction of neuronal inflammation, improvement of cognitive processes and motor activity, as well as reduction of anxiety, has been confirmed in a series of experiments using behavioral tests and neuroanatomical studies. In vitro – in a model of excitotoxicity in a primary culture of brain neurons and in a model of neurodegeneration induced by the administration of beta-amyloid into the brain ventricles. In vivo – in a model of neuroinflammation in transgenic 5xFAD mice, a model of scopolamine-induced amnesia, and a model of acute cerebral ischemia.

Clinical efficacy and safety

In a clinical study, when assessing the change in the total score on the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-cog) and the Pittsburgh Sleep Quality Index (PSQI) between baseline and at the end of the study, the use of the melatonin and memantine combination statistically significantly (p <0.05) led to an improvement in cognitive functions and sleep quality compared to placebo and active control (Memantine).

Pharmacokinetics

Absorption

The mean C_max for melatonin after taking one Miladean tablet is (M±SD) – 6.789±3.895 ng/ml, T_maxMe [Q25;Q75] – 0.456 h. AUC_0-24 for melatonin is (M±SD) – 9.697±7.5 h×ng/ml.

After taking one Miladean tablet, Memantine is absorbed into the blood at T_maxMe [Q25;Q75] – 7.875 h. C_max for memantine is (M±SD) – 7.185±1.462 ng/ml.

AUC_0-168 for memantine is (M±SD) – 546.577±118.997 h×ng/ml;

Distribution

Memantine and Melatonin easily pass through histohematic barriers, including the blood-brain barrier.

The mean residence time (MRT) for melatonin is (M±SD) – 1.219±0.265 h.

MRT for memantine is (M±SD) – 57.356±4.935 h. About 45% of memantine is bound to plasma proteins.

Metabolism

Melatonin is metabolized mainly in the liver, where it undergoes hydroxylation and conjugation with sulfate and glucuronide to form 6-sulfatoxymelatonin; the level of presystemic metabolism can reach 85%.

About 80% of orally administered memantine circulates unchanged. The main metabolites in humans are N-3,5-dimethyl-gludantan, a mixture of 4- and 6-hydroxymemantine isomers, and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites possess NMDA-antagonistic activity. Metabolism catalyzed by the cytochrome P450 system was not detected in vitro.

Elimination

T_1/2 for melatonin is (M±SD) – 0.758±0.182 h.

T_1/2 for memantine is (M±SD) – 55.543±11.753 h. Part of the total renal clearance of memantine is achieved through tubular secretion. Tubular reabsorption of memantine also occurs in the kidneys, probably mediated by proteins involved in cation transport. The rate of renal clearance of memantine may decrease when urine is alkalized to pH 7-9. Urine alkalization can result from drastic changes in diet, such as switching to a vegetarian diet or abundant intake of alkaline gastric buffers.

Indications

• Treatment of mild or moderate cognitive impairment in adults from 18 years of age.

ICD codes

Dosage Regimen

Take orally, in the evening 1-2 hours before sleep.

2 tablets once/day (in the evening) for 8 weeks.

Method of administration

The tablets should be taken immediately after removal from the packaging. The tablets should not be swallowed until they are completely dissolved. Intake of liquid (drinking water) before taking the tablets is allowed to facilitate their better dissolution in the oral cavity, and intake of liquid after complete dissolution of the tablets is allowed.

Missed dose

If a dose is missed, taking a double dose of the drug is prohibited. The patient should wait for the next scheduled dose and take the next dose of the drug.

Special patient groups

Elderly patients: dose adjustment is not required.

Patients with renal impairment: the drug is contraindicated in severe renal impairment and chronic renal failure (see section “Contraindications”).

Patients with hepatic impairment: dose adjustment is not required.

Children: safety and efficacy in children aged 0 to 18 years have not been established. Data are not available.

Adverse Reactions

Summary of adverse reactions

The determination of the frequency of adverse reactions is carried out in accordance with the following criteria: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

In clinical studies of the drug, the following adverse reactions were registered.

