Instructions for Sermion film-coated tablets 30 mg No. 30
Composition
active ingredient: nicergoline;
1 tablet contains nicergoline 30 mg;
excipients: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, magnesium stearate, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, titanium dioxide (E 171), polyethylene glycol 6000, iron oxide yellow (E 172), silicone.
Dosage form
Film-coated tablets.
Main physicochemical properties: round biconvex tablets, coated with an opaque yellow film coating.
Pharmacotherapeutic group
Drugs affecting the cardiovascular system. Peripheral vasodilators. Ergot alkaloids. Nicergoline. ATC code C04A E02.
Pharmacological properties
Pharmacodynamics
Nicergoline is an ergoline derivative with alpha-1-adrenergic blocking activity when administered parenterally. After oral administration, nicergoline undergoes rapid and extensive metabolism to form a number of metabolites, which also exert activity at various levels of the central nervous system.
When administered orally, Sermion® exhibits numerous neuropharmacological effects: it not only increases glucose uptake and consumption in the brain, enhances protein and nucleic acid biosynthesis, but also affects various neurotransmitter systems.
Sermion® improves cerebral cholinergic functions in old animals. Long-term administration of nicergoline in old rats prevented the age-related decrease in acetylcholine levels (in the cerebral cortex and striatum) and also led to a decrease in acetylcholine release (in the hippocampus) in vivo. After long-term oral administration of Sermion®, an increase in choline acetyltransferase activity and muscarinic receptor density was also observed. Moreover, in both in vitro and in vivo studies, nicergoline significantly reduced acetylcholinesterase activity. In these experimental studies, neurochemical effects were observed simultaneously with a stable improvement in behavioral responses. For example, in the maze test, mature animals treated with Sermion® for a long time developed responses similar to those in young animals.
Sermion® has also been shown to reduce cognitive impairment induced by several agents (hypoxia, electroconvulsive therapy (ECT), scopolamine) in animals. Oral administration of Sermion® at low doses increases dopamine metabolism in adult animals, particularly in the mesolimbic region, presumably by modulating dopaminergic receptors. Sermion® improves signal transduction mechanisms in cells in adult animals. Both single and long-term oral administration of the drug have been shown to increase basal and agonist-sensitive phosphoinositide metabolism. Sermion® also increases the activity and translocation to the membrane site of calcium-dependent isoforms of protein kinase C. These enzymes are involved in the mechanism of secretion of soluble amyloid precursor protein, which leads to increased release and reduced production of pathological beta-amyloid, which was demonstrated in human neuroblastoma culture.
Due to its antioxidant effect and ability to activate detoxification enzymes, Sermion® prevents nerve cell death caused by oxidative stress and apoptosis. Sermion® attenuates the age-related decrease in neuronal nitric oxide synthase mRNA expression, which may also contribute to improving cognitive function.
Pharmacodynamic studies in humans were conducted using computer EEG techniques in young and elderly volunteers, as well as elderly patients with cognitive disorders. Sermion® normalized EEG results in elderly patients and young adult patients under hypoxia, increasing α- and β-activity and reducing δ- and θ-activity. In patients with mild to moderate dementia of various origins (senile dementia of the Alzheimer's type and multi-infarct dementia), long-term use of Sermion® (for 2–6 months) showed positive changes in evoked potentials and responses to stimuli; these changes correlated with improvement in clinical symptoms. In view of the above, it is obvious that nicergoline acts by modulating a wide range of cellular and molecular mechanisms involved in the pathogenesis of dementia. Double-blind, placebo-controlled clinical trials included more than 1,500 patients with dementia (Alzheimer's type, vascular and mixed type) who received nicergoline at a dose of 60 mg per day or placebo. After long-term treatment with nicergoline, a lasting reduction in the manifestations of cognitive and behavioral disorders associated with dementia was observed. Improvement in the patients' condition appeared after 2 months of treatment and was maintained for one year of treatment.
The drug has a positive effect on the level of attention, concentration and emotional state. The drug has a beneficial effect not only on cognitive activity, but also on mood and behavioral disorders.
