Denigma®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DENIGMA® (DENIGMA®)

Composition:

Active substance: memantine;

1 tablet contains 10 mg of memantine hydrochloride;

Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry Pink 03F84827 (talc, titanium dioxide (E 171), hypromellose, iron oxide red (E 172), polyethylene glycol).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: oval, biconvex, pink, film-coated tablets, with a score line on one side and smooth on the other.

Pharmacotherapeutic group. Agents used in dementia. ATC code N06D X01.

Pharmacological properties.

Pharmacodynamics.

Glutamatergic neurotransmission, particularly involving NMDA (N-methyl-D-aspartate) receptors, plays a significant role in the symptoms and progression of neurodegenerative dementia.

Memantine is a voltage-dependent, moderate-affinity, non-competitive antagonist of NMDA receptors. Memantine modulates the effects of pathologically elevated glutamate levels, which may lead to neuronal dysfunction.

Pharmacokinetics.

Absorption.

The absolute bioavailability of memantine is approximately 100%. The time to reach peak plasma concentration (Tmax) ranges from 3 to 8 hours. There is no evidence of food affecting absorption.

Distribution.

A daily dose of 20 mg results in a steady-state plasma concentration of memantine ranging from 70 to 150 ng/mL (0.5–1 µmol), with considerable individual variability. When daily doses of 5 to 30 mg are administered, the ratio of active substance concentration in cerebrospinal fluid to that in serum is 0.52. The volume of distribution is approximately 10 L/kg. About 45% of memantine is bound to plasma proteins.

Metabolism.

In humans, approximately 80% of memantine circulates as the parent compound. The main metabolites in humans are N-3,5-dimethyl-gludantane, an isomeric mixture of 4- and 6-hydroxy-memantine, and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites possess NMDA-antagonistic activity. In vitro studies have shown no involvement of cytochrome P450 in memantine metabolism.

In a study using 14C-memantine administered orally, on average 84% of the dose was excreted within 20 days, with over 99% eliminated via the kidneys.

Elimination.

Memantine is eliminated in a monoexponential manner with a half-life (t1/2) ranging from 60 to 100 hours. In volunteers with normal renal function, total clearance (Cltot) is 170 mL/min/1.73 m², partly due to tubular secretion. The renal phase of memantine pharmacokinetics also includes tubular reabsorption, possibly mediated by cationic transport proteins.

The rate of renal elimination of memantine may decrease by 7–9 times under alkaline urine conditions. Urinary alkalinization may occur due to drastic dietary changes, such as switching from a meat-based to a vegetarian diet, or from excessive intake of antacid gastric medications.

Linearity.

Studies in volunteers have demonstrated linear pharmacokinetics within the dose range of 10 to 40 mg.

Pharmacodynamic/pharmacokinetic relationship.

When memantine is administered at a dose of 20 mg per day, the concentration of the active substance in cerebrospinal fluid corresponds to the ki (inhibition constant) for memantine, which is 0.5 µmol in the human frontal cortex.

Clinical characteristics.

Indications.

Alzheimer's disease from moderate to severe stages.

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of memantine and amantadine should be avoided due to the risk of pharmacotoxic psychosis. Both compounds are chemically related NMDA antagonists. The same may apply to ketamine and dextromethorphan. One published report also indicated a potential risk associated with the combination of memantine and phenytoin.

The mechanism of action suggests a possible enhancement of the effects of L-dopa, dopaminergic agonists, and anticholinergic agents when co-administered with NMDA antagonists such as memantine. A reduction in the effects of barbiturates and neuroleptic agents is possible. Concomitant administration of memantine with the muscle relaxants dantrolene or baclofen may modify their effects, potentially necessitating dose adjustments.

Other medicinal products such as cimetidine, ranitidine, procainamide, quinidine, quinine, and nicotine, which utilize the same renal cationic transport system as amantadine, may also potentially interact with memantine, leading to a potential risk of increased plasma concentrations of memantine.

Concomitant administration of memantine with hydrochlorothiazide (HCTZ) or any combination containing HCTZ may result in decreased serum levels of HCTZ.

There have been reports of isolated cases of increased international normalized ratio (INR) in patients receiving warfarin while taking memantine. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is required in patients receiving oral anticoagulants concomitantly.

Pharmacokinetic studies in healthy volunteers revealed no significant interaction effects between memantine and glipizide/metformin, donepezil, or galantamine.

