Sermin

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

Composition:

Active substance: nicergoline;

1 tablet contains 5 mg or 10 mg of nicergoline;

Excipients: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, magnesium stearate, sodium carboxymethylcellulose, titanium dioxide (E 171), sucrose, talc, acacia resin, sandarac resin, magnesium carbonate, colophony, carnauba wax, sunset yellow (E 110) (for 5 mg tablets).

Pharmaceutical form. Sugar-coated tablets.

Main physicochemical properties:

5 mg tablets: round, convex, sugar-coated tablets of orange color;

10 mg tablets: round, convex, sugar-coated tablets of white color.

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

Pharmacological Properties.

Pharmacodynamics.

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

Oral administration of Serminon® demonstrates numerous neuropharmacological effects: it not only enhances glucose uptake and utilization in the brain and stimulates protein and nucleic acid biosynthesis, but also affects various neurotransmitter systems.

Serminon®® improves cerebral cholinergic functions in aged animals. Long-term administration of nicergoline in aged rats prevented age-related declines in acetylcholine levels (in the cerebral cortex and striatum), as well as reduced acetylcholine release (in the hippocampus) under in vivo conditions. Following prolonged oral administration of Serminon®®, increased activity of choline acetyltransferase and higher density of muscarinic receptors were also observed. Moreover, in in vitro and in vivo studies, nicergoline significantly reduced 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 long-term with Serminon® exhibited responses similar to those of young animals.

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

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

Pharmacodynamic studies in humans were conducted using computerized EEG techniques involving young and elderly volunteers, as well as elderly patients with cognitive disorders. Serminon® normalized EEG results in elderly and younger adult patients under hypoxic conditions, increasing α- and β-activity and decreasing δ- and θ-activity. In patients with mild to moderate dementia of various etiologies (senile dementia of Alzheimer type and multi-infarct dementia), long-term treatment with Serminon® (for 2–6 months) resulted in positive changes in evoked potentials and stimulus response; these changes correlate with clinical symptom improvement. Given the above, it is evident that nicergoline acts through broad-spectrum modulation of cellular and molecular mechanisms involved in the pathogenesis of dementia.

More than 1,500 patients with dementia (Alzheimer type, vascular, and mixed type) participated in double-blind, placebo-controlled clinical trials, receiving either nicergoline 60 mg daily or placebo. After long-term treatment with nicergoline, a sustained reduction in cognitive and behavioral symptoms associated with dementia was observed. Clinical improvement in patients emerged after 2 months of treatment and was maintained throughout one year of therapy.

Pharmacokinetics.

Absorption.

After oral administration, nicergoline is rapidly and almost completely absorbed. The peak level of radioactivity following administration of low doses (4–5 mg) of H3-labeled nicergoline to healthy volunteers was observed at 1.5 hours. However, after oral administration of therapeutic doses (30 mg) of C14-labeled nicergoline to healthy volunteers, the peak 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 the two main metabolites of nicergoline – MDL and MMDL, respectively. Peak plasma concentrations of MDL were reached approximately 3–5 hours after single or multiple doses of 30 mg tablets. Peak plasma concentration of MMDL was achieved approximately 0.5–1 hour after a single 30 mg tablet dose.

Distribution.

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

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 during the first sampling period after intravenous administration of a nominal 2 mg dose) is relatively high (224 L), potentially reflecting distribution 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 protein binding remains relatively constant as nicergoline concentration 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.

Metabolism and Excretion.

The drug is predominantly excreted via urine. Within 120 hours after administration, approximately 82% of the total amount of radiolabeled nicergoline is eliminated by 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) undergo conjugation 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.

Special Patient Populations. The effect of renal impairment on the pharmacokinetics of nicergoline was evaluated in patients with mild (creatinine clearance (CrCl) 60–80 mL/min), moderate (CrCl 30–50 mL/min), and severe (CrCl 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 within 120 hours after oral administration of a 30 mg dose of 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 reduction in urinary excretion of MDL (0–72 hours) was 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 caused by atherosclerosis, thrombosis, and cerebral vessel embolism; transient disturbances of cerebral circulation (transient ischemic attacks).

Headache.

As an additional therapy in systemic arterial hypertension.

Contraindications.

Hypersensitivity to any component of the drug or to ergot alkaloids; recent myocardial infarction, acute hemorrhage, orthostatic hypotension, severe bradycardia.

Interaction with other medicinal products and other types of interactions.

The drug should be used with caution in combination with:

antihypertensive agents: nicergoline may enhance their effect. Nicergoline may potentiate 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 (see section "Special precautions");

medicinal products metabolized by the isoenzyme CYP2D6: since nicergoline is metabolized by the CYP2D6 isoenzyme, potential interactions with other medicinal products metabolized via the same pathway cannot be excluded;

antiplatelet agents and anticoagulants (e.g., with acetylsalicylic acid): enhances the effect on hemostasis, thereby potentially increasing bleeding time;

medicinal products affecting uric acid metabolism: nicergoline may cause asymptomatic increases in 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 or elevated blood pressure. These effects may vary, as other studies have not detected 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 develop at the beginning of treatment.

The drug should be used cautiously in patients with a history of hyperuricemia or gout and/or during concomitant treatment with drugs that may affect uric acid metabolism and excretion (see section "Side effects").

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

The product contains sucrose and therefore should not be used in patients with rare hereditary fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency.

Sermin®, 5 mg tablets, contain sunset yellow (E 110), which may cause allergic reactions.

The medicinal product contains less than 1 mmol of sodium (23 mg) per tablet. Patients on a low-sodium diet may be informed that this medicinal product is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

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 Sermin®, 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 passes into breast milk; therefore, Sermin® should not be used in women who are breastfeeding.

Fertility

Nicergoline does not affect fertility in rats.

Ability to influence the speed of reactions when driving vehicles or operating machinery.

Although the clinical effects of Sermin® are utilized to improve attention and concentration, its impact on the ability to drive vehicles or operate machinery has never been studied. In any case, caution is necessary, taking into account the underlying condition of patients. When driving vehicles or operating machinery, it should be borne in mind that dizziness or somnolence may occasionally occur (see section "Side effects").

Dosage and Administration.

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

Dosing 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 in elderly patients is not required.

Patients with renal impairment.

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) (see section "Pharmacokinetics").

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. Safety and efficacy of nicergoline in children have not been established. No data are available.

Overdose.

When nicergoline is administered in high doses, a temporary decrease in arterial blood pressure may occur. Specific treatment is usually not required; it is sufficient to place the patient in a horizontal position for several minutes. In exceptional cases of cerebral or cardiac hypoperfusion, sympathomimetics are recommended along with continuous monitoring of arterial blood pressure.

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 flushes*.

Vascular disorders. Uncommon: arterial 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.

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

Reporting 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 encouraged to report any suspected adverse reactions in accordance with national reporting requirements.

Shelf life

3 years.

Storage conditions

Store at temperatures not exceeding 25 °C.

Packaging

5 mg tablets: 15 tablets in a blister; 2 blisters in a cardboard box.

10 mg tablets: 25 tablets in a blister; 2 blisters in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Pfizer Italia S.r.l.

Manufacturer's address

Localita Marino del Tronto – 63100 Ascoli Piceno (AP), Italy.