Absorption. After oral administration, nicergoline is rapidly and almost completely absorbed. The maximum radioactivity after administration of low doses (4–5 mg) of H3-labeled nicergoline to healthy volunteers was determined after 1.5 hours. However, after oral administration of therapeutic doses (30 mg) of C14-labeled nicergoline to healthy volunteers, the maximum radioactivity in serum was observed 3 hours after dosing. After oral administration of nicergoline (15 mg) in healthy volunteers, the area under the serum radioactivity curve was 81% and 6% of the value 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 administration of a 30 mg tablet. Peak plasma concentrations of MMDL were reached approximately 0.5–1 hour after a single 30 mg tablet.
The absolute bioavailability of nicergoline after oral administration is approximately 5% due to the first-pass effect. Based on the results of determining the levels of the main metabolite MDL, it was found that in healthy volunteers after oral administration of a dose of 30–60 mg, the pharmacokinetics of nicergoline are linear. After a single oral administration of nicergoline at a dose of 30 mg, there was no significant effect of food on the pharmacokinetics of MDL and MMDL.
Distribution. The distribution of the drug into tissues is rapid and extensive, as 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 nicergoline concentration in the first sampling period after intravenous administration of a nominal dose of 2 mg) is relatively high (224 L), potentially reflecting the distribution of nicergoline into blood cells and/or tissues. Nicergoline binds with high affinity to human plasma proteins, with the affinity for α-acid glycoprotein being four times higher than for serum albumin. The percentage of binding is relatively constant when the concentration of nicergoline increases from 1 μg/ml to 500 μg/ml. Both nicergoline metabolites, MDL and MMDL, are characterized by low levels of binding, approximately 14.7% and 34.7%, respectively, over the concentration range
50–200 ng/ml.
Metabolism and excretion. The drug is mainly excreted in the urine. Within 120 hours after administration, approximately 82% of the total amount of radiolabeled nicergoline is excreted by the kidneys, and 10% in the feces. Nicergoline undergoes significant metabolism, mainly by hydrolysis of ester bonds to form MMDL, and then MDL by demethylation (catalytically mediated by the CYP2D6 isoenzyme). Therefore, the pharmacokinetics of nicergoline and its metabolites are affected in patients with a 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 the urine after an oral dose of 15 mg. The mean terminal half-life of MDL is in the range of approximately 11–20 hours.
Special patient populations. 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 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 the urine within 120 hours after oral administration of nicergoline at a dose of 30 mg (38.1%, 42.6% and 25.7% of the administered dose, respectively); for MMDL, the corresponding values were 1.7%, 0.6% and 0.2%. In patients with severe renal impairment, a significant decrease in the excretion of MDL in the urine was determined compared to the other two groups. In addition, patients with mild, moderate, or severe renal impairment had a mean decrease in urinary MDL excretion (0-72 hours) of 32%, 32%, and 59%, respectively, compared to patients with normal renal function in another study using the 30 mg tablet.
The pharmacokinetics of nicergoline in patients with impaired liver function 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 studied.
Indication
Post-stroke conditions, vascular dementia (multi-infarct dementia), degenerative conditions associated with dementia (senile and presenile dementia of the Alzheimer's type, dementia in Parkinson's disease).
Contraindication
Hypersensitivity to nicergoline, ergot alkaloids or any other component of the drug. Recent myocardial infarction, acute bleeding, orthostatic hypotension, severe bradycardia.
Interaction with other medicinal products and other types of interactions
The drug should be used with caution together with:
sympathomimetics (alpha- and beta-): nicergoline may have an antagonistic effect on the vasoconstrictor effect of sympathomimetic agents due to blocking alpha-adrenergic receptors (see section "Special instructions for use");
medicinal products metabolized by the CYP2D6 isoenzyme: since nicergoline is metabolized by the CYP2D6 isoenzyme, the possibility of interactions with other medicinal products metabolized by the same pathway cannot be excluded;
with antiplatelet agents and anticoagulants (e.g. acetylsalicylic acid): enhances the effect on hemostasis, which may increase bleeding time;
Drugs that affect uric acid metabolism: nicergoline may lead to an asymptomatic increase in uric acid concentrations in blood plasma.
Application features
Studies with single or multiple administration of nicergoline have shown that nicergoline can reduce systolic blood pressure and, to a much lesser extent, diastolic blood pressure in normotensive and hypertensive patients. These effects may vary, as other studies have not shown changes in systolic or diastolic blood pressure.
