Niceromax

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NİCEROMAX (NICEROMAX)

Composition:

Active substance: nicergoline;

1 vial contains 4 mg of nicergoline;

Excipients: lactose monohydrate, tartaric acid.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: white porous mass or white powder.

Pharmacotherapeutic group. Drugs affecting the cardiovascular system. Peripheral vasodilators. Ergot alkaloids. ATC code C04AE02.

Pharmacological properties.

Pharmacodynamics.

Nicergoline is a derivative of ergoline with alpha-1-adrenergic blocking activity when administered parenterally. After oral administration, nicergoline undergoes rapid and extensive metabolism, generating several metabolites responsible for its activity at various levels of the central nervous system.

Following oral administration, nicergoline exerts numerous neuropharmacological effects: it not only enhances glucose uptake and utilization in the brain, stimulates biosynthesis of proteins and nucleic acids, but also affects various neurotransmitter systems.

Nicergoline improves cerebral cholinergic functions in aged animals. Long-term administration of nicergoline in aged rats prevented age-related decline in acetylcholine levels (in the cortex and striatum), and also reduced acetylcholine release (in the hippocampus) under in vivo conditions. Following prolonged oral administration of nicergoline, increased activity of choline acetyltransferase and increased density of muscarinic receptors were also observed. Both in vitro and in vivo studies demonstrated that nicergoline significantly reduces acetylcholinesterase activity. In these experimental studies, neurochemical effects were observed simultaneously with sustained improvement in behavioral responses; for example, in mature animals receiving long-term nicergoline, behavioral responses similar to those in young animals were observed.

Administration of nicergoline in animals also reduced cognitive deficits induced by various agents (hypoxia, electroconvulsive therapy (ECT), scopolamine). Oral administration of low doses of nicergoline increased dopamine turnover in mature animals, particularly in the mesolimbic area, likely via modulation of dopaminergic receptors. Nicergoline enhances intercellular signal transduction mechanisms in mature animals. Both after single and repeated oral administration of the drug, increased turnover of basal and agonist-sensitive phosphoinositides was observed. Nicergoline also increases the activity and translocation to the membrane of calcium-dependent isoforms of protein kinase C. These enzymes are involved in the mechanism of secretion of the soluble amyloid precursor protein, leading to enhanced release and reduced production of pathological beta-amyloid, as demonstrated in cultures of human neuroblastoma cells.

Due to its antioxidant effect and ability to activate detoxifying enzymes, nicergoline prevents neuronal cell death caused by oxidative stress and also prevents apoptosis in both in vivo and in vitro experimental models. Nicergoline attenuates age-related decline in mRNA expression of neuronal nitric oxide synthase, which may also contribute to improved cognitive function.

Pharmacodynamic studies in humans using computerized electroencephalography (EEG) techniques were conducted in young and elderly volunteers, as well as in elderly patients with cognitive disorders. Nicergoline exerted a normalizing effect on EEG results in elderly patients and in young adults under hypoxic conditions, increasing α- and β-activity while decreasing δ- and θ-activity. Positive changes in evoked potentials and response to stimuli were recorded in patients with mild to moderate dementia of various etiologies (due to Alzheimer's disease and multi-infarct dementia); after prolonged treatment with nicergoline (2–6 months), these changes correlated with clinical symptom improvement.

Based on the above, it is evident that nicergoline acts by modulating a broad spectrum of cellular and molecular mechanisms involved in the pathophysiology of dementia.

In clinical studies involving more than 1500 patients with dementia (Alzheimer type, vascular, and mixed type) receiving nicergoline at a dose of 60 mg per day or placebo, prolonged treatment with nicergoline resulted in continuous reduction of cognitive and behavioral disturbances associated with dementia. Changes were observable after 2 months of treatment and were maintained throughout one year of therapy.

Pharmacokinetics.