Memantine is in vitro not an inhibitor of CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase, or sulfotransion.

Special precautions for use.

Caution should be exercised when prescribing the medicinal product to patients with epilepsy, patients with a history of seizures, as well as patients with risk factors for developing epilepsy.

Concomitant use with other N-methyl-D-aspartate (NMDA) antagonists such as amantadine, ketamine, or dextromethorphan should be avoided. These compounds affect the same receptor system as memantine, and therefore adverse effects (mainly related to the central nervous system) may occur more frequently or be more pronounced (see section "Interaction with other medicinal products and other forms of interaction").

Certain factors that may increase urinary pH may necessitate careful monitoring of the patient. Such factors include drastic dietary changes, for example switching from a meat-based to a vegetarian diet, or excessive intake of antacid gastric medications. In addition, urinary pH may also be increased in conditions such as renal tubular acidosis (RTA) or severe urinary tract infections caused by Proteus species.

Limited data are available regarding the use of memantine in patients who have recently experienced myocardial infarction, patients with decompensated congestive heart failure (NYHA III-IV), and patients with uncontrolled arterial hypertension; therefore, careful monitoring is required in patients with these conditions.

The medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e. it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no data on the use of memantine during pregnancy. Animal experimental studies have indicated a possibility of delayed intrauterine growth at concentrations equal to or slightly higher than those used in humans. The potential risk for humans is unknown. Memantine should not be used during pregnancy except in cases of extreme necessity.

Breastfeeding.

It is unknown whether memantine passes into breast milk, although this is possible considering the lipophilicity of the substance. Women taking memantine should refrain from breastfeeding.

Fertility.

No negative effect of memantine on fertility in men or women has been observed.

Ability to influence reaction speed when driving or operating machinery.

Moderate to severe forms of Alzheimer's disease usually impair the ability to drive vehicles or operate machinery. Memantine itself has a minor or moderate effect on the ability to drive vehicles or operate machinery; therefore, outpatient patients should exercise particular caution when performing the aforementioned activities.

Dosage and Administration.

Treatment should be initiated and conducted under the supervision of a physician. Therapy should be initiated only if a caregiver is available who will supervise the patient's intake of the medicinal product.

The tablets should be taken once daily at the same time each day, regardless of food intake.

Adults.

The maximum daily dose is 20 mg (2 tablets). To reduce the risk of adverse reactions, the maintenance dose should be established by gradually increasing the dosage by 5 mg per week over the first 3 weeks as follows:

Week 1 (days 1–7):
Take 5 mg (½ tablet) once daily for one week;

Week 2 (days 8–14):
Take 10 mg (1 tablet) once daily for one week;

Week 3 (days 15–21):
Take 15 mg (1½ tablets) once daily for one week;

From week 4 onwards:
Take 20 mg (2 tablets) once daily.

The recommended maintenance dose is 20 mg (2 tablets) once daily.

The duration of treatment is determined individually by a physician experienced in diagnosing and treating Alzheimer's disease. Tolerance and memantine dosage should be regularly evaluated, preferably every three months after initiation of treatment. Thereafter, the clinical effect of memantine and the patient's response to treatment should be regularly assessed according to current clinical guidelines. Maintenance therapy may be continued as long as a favorable therapeutic effect is maintained and the patient tolerates the treatment well. Discontinuation of memantine therapy should be considered if signs of therapeutic benefit disappear or if treatment tolerance deteriorates.

Elderly patients.

The recommended dose for patients aged 65 years and older is 20 mg (2 tablets) once daily, as stated above.

Renal impairment.

For patients with mild renal impairment (creatinine clearance 50–80 mL/min), dose reduction is not required. For patients with moderate renal impairment (creatinine clearance 30–49 mL/min), the daily dose should be reduced to 10 mg (1 tablet). The dose may be increased to 20 mg (2 tablets) once daily according to the standard titration schedule if no adverse reactions occur after at least 7 days of treatment. For patients with severe renal impairment (creatinine clearance 5–29 mL/min), the daily dose should be reduced to 10 mg (1 tablet).

Hepatic impairment.

For patients with mild to moderate hepatic impairment (Child Pugh A, B), dose adjustment is not required. There are no data on the use of memantine in patients with severe hepatic impairment. The use of memantine in patients with severe hepatic impairment is not recommended.

Children.

The medicinal product should not be used in children under 18 years of age due to insufficient data on safety and efficacy.

Overdose.

Data on overdose are limited.

