Nicergoline

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NİCERGOLİN (NICERGOLINЕ)

Composition:

Active substance: nicergolinе;

1 tablet contains nicergoline – 10 mg;

Excipients: lactose monohydrate; magnesium carbonate heavy; stearic acid; potato starch; sugar; talc; titanium dioxide (E 171); povidone; colloidal anhydrous silicon dioxide; white wax.

Dosage form. Film-coated tablets.

Main physico-chemical properties: film-coated white tablets. Two layers are visible in cross-section.

Pharmacotherapeutic group.

Peripheral vasodilators. Ergot alkaloids.

ATC code С04А Е02.

Pharmacological Properties

Pharmacodynamics

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

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

Nicergoline improves cerebral cholinergic functions in aged animals. Chronic administration of nicergoline in aged rats prevented age-related decreases in acetylcholine levels (in the cortex and striatum) and reduced acetylcholine release (in the hippocampus) under in vivo conditions. Following prolonged oral administration, increased activity of choline acetyltransferase and increased density of muscarinic receptors were also observed. Moreover, in in vitro and in vivo studies, nicergoline significantly enhanced acetylcholinesterase activity. In these experimental studies, neurochemical effects were observed concurrently with sustained improvement in behavioral responses; for example, in maze tests, mature animals treated chronically with nicergoline exhibited responses similar to those of young animals.

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 metabolism in mature animals, particularly in the mesolimbic region, likely via modulation of dopaminergic receptors. Nicergoline enhances signal transduction mechanisms in cells of mature animals. Both after single and repeated oral administration, an increase in basal and agonist-sensitive phosphoinositide metabolism was observed. Nicergoline also enhances the activity and translocation to the membrane of calcium-dependent isoforms of protein kinase C. Due to its antioxidant effect and ability to activate detoxifying enzymes, nicergoline prevents neuronal cell death caused by oxidative stress and apoptosis. Nicergoline attenuates age-related reduction in mRNA expression of neuronal nitric oxide synthase, which may also contribute to improved cognitive function.

Pharmacokinetics

After oral administration, nicergoline is rapidly and almost completely absorbed. The maximum level of radioactivity following administration of low doses (4–5 mg) of H-labeled nicergoline to healthy volunteers was observed at 1.5 hours. However, after oral administration of therapeutic doses (30 mg) of C-labeled nicergoline to healthy volunteers, the maximum level of radioactivity in blood serum occurred 3 hours after dosing. After oral administration of nicergoline (15 mg) to healthy volunteers, the area under the serum radioactivity curve accounted for 81% and 6% of the values calculated for two major metabolites of nicergoline—MDL and MMDL, respectively. Peak plasma concentrations of MDL were reached approximately 3–5 hours after single or multiple doses of the 30 mg tablet. Peak plasma concentrations of MMDL were achieved approximately 0.5–1 hour after single administration of the 30 mg tablet.

The absolute bioavailability of nicergoline after oral administration is approximately 5%, due to the first-pass effect. Based on measurements of the main metabolite MDL, the pharmacokinetics of nicergoline were found to be linear in healthy volunteers after oral administration of 30–60 mg doses. After single oral administration of 30 mg nicergoline, food had no significant effect on the pharmacokinetics of MDL and MMDL.

Distribution of the drug in tissues is rapid and extensive, reflected by the short distribution phase of serum radioactivity. The volume of distribution of nicergoline in the central compartment (approximately calculated by dividing the dose by the plasma concentration of nicergoline at the first sampling time after intravenous administration of a nominal 2 mg dose) is relatively high (224 L), potentially reflecting distribution of nicergoline into blood cells and/or tissues. Nicergoline is highly bound to human plasma proteins, with affinity for α-acid glycoprotein four times higher than for serum albumin. The percentage of binding remains relatively constant as the concentration of nicergoline increases from 1 µg/mL to 500 µg/mL. Both metabolites of nicergoline, MDL and MMDL, exhibit low binding levels, approximately 14.7% and 34.7%, respectively, within the concentration range of 50–200 ng/mL. The drug is predominantly excreted in urine. Within 120 hours after administration, approximately 82% of the total administered dose of radiolabeled nicergoline is eliminated via the kidneys, and 10% via feces. Nicergoline undergoes extensive metabolism, primarily through hydrolysis of ester bonds, forming MMDL, which is then converted to MDL via demethylation (catalyzed by the CYP2D6 isoenzyme). Therefore, the pharmacokinetics of nicergoline and its metabolites are influenced in patients with genetic deficiency of CYP2D6. The active metabolites formed (MMDL and MDL) are conjugated with glucuronic acid. The main metabolite MDL accounts for 51% of the total dose and 76% of the radioactivity detected in urine after oral administration of a 15 mg dose. The mean terminal half-life of MDL ranges from approximately 11 to 20 hours.

The effect of renal impairment 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 dysfunction. 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 within 120 hours after oral administration of 30 mg nicergoline (38.1%, 42.6%, and 25.7% of the administered dose, respectively); corresponding values for MMDL were 1.7%, 0.6%, and 0.2%. In patients with severe renal impairment, a significant reduction in urinary excretion of MDL was observed compared to the other two groups. Additionally, in patients with mild, moderate, or severe renal impairment, mean reductions in urinary excretion of MDL (0–72 hours) were 32%, 32%, and 59%, respectively, compared to patients with normal renal function participating in another study using 30 mg tablets.