Psychiatric disorders: frequency unknown – insomnia, sleep disorder, drowsiness, lethargy, anxiety, disorientation.

Nervous system disorders frequency unknown – headache, dizziness, somnolence.

Cardiovascular system disorders frequency unknown – right bundle branch block, atrioventricular block, hypertensive crisis.

Gastrointestinal disorders frequency unknown – nausea, pain in the upper abdomen, dry mouth.

Laboratory and instrumental data frequency unknown – increased blood pressure, increased amylase level, increased blood alkaline phosphatase level.

Adverse reactions known for melatonin

Immune system disorders frequency unknown – allergic reactions.

Metabolism and nutrition disorders frequency unknown – edema in the first week of administration.

Psychiatric disorders frequency unknown – morning sleepiness.

Nervous system disorders frequency unknown – headache.

Gastrointestinal disorders frequency unknown – nausea, vomiting, diarrhea.

Adverse reactions known for memantine

Infections and infestations uncommon – fungal infections.

Blood and lymphatic system disorders frequency unknown – agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombocytopenic purpura.

Immune system disorders common – hypersensitivity to the drug; frequency unknown – Stevens-Johnson syndrome.

Psychiatric disorders uncommon – confusion, hallucinations (mainly observed in patients with severe Alzheimer’s disease); frequency unknown – depression, suicidal thoughts and suicide attempts (observed in clinical practice in patients with Alzheimer’s disease), psychotic reactions.

Nervous system disorders common – headache, dizziness, drowsiness, balance disorder; uncommon – gait disturbance; very rare – seizures.

Cardiac disorders uncommon: cardiac failure.

Vascular disorders common – increased blood pressure; uncommon – venous thrombosis/thromboembolism.

Respiratory, thoracic and mediastinal disorders common – dyspnea.

Gastrointestinal disorders common – constipation; uncommon – nausea, vomiting; frequency unknown – pancreatitis.

Hepatobiliary disorders common – increased liver function tests; frequency unknown – hepatitis.

Renal and urinary disorders frequency unknown – acute renal failure.

General disorders and administration site conditions uncommon – fatigue.

Contraindications

• Hypersensitivity to melatonin, memantine, or any of the excipients included in the drug;
• Severe renal impairment;
• Chronic renal failure;
• Autoimmune diseases;
• Leukemia;
• Myeloma;
• Epilepsy;
• Diabetes mellitus;
• Pregnancy;
• Lactation period;
• Age under 18 years.

With caution

In patients with a history of seizures or patients predisposed to epilepsy; in patients with thyrotoxicosis.

Use in Pregnancy and Lactation

Pregnancy

Due to the lack of clinical data, the use of the drug during pregnancy and in women planning pregnancy is contraindicated. If pregnancy occurs, the drug should be discontinued.

Pregnancy planning

Women planning pregnancy should be informed about the weak contraceptive effect of melatonin.

Breastfeeding period

The drug is contraindicated during breastfeeding. Women taking Miladean should stop breastfeeding.

Fertility

Data on the effect of the drug on fertility are not available.

Use in Hepatic Impairment

Dose adjustment is not required.

Use in Renal Impairment

The drug is contraindicated in severe renal impairment and chronic renal failure (see section “Contraindications”).

Pediatric Use

Safety and efficacy in children aged 0 to 18 years have not been established. Data are not available.

Geriatric Use

Dose adjustment is not required.

Special Precautions

Concomitant use of memantine and antagonists of N-methyl-D-aspartate receptors (NMDA receptors), such as amantadine, ketamine, or dextromethorphan, should be avoided. These compounds act on the same receptor system as Memantine, so adverse reactions (mainly related to the CNS) may occur more frequently and be more pronounced.

The presence of a number of factors that may increase the hydrogen index (pH) of urine in patients requires careful medical supervision. These include: drastic changes in diet, such as switching from a meat diet to a vegetarian one, or large consumption of alkaline gastric buffer solutions. Renal tubular acidosis or severe urinary tract infections caused by Proteus bacteria can also lead to an increase in urine pH.