Symptoms.

Administration of relatively high doses (200 mg and 105 mg daily for 3 days, respectively) was associated with symptoms such as fatigue, weakness and/or diarrhea, or no symptoms at all. In cases of overdose with doses below 140 mg, or when the ingested dose was unknown, patients experienced symptoms related to the central nervous system (confusion, lethargy, somnolence, dizziness, agitation, aggression, hallucinations, gait disturbances) and/or gastrointestinal symptoms (vomiting, diarrhea).

In the most severe known case of memantine overdose (2000 mg), the patient developed central nervous system disturbances (the patient remained in a coma for 10 days, followed by diplopia and agitation). After symptomatic treatment and plasmapheresis, the patient recovered without sequelae.

In another case of high-dose memantine overdose (400 mg), central nervous system disturbances were observed, including restlessness, psychosis, visual hallucinations, seizure tendency, somnolence, stupor, and loss of consciousness. The patient recovered.

Treatment.

Treatment is symptomatic; there is no specific antidote. Standard clinical procedures to remove the active substance from the body should be applied: gastric lavage, administration of activated charcoal (to prevent possible enterohepatic recirculation of memantine), acidification of urine, and forced diuresis.

If clinical signs or symptoms indicate excessive central nervous system stimulation, symptomatic treatment should be administered with caution.

Side effects.

The adverse reactions listed below are defined by frequency as follows: 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).

Infections and infestations.

Uncommon: fungal infections.

Immune system disorders.

Common: hypersensitivity reactions.

Psychiatric disorders.

Common: somnolence.

Uncommon: confusion, hallucinations¹.

Not known: psychotic reactions².

Nervous system disorders.

Common: dizziness, impaired balance.

Uncommon: gait disturbance.

Very rare: convulsions.

Cardiac disorders.

Uncommon: heart failure.

Vascular disorders.

Common: arterial hypertension.

Uncommon: venous thrombosis/thromboembolism.

Respiratory system disorders.

Common: dyspnea (shortness of breath).

Gastrointestinal disorders.

Common: constipation.

Uncommon: vomiting.

Not known: pancreatitis².

Hepatobiliary disorders.

Common: increased liver function test parameters.

Not known: hepatitis.

General disorders and administration site conditions.

Common: headache.

Uncommon: fatigue.

¹ Hallucinations were mainly observed in patients with severe Alzheimer's disease.

² Individual reports in the post-marketing period.

Alzheimer's disease is associated with depression, suicidal ideation, and suicide attempts. Such cases have also been reported during treatment with memantine.

Reporting of adverse reactions.

Reporting of adverse reactions after marketing authorization of the medicinal product is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

14 tablets in a blister; 1 blister in a cardboard package.

14 tablets in a blister; 1 blister in a cardboard package; 10 cardboard packages in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's address and location of its business activities.

40020, Ukraine, Sumy region, Sumy, Davydovskoho Hryhoriia St., 54.

INSTRUCTION

for medical use of the medicinal product

DENIGMA®

(DENIGMA®)

Composition:

Active ingredient: memantine;

1 tablet contains 10 mg of memantine hydrochloride;

Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry Pink 03F84827 (talc, titanium dioxide (E 171), hypromellose, iron oxide red (E 172), polyethylene glycol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, biconvex, pink-colored, film-coated tablets, with a score line on one side and smooth on the other.

Pharmacotherapeutic group. Agents used in dementia. ATC code N06D X01.

Pharmacological Properties.

Pharmacodynamics.

Glutamatergic neurotransmission, particularly involving NMDA (N-methyl-D-aspartate) receptors, plays a significant role in the symptoms and progression of neurodegenerative dementia.

Memantine is a voltage-dependent, moderate-affinity, non-competitive antagonist of NMDA receptors. Memantine modulates the effects of pathologically elevated glutamate levels, which may lead to neuronal dysfunction.

Pharmacokinetics.

Absorption.

The absolute bioavailability of memantine is approximately 100%. The time to reach peak plasma concentration (Tmax) ranges from 3 to 8 hours. There is no evidence of food influence on absorption.

Distribution.

A daily dose of 20 mg results in a steady-state plasma concentration of memantine ranging from 70 to 150 ng/mL (0.5–1 µmol), with considerable individual variability. When daily doses of 5 to 30 mg are administered, the ratio of active substance concentration in cerebrospinal fluid to that in blood serum is 0.52. The volume of distribution is approximately 10 L/kg. Approximately 45% of memantine is bound to plasma proteins.