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

The pharmacokinetics of nicergoline have not been studied in children.

The effect of age (in elderly patients) on the pharmacokinetics of nicergoline has not been fully investigated.

Clinical characteristics.

Indications.

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

Headache.

As additional therapy in systemic arterial hypertension.

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

Interaction with other medicinal products and other forms of interactions.

The drug should be used with caution in combination with:

• antihypertensive agents: nicergoline may enhance their effect. Nicergoline may enhance the cardiac effects of beta-blockers;
• sympathomimetics (alpha- and beta-): nicergoline may exert antagonistic action against the vasoconstrictive effect of sympathomimetic agents due to blockade of alpha-adrenergic receptors;
• medicinal products metabolized by the isoenzyme CYP2D6: since nicergoline is metabolized by the isoenzyme CYP2D6, potential interactions with other medicinal products metabolized via the same pathway cannot be excluded;
• antiplatelet agents and anticoagulants (e.g., acetylsalicylic acid): enhances the effect on hemostasis, thereby possibly increasing bleeding time;
• medicinal products affecting uric acid metabolism: nicergoline may cause asymptomatic elevation of plasma uric acid concentrations.

Special precautions for use

Studies with single or repeated administration of nicergoline have shown that nicergoline may reduce systolic blood pressure and, to a much lesser extent, diastolic blood pressure in patients with normal blood pressure as well as in patients with elevated blood pressure. These effects may vary, since other studies have not revealed changes in systolic or diastolic blood pressure.

Patients taking nicergoline should use sympathomimetics (alpha- and beta-receptor agonists) with caution (see section "Interaction with other medicinal products and other forms of interaction").

The drug should be used with caution in patients with exertional angina and severe atherosclerosis. Orthostatic hypotension may occur at the beginning of treatment.

The drug should be used with caution in patients with hyperuricemia or history of gout and/or concomitant therapy with drugs that may affect uric acid metabolism and excretion.

Fibrosis (e.g., pulmonary, cardiac, cardiac valve fibrosis, and retroperitoneal fibrosis) has been associated with the use of certain ergot alkaloids that possess agonistic activity at serotonin 5-HT2β receptors.

Cases of ergotism symptoms (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 of ergot overdose.

The drug should not be administered to patients with hereditary galactose intolerance, lactase deficiency, or glucose/galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Nicergoline has no toxic effect on reproductive function in pregnant female rats and rabbits. Clinical studies in pregnant women have not been conducted.

Considering the indications for nicergoline, its use in pregnant women and women who are breastfeeding is unlikely. During pregnancy, nicergoline should be used only when the potential benefit to the patient outweighs the potential risk to the fetus.

Breastfeeding.

It is unknown whether nicergoline is excreted in human breast milk; therefore, nicergoline should not be administered to women who are breastfeeding.

Fertility.

Nicergoline has no effect on fertility in rats.

Ability to influence reaction speed when driving or operating machinery. Although the clinical effects of nicergoline are utilized to improve attention and concentration, its impact on the ability to drive or operate machinery or other automated systems has never been studied. In any case, caution is necessary, taking into account the underlying disease of patients. When driving vehicles or operating other automated systems, it should be kept in mind that dizziness or drowsiness may occasionally occur (see section "Adverse reactions").

Method of Administration and Dosage.

The recommended daily dose of the drug is 5–10 mg three times a day at equal intervals, preferably between meals, for continuous treatment.

Dosage regimens, duration of treatment, and route of administration depend on the severity of individual clinical manifestations of the disease.

Based on pharmacokinetic and tolerability studies, dosage adjustment is not required for elderly patients.

Patients with impaired renal function.

Since renal excretion is the main route of elimination (80%) of nicergoline and its metabolites, a reduced dose is recommended for patients with impaired renal function (serum creatinine level ≥ 2 mg/mL).

The therapeutic effect develops gradually. Since therapy is usually long-term, the physician should evaluate the appropriateness of continuing treatment at least every 6 months.

Children. The drug is not intended for use in children.

Overdose.

When high doses of nicergoline are administered, a temporary decrease in arterial blood pressure may occur. Usually, this condition does not require specific treatment—placing the patient in a lying position for several minutes is sufficient. In exceptional cases of insufficient cerebral and cardiac perfusion, the use of sympathomimetic agents and continuous monitoring of arterial blood pressure is advisable.

Adverse Reactions

Frequency categories are 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).

Within each frequency category, adverse reactions are listed in order of decreasing severity.

Psychiatric disorders. Uncommon: anxiety, confusion, insomnia.

Nervous system disorders. Uncommon: somnolence, dizziness, headache; frequency not known: hot flush*.

Vascular disorders. Uncommon: hypotension, hyperemia.

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 concentration.

Available data indicate elevated levels of uric acid in blood.

*Frequency assessment of adverse reactions was based on studies included in the Integrated Safety Summary (events occurring after treatment initiation, regardless of causality). This integrated safety analysis includes data from eight (8) double-blind, controlled studies involving patients with mild to moderate dementia, of whom 1246 received nicergoline. The "rule of three" was not applied, as the nicergoline Integrated Safety Summary database included fewer than 3000 patients.

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 are requested to report any suspected adverse reactions in accordance with regulatory requirements.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister, 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Halychpharm".

Manufacturer's address and location of its business activities.

6/8 Opryshkovska Street, Lviv, 79024, Ukraine.