Sympathomimetics (alpha and beta receptor agonists) should be used with caution in patients taking nicergoline (see section "Interaction with other medicinal products and other types of interactions").
The drug should be used with caution in patients with a history of hyperuricemia or gout and/or during concomitant treatment with drugs that may affect the metabolism and excretion of uric acid (see section "Adverse reactions").
The development of fibrosis (e.g., pulmonary, cardiac, valvular, and retroperitoneal fibrosis) has been associated with the use of certain ergot alkaloids that possess agonist activity at serotonin 5-HT2β receptors.
Symptoms of ergotism (including nausea, vomiting, diarrhea, abdominal pain, and peripheral vasoconstriction) have been reported with the use of some ergot alkaloids and their derivatives.
Before prescribing this class of medications, doctors need to be familiar with the signs of ergot overdose.
Ability to influence reaction speed when driving vehicles or other mechanisms
Although the clinical effects of Sermion® are used to improve attention and concentration, its effect on the ability to drive and use machines has never been studied. Therefore, treatment should be carried out with caution, taking into account the underlying disease of the patients. When driving or operating machinery, it should be taken into account that dizziness or drowsiness may occasionally occur (see section "Adverse reactions").
Use during pregnancy or breastfeeding
Pregnancy
Nicergoline has no reproductive toxicity in pregnant rats and rabbits. No clinical studies have been conducted in pregnant women. Given the approved indications, the use of nicergoline in pregnant and lactating women is unlikely. During pregnancy, nicergoline should be used only if the potential benefit to the patient outweighs the potential risk to the fetus.
Breast-feeding
It is not known whether nicergoline passes into breast milk, therefore Sermion® should not be used by women who are breastfeeding.
Fertility
In a study in rats, nicergoline did not affect fertility.
Method of administration and doses
The recommended daily dose is 1 tablet 1 or 2 times a day (30-60 mg). The usual daily dose for adults is 30 mg. It can be temporarily increased to 60 mg.
According to the results of pharmacokinetic and tolerability studies, no dose adjustment is required for elderly patients.
Patients with renal impairment.
Since renal excretion is the main route of elimination (80%) of nicergoline and its metabolites, a dose reduction is recommended for patients with impaired renal function (serum creatinine ≥ 2 mg/ml) (see section "Pharmacokinetics"). The effect of the treatment appears gradually. Since therapy is usually carried out for a long time, the doctor should assess the feasibility of continuing treatment at least every 6 months.
Children
The safety and efficacy of nicergoline in children have not been established. No data are available.
Overdose
When using high doses of nicergoline, a temporary decrease in blood pressure is possible. Usually, this condition does not require special treatment, it is enough to lie down for a few minutes. In exceptional cases of severe cerebral and cardiac circulatory failure, it is advisable to use sympathomimetics and constant monitoring of blood pressure.
Adverse reactions
The frequency categories are expressed as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency unknown (frequency cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Nervous system disorders: Uncommon: drowsiness, dizziness, headache; frequency unknown: feeling hot*.
Vascular disorders: Uncommon: hypotension, flushing.
Gastrointestinal disorders: Common: abdominal discomfort; uncommon: diarrhea, nausea, constipation.
Skin and subcutaneous tissue disorders: Uncommon: pruritus; frequency unknown: rash*.
General disorders and administration site conditions Not known: fibrosis*.
Research findings: Uncommon: increased blood uric acid concentration.
*The frequency of adverse reactions was based on the studies in the Comprehensive Safety Summary (reactions that occurred after initiation of treatment for any reason). This pooled safety analysis includes data from eight (8) double-blind, controlled studies in patients with mild to moderate dementia, of which 1246 patients received nicergoline. The “rule of three” was not applied because there were fewer than 3000 patients in the Comprehensive Safety Summary database for nicergoline.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions in the post-marketing period is an important measure. This allows for continued monitoring of the benefit/risk balance of the drug. Physicians are encouraged to report any suspected adverse reactions.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C.
Packaging
15 tablets in a blister; 2 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Pfizer Italia Srl
Location of the manufacturer and its business address
Locality Marino del Tronto ‒ 63100 Ascoli Piceno (AP), Italy/Localita Marino del Tronto ‒ 63100 Ascoli Piceno (AP), Italy.