Biological Transformation.

In humans, about 80% of memantine circulates in its original form. The main metabolites in humans are N-3,5-dimethyl-gludantane, an isomeric mixture of 4- and 6-hydroxy-memantine, and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites possess NMDA-antagonistic properties. No involvement of cytochrome P450 in metabolism has been demonstrated in vitro.

In a study using 14C-labeled memantine administered orally, on average 84% of the dose was excreted within 20 days, with over 99% eliminated via the kidneys.

Elimination.

Memantine is eliminated in a mono-exponential manner with a half-life (t1/2) ranging from 60 to 100 hours. In volunteers with normal renal function, total clearance (Cltot) is 170 mL/min/1.73 m², partly due to tubular secretion. The renal phase of memantine pharmacokinetics also includes tubular reabsorption, possibly mediated by cationic transport proteins.

The rate of renal elimination of memantine may decrease by 7–9 times under alkaline urine conditions. Urinary alkalinization may occur due to drastic dietary changes, such as switching from a meat-based to a vegetarian diet, or due to excessive intake of antacid gastric medications.

Linearity.

Studies in volunteers have demonstrated linear pharmacokinetics within the dose range of 10 to 40 mg.

Pharmacodynamic/Pharmacokinetic Relationship.

When memantine is administered at a dose of 20 mg per day, the concentration of the active substance in cerebrospinal fluid corresponds to the ki value (inhibition constant) for memantine, which is 0.5 µmol in the human frontal brain cortex.

Clinical characteristics.

Indications.

Alzheimer's disease from moderate to severe stages.

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product.

Interaction with other medicinal products and other types of interactions.

Concomitant use of memantine and amantadine should be avoided due to the risk of pharmacotoxic psychosis. Both compounds are chemically related NMDA antagonists. The same may apply to ketamine and dextromethorphan. One published report also indicated a potential risk with the combination of memantine and phenytoin.

The mechanism of action suggests a possible enhancement of the effects of L-dopa, dopaminergic agonists, and anticholinergic agents when used concomitantly with NMDA antagonists such as memantine. A reduction in the effects of barbiturates and neuroleptic agents is possible. Concomitant administration of memantine with the muscle relaxants dantrolene or baclofen may modify their effects, possibly necessitating dose adjustments.

Other medicinal products such as cimetidine, ranitidine, procainamide, quinidine, quinine, and nicotine, which use the same renal cationic transport system as amantadine, may also potentially interact with memantine, leading to a potential risk of increased plasma levels of memantine.

When memantine is co-administered with hydrochlorothiazide (HCTZ) or any combination containing HCTZ, a decreased serum level of HCTZ may occur.

There have been reports of isolated cases of increased international normalized ratio (INR) in patients receiving warfarin when memantine was initiated. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is required in patients receiving oral anticoagulants concomitantly with memantine.

In pharmacokinetic studies in healthy volunteers, no significant interaction effects were observed between memantine and glimepiride/metformin, donepezil, or galantamine.

Memantine is in vitro not an inhibitor of CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase, or sulfotransferase.

Special precautions for use

Caution should be exercised when prescribing the medicinal product to patients with epilepsy, patients with a history of seizures, as well as patients with risk factors for developing epilepsy.

Concomitant use with other N-methyl-D-aspartate (NMDA) antagonists such as amantadine, ketamine, or dextromethorphan should be avoided. These compounds affect the same receptor system as memantine, and therefore adverse effects (mainly related to the central nervous system) may occur more frequently or be more pronounced (see section "Interaction with other medicinal products and other forms of interaction").

Certain factors that may increase urine pH may necessitate careful monitoring of the patient. Such factors include drastic dietary changes, for example switching from a meat-based to a vegetarian diet, or excessive intake of antacid gastric medications. In addition, urine pH may also be elevated in certain conditions such as renal tubular acidosis (RTA) or in severe urinary tract infections caused by Proteus species.

Limited data are available on the use of memantine in patients who have recently suffered myocardial infarction, patients with decompensated congestive heart failure (NYHA III–IV), and patients with uncontrolled arterial hypertension. Therefore, careful monitoring is required in patients with these conditions.

The medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e. it is practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

There are no data on the use of memantine during pregnancy. Animal studies have shown that exposure to concentrations equal to or slightly higher than those used in humans may lead to delayed intrauterine growth. The potential risk to humans is unknown. Memantine should not be used during pregnancy except in cases of extreme necessity.