Patients with a history of myocardial infarction, decompensated chronic heart failure (NYHA functional class III), or uncontrolled arterial hypertension were excluded from most clinical studies of memantine. Therefore, data on the use of memantine in such patients are limited, and the intake of Miladean should be carried out under the careful supervision of a physician.

Excipients

Sodium in Miladean is contained in the excipient sodium stearyl fumarate. The drug contains less than 1 millimole (23 mg) of sodium per tablet, i.e., it is essentially sodium-free.

Effect on ability to drive vehicles and operate machinery

It has not been studied; however, considering the mechanism of action and the profile of possible adverse reactions, it can be assumed that the drug has a moderate effect on the ability to drive vehicles and operate machinery. Patients should be warned about the possibility of adverse reactions that affect these abilities (see section “Adverse Reactions”).

Overdose

Symptoms

Symptoms of melatonin overdose have not been described.

It is assumed that the symptoms of drug overdose should correspond to the possible symptoms of memantine overdose. Known symptoms of memantine overdose are an increase in the severity of adverse reactions, such as fatigue, weakness, diarrhea, confusion, drowsiness, dizziness, agitation, hallucinations, gait disturbance, nausea.

Treatment

In case of overdose, treatment should be symptomatic. There is no specific antidote for intoxication or overdose. If necessary, standard therapeutic measures aimed at removing memantine from the body are carried out, such as gastric lavage, intake of activated charcoal (to prevent potential recirculation in the intestine and liver), acidification of urine, forced diuresis.

Drug Interactions

Clinical studies on the drug interaction of the Melatonin + Memantine combination with other drugs have not been conducted.

Interactions related to the presence of melatonin in the composition

Melatonin enhances the effect of drugs that depress the CNS and beta-blockers.

Melatonin is not recommended to be taken concomitantly with hormonal drugs.

Melatonin is incompatible with MAO inhibitors, corticosteroids, and cyclosporine.

Interactions related to the presence of memantine in the composition

Levodopa, dopamine receptor agonists, and anticholinergic agents

When used concomitantly with levodopa preparations, dopamine receptor antagonists, anticholinergic agents, the effect of the latter may be enhanced.

Barbiturates and antipsychotics

When memantine is used concomitantly with barbiturates, antipsychotics, the effect of the latter may be reduced.

Dantrolene and baclofen

When used concomitantly, Memantine may change (enhance or reduce) the effect of dantrolene or baclofen, so the doses of the drugs should be selected individually.

Amantadine, ketamine, phenytoin, and dextromethorphan

Concomitant use with amantadine, ketamine, phenytoin, and dextromethorphan should be avoided due to an increased risk of psychosis.

Cimetidine, ranitidine, procainamide, quinidine, quinine, and nicotine

An increase in the plasma concentration of cimetidine, ranitidine, procainamide, quinidine, quinine, and nicotine is possible when taken concomitantly with memantine.

Hydrochlorothiazide

A decrease in the concentration of hydrochlorothiazide is possible when used concomitantly with memantine. Memantine may increase the excretion of hydrochlorothiazide.

Indirect anticoagulants

An increase in INR is possible in patients taking oral anticoagulants (warfarin).

Antidepressants, SSRIs and MAO Inhibitors

Concomitant use with antidepressants, selective serotonin reuptake inhibitors and MAO inhibitors requires careful patient monitoring.

Glibenclamide, Metformin and Donepezil

There is no pharmacological interaction of memantine with glibenclamide, metformin, or donepezil.

Galantamine

In clinical studies involving young healthy volunteers, no significant effect of memantine on the pharmacokinetics of galantamine was identified.

Under in vitro conditions, Memantine does not inhibit the CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A isoenzymes, flavin-containing monooxygenase, epoxide hydrolase, or sulfation.

Storage Conditions

The drug should be stored at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.