Denigma

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

Composition:

Active substance: memantine hydrochloride;

One film-coated tablet contains 20 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, smooth on both sides.

Pharmacotherapeutic group. Agents used in dementia. ATC code N06DX01.

Pharmacological properties.

Pharmacodynamics.

Disruption of 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) is 3 to 8 hours. There is no evidence of food effects 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 drug concentration in cerebrospinal fluid to plasma 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 the 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 be reduced by 7–9 times under alkaline urine conditions. Urinary alkalinization may occur due to radical 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 (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 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, 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 interact with memantine, potentially increasing its plasma concentration.

When memantine is co-administered 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 concomitantly with memantine. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is required in patients receiving oral anticoagulants concurrently.

Pharmacokinetic studies in healthy volunteers have not revealed 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 sulfation.

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 cause an increase in urine pH may necessitate careful monitoring of the patient. Such factors include radical dietary changes, for example switching from a meat-based diet to a vegetarian diet, or excessive intake of antacid gastric medications. In addition, urine pH may also increase 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), as well as those 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 indicate a potential for delayed intrauterine growth at concentrations equal to or slightly higher than those used in humans. 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 lipophilic nature 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.

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

Dosage and Administration

Treatment should be initiated and conducted under the supervision of a physician. Therapy should be started only if a caregiver is available who can 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. 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:

1st week (days 1–7):

take 5 mg* once daily for one week;

2nd week (days 8–14):

take 10 mg* once daily for one week;

3rd week (days 15–21):

take 15 mg* once daily for one week;

from week 4 onwards:

take 20 mg once daily.

*If a single dose <20 mg is prescribed — use the corresponding dosage strength.

The recommended maintenance dose is 20 mg once daily.

The duration of treatment is determined individually by a physician experienced in the diagnosis and treatment of 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 therapeutic benefits disappear or if tolerance to treatment worsens.

Elderly patients.

The recommended dose for patients aged 65 years and older is 20 mg once daily, as described above.

Renal impairment.

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

*If a single dose <20 mg is prescribed — use the corresponding dosage strength.

Hepatic impairment.

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

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, gait disturbances) and/or gastrointestinal symptoms (vomiting, diarrhea).

In the most severe known case of memantine overdose (2000 mg), the patient experienced central nervous system disturbances (the patient was comatose 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), urinary acidification, and forced diuresis.

If clinical signs or symptoms indicating excessive central nervous system stimulation are present, 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 (≥ 1/1000 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, hallucinations¹.

Not known: psychotic reactions².

Nervous system disorders

Common: dizziness, loss of balance.

Uncommon: gait disturbance.

Very rare: seizures.

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.

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

²Individual post-marketing case 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 suspected adverse reactions.

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

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

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

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

Prescription status. Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of manufacturing site.

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

INSTRUCTIONS

for medical use of the medicinal product

DENIGMA®

(DENIGMA®)

Composition:

Active ingredient: memantine hydrochloride;

1 film-coated tablet contains 20 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, smooth on both sides.

Pharmacotherapeutic group. Medicinal products used in dementia. ATC code N06D X01.

Pharmacological properties.

Pharmacodynamics.

Disruption of 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 intake affecting 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 ranging from 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 binds 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 properties. No involvement of cytochrome P450 in metabolism has been observed in vitro.

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.

Renal elimination of memantine may decrease by 7–9 fold under alkaline urine conditions. Urine 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 lobe of the brain.

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 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 possible risk associated with the combination of memantine and phenytoin.

The mechanism of action suggests a potential 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 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 interact with memantine, potentially increasing its plasma concentration.

When memantine is co-administered with hydrochlorothiazide (HCT) or any combination containing HCT, a decrease in serum HCT levels may occur.

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

Pharmacokinetic studies in healthy volunteers have not revealed 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 sulfation.

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 be more frequent or more pronounced (see section "Interaction with other medicinal products and other forms of interaction").

Certain factors that lead to an increase in urine pH may necessitate careful monitoring of the patient. Such factors include radical dietary changes, for example switching from a meat-based diet to a vegetarian diet, or excessive intake of antacid gastric medications. In addition, urine 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), as well as those with uncontrolled arterial hypertension; therefore, careful monitoring of patients with these conditions 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 experimental studies indicate a potential for delayed intrauterine growth at concentrations equal to or slightly higher than those used in humans. 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 effects of memantine on fertility in men or women have been observed.

Ability to influence reaction speed when driving vehicles or operating machinery

Moderate to severe forms of Alzheimer's disease typically impair the ability to drive vehicles or operate machinery. Memantine has a minor or moderate effect on the ability to drive vehicles or operate machinery; therefore, outpatients should exercise particular caution when performing the above-mentioned activities.

Dosage and Administration

Treatment should be initiated and supervised by a physician. Therapy should only be initiated if a caregiver is available who can supervise the patient’s intake of the medicinal product.

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

Adults.

The maximum daily dose is 20 mg. To reduce the risk of adverse reactions, the maintenance dose should be reached 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* once daily for one week;

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

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

Starting from week 4:
Take 20 mg once daily.

*If a single dose <20 mg is prescribed — use the corresponding dosage strength.

The recommended maintenance dose is 20 mg once daily.

The duration of treatment should be determined individually by a physician experienced in the diagnosis and treatment of Alzheimer’s disease. Tolerance and dosage of memantine should be regularly evaluated, preferably within 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 treatment may be continued as long as a favorable therapeutic effect persists and the patient tolerates the treatment well. Discontinuation of memantine therapy should be considered if therapeutic benefits disappear or if treatment tolerance deteriorates.

Elderly patients.

The recommended dose for patients aged 65 years and older is 20 mg once daily, as described above.

Renal impairment.

For patients with mild renal impairment (creatinine clearance 50–80 mL/min), no dose reduction is required. For patients with moderate renal impairment (creatinine clearance 30–49 mL/min), the daily dose should be reduced to 10 mg*. The dose may be increased to 20 mg once daily following 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*.

*If a single dose <20 mg is prescribed — use the corresponding dosage strength.

Hepatic impairment.

No dose adjustment is required for patients with mild to 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 is not recommended for 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 symptoms (vomiting and diarrhea).

In the most severe known case of memantine overdose (2000 mg), the patient experienced central nervous system disturbances (the patient remained comatose 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 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.

Side effects.

The adverse reactions listed below are defined by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 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, hallucinations¹.

Not known: psychotic reactions².

Nervous system disorders.

Common: dizziness, loss of balance.

Uncommon: gait disturbance.

Very rare: seizures.

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 predominantly observed in patients with severe Alzheimer's disease.

² Individual post-marketing case 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 suspected adverse reactions.

Reporting suspected adverse reactions after a medicine has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

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 "GLEDFARM LTD".

Manufacturer's address and location of its business activity.

54 Davydovskoho Hryhorii Street, Sumy, Sumy Oblast, 40020, Ukraine.