Breastfeeding

It is unknown whether memantine passes into breast milk, although this is possible considering the lipophilicity of the substance. Women taking memantine should avoid breastfeeding.

Fertility

No negative effect of memantine on fertility in men or women has been observed.

Ability to influence the reaction rate when driving vehicles or operating machinery

Alzheimer's disease, from moderate to severe stages, usually impairs the ability to drive vehicles and operate machinery. Memantine itself has a minor or moderate effect on the ability to drive vehicles and operate machinery; therefore, outpatient patients should exercise particular caution when performing the aforementioned activities.

Method of Administration and Dosage

Treatment should be initiated and managed under the supervision of a physician. Therapy should be initiated only if a caregiver is available who can supervise the patient's intake of the medication.

The tablets should be taken once daily at the same time each day, regardless of food intake.

Adults.

The maximum daily dose is 20 mg (2 tablets). To reduce the risk of adverse reactions, the maintenance dose should be established by gradually increasing the dosage by 5 mg per week over the first 3 weeks as follows:

1st week (days 1–7):

Take 5 mg (½ tablet) once daily for one week;

2nd week (days 8–14):

Take 10 mg (1 tablet) once daily for one week;

3rd week (days 15–21):

Take 15 mg (1½ tablets) once daily for one week;

Starting from week 4:

Take 20 mg (2 tablets) once daily for one week.

The recommended maintenance dose is 20 mg (2 tablets) once daily.

The duration of treatment is determined individually by a physician experienced in diagnosing and treating Alzheimer's disease. Tolerability and dosage of memantine should be regularly assessed, preferably within three months after initiation of treatment. Thereafter, the clinical effect of memantine and the patient's response to treatment should be regularly evaluated according to current clinical guidelines. Maintenance therapy may be continued as long as the therapeutic effect remains favorable and the patient tolerates the treatment well. Consideration should be given to discontinuing memantine treatment if therapeutic benefits are lost or if tolerability worsens.

Elderly Patients.

The recommended dose for patients aged 65 years and older is 20 mg (2 tablets) once daily, as stated above.

Renal Impairment.

For patients with mild renal impairment (creatinine clearance 50–80 mL/min), no dose adjustment is required. For patients with moderate renal impairment (creatinine clearance 30–49 mL/min), the daily dose should be reduced to 10 mg (1 tablet). The dose may be increased to 20 mg (2 tablets) once daily according to the standard titration schedule if no adverse reactions occur after at least 7 days of treatment. For patients with severe renal impairment (creatinine clearance 5–29 mL/min), the daily dose should be reduced to 10 mg (1 tablet).

Hepatic Impairment.

For patients with mild to moderate hepatic impairment (Child Pugh A, B), dose adjustment is not required. There are no data on the use of memantine in patients with severe hepatic impairment. The use of memantine in patients with severe hepatic impairment is not recommended.

Children.

The medicinal product is not recommended for use in children under 18 years of age due to insufficient data on safety and efficacy.

Overdose.

Data on overdose are limited.

Symptoms.

Administration of relatively high doses (200 mg and 105 mg daily for 3 days, respectively) has been associated with symptoms such as fatigue, weakness, and/or diarrhea, or no symptoms at all. In cases of overdose with doses below 140 mg or when the dose was unknown, patients experienced symptoms related to the central nervous system (confusion, lethargy, somnolence, dizziness, agitation, aggression, hallucinations, and gait disturbances) and/or gastrointestinal tract (vomiting and diarrhea).

In the most severe known case of memantine overdose (2000 mg), the patient experienced central nervous system disturbances (the patient remained in a coma for 10 days, followed by diplopia and agitation). After symptomatic treatment and plasmapheresis, the patient recovered without sequelae.

In another case of overdose with a high dose of memantine (400 mg), central nervous system disturbances were observed, including restlessness, psychosis, visual hallucinations, seizure tendency, somnolence, stupor, and loss of consciousness. The patient recovered.

Treatment.

Treatment is symptomatic; there is no specific antidote. Standard clinical procedures should be applied to remove the active substance from the body: gastric lavage, administration of activated charcoal (to prevent possible enterohepatic recirculation of memantine), urinary acidification, and forced diuresis.

In cases of clinical signs or symptoms indicating excessive central nervous system stimulation, symptomatic treatment should be administered with caution.

Adverse reactions.