After intravenous infusion of 2 mg H3-nicergoline over approximately 10 minutes in 3 healthy subjects, nicergoline underwent rapid hydrolysis of the ester bond, forming the metabolite 1-methyl-10-methoxydihydrolysergol (MMDL). Subsequent demethylation at position 1 of the ergoline structure yielded the main metabolite, 10-methoxydihydrolysergol (MDL). Unchanged nicergoline was detected in all three subjects up to 90 minutes after infusion, with a mean plasma concentration of approximately 4.5 ng/mL at 20 minutes, followed by a rapid decline associated with a half-life of less than 30 minutes. Maximum concentration of MMDL was observed already at 20 minutes after administration, and its levels declined rapidly thereafter over an 8-hour period. Maximum concentration of MDL was approximately 2.2 ng/mL at 4 hours after completion of infusion, followed by a slower elimination phase compared to MMDL. Approximately 50% and 10% of the administered radioactive dose were excreted in urine over 4 days and in feces over 7 days, respectively.

Special patient groups

The effect of impaired renal function on the pharmacokinetics of nicergoline was evaluated in patients with mild (creatinine clearance (CLcr) 60–80 mL/min), moderate (CLcr 30–50 mL/min), and severe (CLcr 10–25 mL/min) renal impairment. In patients with mild (n=5), moderate (n=5), and severe (n=4) renal impairment, significant differences were observed in the amount of MDL excreted in urine over 120 hours after a single 30 mg oral dose of nicergoline (38.1%, 42.6%, and 25.7% of the dose, respectively); corresponding values for MMDL were 1.7%, 0.6%, and 0.2%, respectively. Patients with severe renal impairment showed a marked reduction in urinary excretion of MDL compared to the other two groups. Additionally, in patients with mild, moderate, and severe renal impairment, mean reduction in urinary excretion of MDL (0–72 hours) was 32%, 32%, and 59%, respectively, compared to patients with normal renal function in another study receiving 30 mg tablets.

The pharmacokinetics of nicergoline has not been studied in patients with hepatic impairment.

The pharmacokinetics of nicergoline has not been studied in children.

The pharmacokinetics of nicergoline in elderly patients has not been fully studied.

Clinical Characteristics.

Indications.

Acute and chronic cerebrovascular metabolic disorders due to atherosclerosis, thrombosis and embolism of cerebral vessels, transient disturbances of cerebral circulation (transient ischemic attacks).

Headache.

Additional therapy in the treatment of arterial hypertension.

Contraindications.

Hypersensitivity to the active substance, ergot alkaloids, or to any component of the drug. Recent myocardial infarction, acute bleeding, orthostatic hypotension, severe bradycardia.

Interaction with other medicinal products and other forms of interaction.

The drug should be used with caution in combination with:

• antihypertensive agents (nicergoline may potentiate their effect); nicergoline may potentiate the cardiac effects of β-blockers;
• sympathomimetic agents (alpha and beta): nicergoline may antagonize the vasoconstrictive effects of sympathomimetic drugs due to its alpha-adrenergic blocking effect (see section "Special precautions");
• drugs metabolized by the CYP2D6 isoenzyme: since nicergoline is metabolized by the CYP2D6 isoenzyme, interactions with other medicinal products metabolized via the same pathway cannot be excluded;
• antiplatelet agents and anticoagulants (e.g., acetylsalicylic acid): nicergoline enhances the effect on hemostasis, thereby possibly prolonging bleeding time;
• drugs affecting uric acid metabolism: nicergoline may cause asymptomatic increase in plasma uric acid levels.

Special precautions for use

Studies with single or multiple doses of nicergoline have shown that nicergoline may reduce systolic arterial pressure and, to a lesser extent, diastolic arterial pressure in normotensive patients and in patients with elevated blood pressure. This effect of nicergoline on blood pressure may be variable, as other studies have not demonstrated changes in systolic or diastolic blood pressure.

Sympathomimetic agents (alpha and beta agonists) should be used with caution in patients receiving nicergoline (see section "Interaction with other medicinal products and other forms of interaction").

Nicergoline should be prescribed with caution in patients with hyperuricemia or a history of gout and/or during concomitant treatment with drugs that may affect uric acid metabolism and excretion (see section "Undesirable effects").

Fibrotic disorders (e.g., pulmonary fibrosis, cardiac fibrosis, valvular heart disease, and retroperitoneal fibrosis) have been associated with the use of certain ergot alkaloids possessing agonistic activity at 5-HT_2B serotonin receptors.

