Denigma

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

Composition:

Active substance: memantine hydrochloride;

1 ml of solution contains 2 mg of memantine hydrochloride;

Excipients: glycerol; citric acid, monohydrate; methylparahydroxybenzoate (E 218); propylparahydroxybenzoate (E 216); propylene glycol; sodium citrate; sorbitol solution (E 420); flavouring additive "Tropical"; purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: colourless, clear solution with a characteristic odour.

Pharmacotherapeutic group. Agents used in dementia.

ATC code N06D X01.

Pharmacological properties.

Pharmacodynamics.

Disturbance of glutamatergic neurotransmission, particularly involving NMDA (N-methyl-D-aspartate) receptors, plays an important 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 pathological elevation in glutamate levels, which may lead to neuronal dysfunction.

Pharmacokinetics.

Absorption. After oral administration, memantine is well absorbed. Absolute bioavailability of memantine is approximately 100%. Time to peak plasma concentration (Tmax) is 3 to 7 hours. There is no evidence of food effects on absorption.

Distribution. The mean volume of distribution of memantine is 9–11 L/kg. Approximately 45% of memantine is bound to plasma proteins.

Metabolism. Memantine undergoes partial hepatic metabolism. The hepatic microsomal CYP450 enzyme system does not play a significant role in memantine metabolism.

Elimination. Memantine is primarily excreted unchanged (approximately 48%) in urine. Terminal half-life ranges from 60 to 80 hours.

The remainder is predominantly converted into three polar metabolites with minimal NMDA receptor antagonistic activity: glucuronide conjugate, 6-hydroxymemantine, and 1-nitroso-deaminated memantine. Overall, 74% of the administered dose is excreted as the sum of the parent active substance and its glucuronide conjugate. Renal clearance includes active tubular secretion regulated by pH-dependent tubular reabsorption.

Clinical characteristics.

Indications.

Alzheimer's disease from mild to severe stages.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Due to the pharmacological effect and mechanism of action of memantine, the following interactions are possible.

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 use of memantine with muscle relaxants, dantrolene, or baclofen may modify their effects and necessitate dose adjustments.

Concomitant use of memantine and amantadine should be avoided due to the risk of developing a pharmacotoxic psychosis. Both compounds are chemically related NMDA antagonists. The same may apply to ketamine and dextromethorphan (see section "Special precautions for use").

There are data regarding the risk of psychosis with concomitant use of memantine and phenytoin.

Other substances 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 risk of increased plasma concentrations.

When memantine is used 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 and memantine concurrently.

There is no evidence of significant interaction effects between memantine and glipizide/metformin or donepezil. No influence of memantine on the pharmacokinetics of galantamine has been observed.

Memantine does not inhibit CYP isoenzymes 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase, or sulfotransferase in vitro.

Special precautions for use

Caution should be exercised when prescribing the drug to patients with epilepsy, those 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 occur more frequently or be more pronounced (see section "Interaction with other medicinal products and other forms of interactions").

Certain factors that increase urine pH may necessitate close 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. Additionally, 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 experienced myocardial infarction, patients with decompensated congestive heart failure (functional class III–IV according to NYHA [New York Heart Association] classification), or those with uncontrolled arterial hypertension. Therefore, careful monitoring is required in patients with these conditions.

Excipients

Denigma®, oral solution 2 mg/mL, contains 0.65 g of sorbitol in 1 mL (equivalent to 6.5 g when the maximum recommended daily dose is administered). If intolerance to certain sugars has been diagnosed, consult a physician before taking this medicinal product.

The product contains methylparahydroxybenzoate and propylparahydroxybenzoate, which may cause allergic reactions (possibly delayed).

Use during pregnancy or breastfeeding

Pregnancy. There are no data on the use of memantine during pregnancy. Animal experimental studies have indicated 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 period. It is unknown whether memantine passes into breast milk, although this is possible considering the lipophilic nature of the substance. Women taking memantine should refrain from 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 has a minor or moderate effect on the ability to drive vehicles or operate machinery; therefore, outpatients should exercise particular caution when performing the aforementioned activities.

Dosage and Administration.

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of dementia in Alzheimer's disease. Therapy should be initiated only if a caregiver is available who will supervise the patient's intake of the medication. Diagnosis should be established according to current guidelines. Tolerability and dosing of memantine should be regularly evaluated, preferably within 3 months after initiation of therapy. Thereafter, a repeated assessment of the clinical benefit of memantine treatment and patient tolerability should be performed on a regular basis according to current clinical guidelines. Maintenance treatment may be continued as long as the therapeutic effect remains favorable and the patient tolerates memantine well. The decision to discontinue memantine treatment should be considered in cases of absence of therapeutic effect or if the patient does not tolerate the medication.

The medicinal product Denigma®, oral solution, should be taken once or twice daily at the same time each day, independent of food intake. The recommended initial dose is 5 mg once daily. The dose should be increased by 5 mg weekly (see table). The maximum daily dose is 20 mg.

Table.

Dosing for adult patients with normal renal function

Do not mix the medicinal product with any other liquid. The oral solution should be measured using the special dosing spoon provided with the medication.

If a patient misses one dose of the medicinal product Denigma®, it is not necessary to double the dose at the next administration. The next dose should be taken according to the prescribed schedule. If a patient has missed taking Denigma® for several days, it may be necessary to reduce the dose first, followed by gradual dose escalation according to the scheme described above.

Elderly patients.

The recommended dose for patients aged 65 years and older is 20 mg once daily (10 mL), 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 recommended daily dose is 10 mg. If this dose is well tolerated for at least 7 days of treatment, it may be increased to 20 mg once daily according to the standard dose titration schedule. For patients with severe renal impairment (creatinine clearance 5–29 mL/min), a daily dose of 10 mg should be administered.

Hepatic impairment.

For patients with mild or moderate hepatic impairment (Child-Pugh classes A and B), no dose adjustment is required. There is insufficient data on the use of memantine in patients with severe hepatic impairment; therefore, memantine is not recommended in patients with severe hepatic impairment.

Children.

This medicinal product is not intended for use in children under 18 years of age.

Overdose.

Data regarding 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 comatose 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), acidification of urine, and forced diuresis.

If clinical signs or symptoms indicate excessive general stimulation of the central nervous system, symptomatic treatment measures should be applied with caution.

Adverse Reactions

The frequency of the adverse reactions listed below is defined 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 the available data.

Blood and lymphatic system disorders

Not known: agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura.

Infections and infestations

Uncommon: fungal infections.

Immune system disorders

Common: hypersensitivity reactions.

Not known: allergic reactions.

Skin and subcutaneous tissue disorders

Not known: allergic skin reactions, including Stevens-Johnson syndrome.

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: 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: pancreatitis^2.

Hepatobiliary disorders

Common: increased liver function test parameters.

Not known: hepatitis.

Renal and urinary disorders

Not known: acute renal function impairment (including increased creatinine and renal failure).

General disorders and administration site conditions

Common: headache.

Uncommon: increased fatigue.

^1 Hallucinations were mainly 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 adverse reactions.

Reporting suspected adverse reactions after registration of a medicinal product is highly 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 all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach of children.

After first opening of the bottle, the medicinal product should not be stored for more than 3 months.

Packaging.

100 ml of solution in a bottle. Each bottle is supplied in a cardboard package with a measuring spoon.

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's location and address of its business operations.

40020, Ukraine, Sumy region, Sumy city, Skryabina St., 54.

or

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's location and address of its business operations.

40020, Ukraine, Sumy region, Sumy city, Hryhoriya Davydovskoho St., 54.