The adverse reactions listed below are categorized by frequency as follows: 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 available data).

Infections and infestations.

Uncommon: fungal infections.

Immune system disorders.

Common: hypersensitivity reactions.

Psychiatric disorders.

Common: somnolence.

Uncommon: confusion, hallucinations¹.

Not known: psychotic reactions².

Nervous system disorders.

Common: dizziness, loss of balance.

Uncommon: gait disturbance.

Very rare: convulsions.

Cardiac disorders.

Uncommon: heart failure.

Vascular disorders.

Common: arterial hypertension.

Uncommon: venous thrombosis/thromboembolism.

Respiratory system disorders.

Common: dyspnoea (shortness of breath).

Gastrointestinal disorders.

Common: constipation.

Uncommon: vomiting.

Not known: pancreatitis².

Hepatobiliary disorders.

Common: increased liver function test parameters.

Not known: hepatitis.

General disorders and administration site conditions.

Common: headache.

Uncommon: fatigue.

¹ Hallucinations were predominantly observed in patients with severe Alzheimer's disease.

² Individual post-marketing reports.

Alzheimer's disease is associated with depression, suicidal ideation, and suicide attempts. Such cases have also been reported during treatment with memantine.

Reporting of adverse reactions.

Reporting of adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.

14 tablets in a blister pack; 1 blister pack in a cardboard box.

14 tablets in a blister pack; 1 blister pack in a cardboard box; 10 cardboard boxes in a cardboard carton.

Prescription status. Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of operations.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.

INSTRUCTION

for medical use of the medicinal product

DENIGMA®

(DENIGMA®)

Composition:

Active substance: memantine;

1 tablet contains 10 mg of memantine hydrochloride;

Inactive ingredients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry Pink 03F84827 (talc, titanium dioxide (E 171), hypromellose, iron oxide red (E 172), polyethylene glycol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: oval, biconvex, pink, film-coated tablets, with a break line on one side and smooth on the other side.

Pharmacotherapeutic group. Agents used in dementia. ATC code N06D X01.

Pharmacological properties.

Pharmacodynamics.

Glutamatergic neurotransmission, particularly involving NMDA (N-methyl-D-aspartate) receptors, plays a significant role in the symptoms and progression of neurodegenerative dementia.

Memantine is a voltage-dependent, moderate-affinity, non-competitive antagonist of NMDA receptors. Memantine modulates the effects of pathologically elevated glutamate levels, which may lead to neuronal dysfunction.

Pharmacokinetics.

Absorption.

The absolute bioavailability of memantine is approximately 100%. The time to reach peak plasma concentration (Tmax) ranges from 3 to 8 hours. There is no evidence of food influence on absorption.

Distribution.

A daily dose of 20 mg results in a steady-state plasma concentration of memantine between 70 and 150 ng/mL (0.5–1 µmol), with considerable individual variability. When daily doses of 5 to 30 mg are administered, the ratio of active substance concentration in cerebrospinal fluid to that in serum is 0.52. The volume of distribution is approximately 10 L/kg. About 45% of memantine is bound to plasma proteins.

Biological transformation.

In humans, approximately 80% of memantine circulates as the parent compound. The main metabolites in humans are N-3,5-dimethyl-gludantane, an isomeric mixture of 4- and 6-hydroxy-memantine, and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites possess NMDA-antagonistic properties. In vitro studies have shown no involvement of cytochrome P450 in memantine metabolism.

In a study using 14C-memantine administered orally, on average 84% of the dose was excreted within 20 days, with over 99% eliminated via the kidneys.

Elimination.

Memantine is eliminated in a monoexponential manner with a half-life (t1/2) ranging from 60 to 100 hours. In volunteers with normal renal function, total clearance (Cltot) is 170 mL/min/1.73 m², partly due to tubular secretion. The renal phase of memantine pharmacokinetics also includes tubular reabsorption, possibly mediated by cationic transport proteins.

The rate of renal elimination of memantine may decrease by 7–9 times under alkaline urine conditions. Urinary alkalinization may occur due to drastic dietary changes, such as switching from a meat-based to a vegetarian diet, or due to excessive intake of antacid gastric medications.

Linearity.

Studies in volunteers have demonstrated linear pharmacokinetics within the dose range of 10 to 40 mg.

Pharmacodynamic/pharmacokinetic relationship.