Cases of ergotism (including nausea, vomiting, diarrhea, abdominal pain, and peripheral vasoconstriction) have been reported with the use of certain ergot alkaloids and their derivatives.

Before prescribing this class of medicinal products, physicians should be familiar with the signs and symptoms of ergot overdose.

Use during pregnancy or breastfeeding

Pregnancy

Nicergoline showed no toxic effect on reproductive function in pregnant female rats and rabbits. Studies in pregnant women have not been conducted. Considering the approved indications, use of the drug in pregnant women and in women who are breastfeeding is unlikely. Nicergoline may be used during pregnancy only if the expected benefit to the woman outweighs the potential risk to the fetus.

Breastfeeding

It is unknown whether nicergoline is excreted in human milk; therefore, the medicinal product should not be used in women who are breastfeeding.

Fertility

In a study in rats, nicergoline had no effect on fertility.

Effects on ability to drive and use machines

Although the clinical action of Nicomax is aimed at improving alertness and concentration, the effect of the drug on reaction speed while driving or operating machinery has not been specifically studied. In any case, caution should be exercised, taking into account the patient's underlying condition.

When driving vehicles or operating machinery, the possibility of dizziness or somnolence should be taken into account (see section "Undesirable effects").

Administration and dosage

Intramuscular injections: 2–4 mg (2–4 mL) twice daily (the lyophilisate should be reconstituted with water for injections or sodium chloride physiological solution to a volume of 2–4 mL).

Slow intravenous infusion: 4–8 mg dissolved in 100 mL of physiological saline or glucose solution. According to the physician’s decision, this dose may be repeated several times daily.

There is experience with intra-arterial administration of nicergoline: 4 mg dissolved in 10 mL of physiological saline administered over 2 minutes.

The dosing regimen, duration of treatment, and route of administration depend on the individual clinical situation. In some cases, it may be appropriate to initiate treatment with parenteral administration of the drug, followed by long-term oral therapy.

Therapeutic effects develop gradually. Since therapy is usually long-term, the physician must periodically evaluate the continued need for treatment at regular intervals, but no less frequently than every 6 months.

Elderly patients. Based on pharmacokinetic and tolerability study results, dosage adjustment is not required for elderly patients.

Patients with renal impairment. Since renal excretion in urine is the main elimination pathway (80%) for nicergoline and its metabolites, dosage reduction is recommended for patients with impaired renal function (serum creatinine level ≥2 mg/dL) (see section "Pharmacokinetics").

Children.

The safety and efficacy of nicergoline in children have not been established. Data are lacking.

Overdose.

When nicergoline is administered in high doses, a temporary decrease in arterial blood pressure may occur. Specific treatment is usually not required; remaining at rest for several minutes is sufficient. In exceptional cases, if pronounced cerebral or cardiac hypoperfusion develops, sympathomimetic agents are recommended, along with continuous monitoring of arterial blood pressure.

Adverse Reactions

The adverse reactions listed below are categorized by system organ classes and in order of decreasing severity. Frequency is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Psychiatric disorders: uncommon – agitation, confusion, insomnia.

Nervous system disorders: uncommon – somnolence, dizziness, headache; frequency not known – hot flushes.

Vascular disorders: uncommon – hypotension, flushing.

Gastrointestinal disorders: common – abdominal discomfort; uncommon – diarrhea, nausea, constipation.

Skin and subcutaneous tissue disorders: uncommon – pruritus; frequency not known – rash.

General disorders and administration site conditions: frequency not known – fibrosis.

Investigations: uncommon – increased blood uric acid levels.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after registration of the medicinal product is an important activity. It allows continued monitoring of the benefit-risk balance of the drug. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibilities.

For intravenous injection/infusion, use physiological saline or glucose solution.

Do not mix with other medicinal products. Use only recommended solvents.

Packaging.

4 vials with lyophilisate in a blister pack, 1 blister pack per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

LLC **"**FARMEKS GROUP".

Manufacturer's address and location of business activity.

100 Shevchenka St., Boryspil, Kyiv Oblast, 08301, Ukraine.