When memantine is administered at a dose of 20 mg per day, the concentration of the active substance in cerebrospinal fluid corresponds to the ki value (inhibition constant) for memantine, which is 0.5 µmol in the human frontal brain lobe.

Clinical characteristics.

Indications.

Moderate to severe Alzheimer's disease.

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of memantine and amantadine should be avoided due to the risk of pharmacotoxic psychosis. Both compounds are chemically related NMDA antagonists. The same may apply to ketamine and dextromethorphan. One published report also indicated a potential risk with the combination of memantine and phenytoin.

The mechanism of action suggests a possible enhancement of the effects of L-dopa, dopaminergic agonists, and anticholinergic agents when used concomitantly with NMDA antagonists such as memantine. A reduction in the effects of barbiturates and neuroleptic agents is possible. Concomitant administration of memantine with the muscle relaxants dantrolene or baclofen may modify their effects, possibly necessitating dose adjustments.

Other medicinal products such as cimetidine, ranitidine, procainamide, quinidine, quinine, and nicotine, which use the same renal cation transport system as amantadine, may also potentially interact with memantine, leading to a risk of increased plasma levels of memantine.

When memantine is administered concomitantly with hydrochlorothiazide (HCTZ) or any combination containing HCTZ, a decrease in serum levels of HCTZ may occur.

There have been reports of isolated cases of increased international normalized ratio (INR) in patients taking warfarin while receiving memantine. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is required in patients receiving oral anticoagulants concomitantly with memantine.

In pharmacokinetic studies in healthy volunteers, no significant interaction effects between memantine and glimepiride/metformin, donepezil, or galantamine were observed.

Memantine is not an inhibitor in vitro of CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase, or sulfotransferase.

Special precautions for use

Caution should be exercised when prescribing the medicinal product to patients with epilepsy, patients with a history of seizures, and patients with risk factors for developing epilepsy.

Concomitant use with other N-methyl-D-aspartate (NMDA) antagonists such as amantadine, ketamine, or dextromethorphan should be avoided. These compounds affect the same receptor system as memantine, and therefore adverse effects (mainly related to the central nervous system) may be more frequent or more pronounced (see section "Interaction with other medicinal products and other forms of interaction").

Certain factors that may increase urinary pH may necessitate careful monitoring of the patient. Such factors include a radical change in diet, for example switching from a meat-based to a vegetarian diet, or excessive use of antacid gastric medications. In addition, urinary pH may also increase in conditions such as renal tubular acidosis (RTA) or in severe urinary tract infections caused by Proteus species.

Limited data are available on the use of memantine in patients who have recently suffered myocardial infarction, patients with decompensated congestive heart failure (NYHA III–IV), and patients with uncontrolled arterial hypertension; therefore, careful monitoring of such patients is required.

The medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e. it is practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

There are no data on the use of memantine during pregnancy. Animal studies have shown a potential for delayed intrauterine growth at concentrations equal to or slightly higher than those used in humans. The potential risk for humans is unknown. Memantine should not be used during pregnancy except in cases of extreme necessity.

Breastfeeding

It is unknown whether memantine passes into breast milk, although this is possible given the lipophilic nature of the substance. Women taking memantine should avoid breastfeeding.

Fertility

No negative effects of memantine on fertility in men or women have been observed.

Ability to influence reaction speed when driving or operating machinery

Moderate to severe Alzheimer's disease generally impairs the ability to drive vehicles or operate machinery. Memantine itself has a negligible or moderate effect on the ability to drive vehicles or operate machinery; therefore, outpatient patients should exercise particular caution when performing the aforementioned activities.

Dosage and Administration

Treatment should be initiated and conducted under medical supervision. Therapy should only be initiated if a caregiver is available to supervise the patient's intake of the medicinal product.

The tablets should be taken once daily at the same time each day, regardless of food intake.

Adults

The maximum daily dose is 20 mg (2 tablets). To reduce the risk of adverse reactions, the maintenance dose should be established by gradually increasing the dose by 5 mg per week over the first 3 weeks as follows:

Week 1 (days 1–7):
Take 5 mg (½ tablet) once daily for one week;

Week 2 (days 8–14):
Take 10 mg (1 tablet) once daily for one week;

Week 3 (days 15–21):
Take 15 mg (1½ tablets) once daily for one week;

From week 4 onwards:
Take 20 mg (2 tablets) once daily.

The recommended maintenance dose is 20 mg (2 tablets) daily.

The duration of treatment is determined individually by a physician experienced in diagnosing and treating Alzheimer's disease. Tolerance and memantine dosage should be regularly assessed, preferably every three months after initiating treatment. Thereafter, the clinical effect of memantine and the patient's response to treatment should be regularly evaluated according to current clinical guidelines. Maintenance therapy may be continued as long as a favorable therapeutic effect is maintained and the patient tolerates the treatment well. Consideration should be given to discontinuing memantine treatment if therapeutic benefits are lost or if treatment tolerance deteriorates.

Elderly patients

The recommended dose for patients aged 65 years and older is 20 mg (2 tablets) daily, as described above.

Renal impairment

For patients with mild renal impairment (creatinine clearance 50–80 mL/min), no dose adjustment is required. For patients with moderate renal impairment (creatinine clearance 30–49 mL/min), the daily dose should be reduced to 10 mg (1 tablet). The dose may be increased to 20 mg (2 tablets) daily according to the standard titration schedule if no adverse reactions occur after at least 7 days of treatment. For patients with severe renal impairment (creatinine clearance 5–29 mL/min), the daily dose should be reduced to 10 mg (1 tablet).

Hepatic impairment

Dose adjustment is not required for patients with mild or moderate hepatic impairment (Child Pugh A, B). There are no data on the use of memantine in patients with severe hepatic impairment. The use of memantine in patients with severe hepatic impairment is not recommended.

Children

The medicinal product should not be used in children under 18 years of age due to insufficient data on safety and efficacy.

Overdose

Data on overdose are limited.

Symptoms

Administration of relatively high doses (200 mg and 105 mg daily for 3 days, respectively) was associated with symptoms such as fatigue, weakness and/or diarrhea, or no symptoms at all. In cases of overdose with doses below 140 mg, or when the dose was unknown, patients experienced symptoms related to the central nervous system (confusion, lethargy, somnolence, dizziness, agitation, aggression, hallucinations, and gait disturbances) and/or gastrointestinal tract (vomiting and diarrhea).

In the most severe known case of memantine overdose (2000 mg), the patient experienced central nervous system disturbances (the patient remained in a coma for 10 days, followed by diplopia and agitation). The patient recovered fully after symptomatic treatment and plasmapheresis.

In another case of high-dose memantine overdose (400 mg), central nervous system disturbances were observed, including anxiety, psychosis, visual hallucinations, seizure tendency, somnolence, stupor, and loss of consciousness. The patient recovered.

Treatment

Treatment is symptomatic; there is no specific antidote. Standard clinical procedures should be applied to remove the active substance from the body: gastric lavage, administration of activated charcoal (to prevent possible enterohepatic recirculation of memantine), urinary acidification, and forced diuresis.

In cases of clinical signs or symptoms indicating excessive central nervous system stimulation, symptomatic treatment should be administered with caution.

Adverse reactions.

The adverse reactions listed below are defined by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), not known (cannot be estimated from available data).

Infections and infestations.

Uncommon: fungal infections.

Immune system disorders.

Common: hypersensitivity reactions.

Psychiatric disorders.

Common: somnolence.

Uncommon: confusion, hallucinations^1.

Not known: psychotic reactions^2.

Nervous system disorders.

Common: dizziness, loss of balance.

Uncommon: gait disturbance.

Very rare: convulsions.

Cardiac disorders.

Uncommon: heart failure.

Vascular disorders.

Common: arterial hypertension.

Uncommon: venous thrombosis/thromboembolism.

Respiratory system disorders.

Common: dyspnea (shortness of breath).

Gastrointestinal disorders.

Common: constipation.

Uncommon: vomiting.

Not known: pancreatitis^2.

Hepatobiliary disorders.

Common: increased liver function test parameters.

Not known: hepatitis.

General disorders and administration site conditions.

Common: headache.

Uncommon: fatigue.

^1 Hallucinations were predominantly observed in patients with severe Alzheimer's disease.

^2 Individual case reports in the post-marketing period.

Alzheimer's disease is associated with depression, suicidal ideation, and suicide attempts. Such cases have also been reported during treatment with memantine.

Reporting of adverse reactions.

Reporting of adverse reactions after marketing authorization of a medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

14 tablets in a blister; 1 blister per cardboard pack.

14 tablets in a blister; 1 blister per cardboard pack; 10 cardboard packs in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

TOV "KUSUM PHARM".

Manufacturer's address and location of business activity.

40020, Ukraine, Sumy Oblast, Sumy, Skryabina St., 54.