Sermion

10 mg sugar-coated tablet: Each sugar-coated tablet contains 10 mg of nicergoline.
30 mg film-coated tablet: Each film-coated tablet contains 30 mg of nicergoline.

Pharmacology: Pharmacodynamics: Nicergoline is an ergoline derivative with alpha-1 adrenergic blocking activity, when administered parenterally. After oral administration, the product undergoes a rapid and extensive metabolism, from which a series of metabolites originates, also responsible for the activities observed at several CNS levels.
Orally administered, nicergoline exerts multiple neuropharmacological actions: Not only it enhances the cerebral glucose uptake and consumption, the protein and nucleic acid biosynthesis, but it seems to act on various neurotransmitter systems.
Nicergoline improves the cerebral cholinergic functions in aged animals. Chronic nicergoline treatment in aged rats prevented the age-related reduction of Ach levels (in the cortex and in the striatum) and of release (in the hippocampus) in vivo. Increased CAT (choline-acetyltransferase) activity and muscarinic receptor density were also observed after chronic oral treatment with nicergoline. Furthermore, in both in vitro and in vivo experiments nicergoline significantly decreases AchE (acetylcholine esterase) activity. In these experiments the neurochemical effects were parallel with consistent behavioral improvements, for example in the maze test, where chronic nicergoline treatment in aged animals induced a response similar to that of younger animals.
Nicergoline was also able to improve the cognitive deficit induced by several agents (hypoxia, ECT, scopolamine) in animals. Low doses of nicergoline administered orally increase dopamine turnover in aged animals, particularly in the mesolimbic area, probably by modulating dopaminergic receptors. Nicergoline improves the cellular signal transduction mechanisms in aged animals. Both single and chronic oral treatment increased the basal and agonist-sensitive phosphoinositide turnover. Nicergoline also increases the activity and the translocation to the membrane compartment of the Ca-dependent PKC isoforms. These enzymes participate in the secretion mechanism of soluble amyloid precursor protein (APP) which leads to the increase of its release and the reduction of abnormal beta-amyloid production, as it was demonstrated in human neuroblastoma cultures.
Its antioxidant effect and by activating the detoxication enzymes, nicergoline prevents nerve cells from oxidative stress-caused death and from apoptosis in both in vivo and in vitro experimental models. Nicergoline reduces the age-related decrease of neuronal Nitric Oxide Synthase (nNOS) mRNA expression, which may contribute to the improvement of the cognitive function.
Human experiments: Human pharmacodynamic studies using computerized EEG techniques have been performed in young and aged volunteers as well as in elderly patients with cognitive disorders. Nicergoline had a normalizing effect on the EEG of elderly patients and younger adults under hypoxia, increasing α and β activity and decreasing δ and θ activity. Positive changes in event contingent potential and evoked reaction have been recorded in patients affected by mild to moderate dementia of various origin (SDAT and MID), following nicergoline chronic treatment (2-6 months), these changes are correlated with the improvement of clinical symptoms.
Based on the previously mentioned, it is obvious that nicergoline acts by the broad-spectrum modulation of cellular and molecular mechanisms involved in the pathophysiology of dementia.
In double-blind, placebo-controlled clinical studies more than 1500 patients were involved with dementia (Alzheimer's type, vascular and mixed type dementia) receiving 60 mg nicergoline per day or placebo. Following long-term nicergoline treatment, a continuous improvement in cognitive and behavioral disturbances associated with dementia were observed. The change could be observed after 2 months of treatment and were permanent during one year treatment.
Pharmacokinetics: Absorption: Nicergoline is rapidly and almost completely absorbed following oral administration. The peak serum radioactivity after administration of low doses (4-5 mg) of radioactive H³ labelled nicergoline to healthy volunteers occurred in 1.5 hours post-dose. However therapeutic oral doses (30 mg) of C¹⁴ labelled nicergoline in healthy volunteers showed peak serum radioactivity in 3 hours post-dose.
After oral administration of nicergoline (15 mg) in healthy volunteers, the area under the curve of plasma radioactivity (AUC) for main active metabolite MDL and the second active metabolite MMDL were 81% and 6% of AUC of total radioactivity, respectively. Peak plasma levels of MDL following administration of 30 mg tablet as single dose or multiple doses were achieved approximately 3-5 hours post-dose. Peak plasma levels of MMDL following administration of a single dose of 30 mg tablet were generally achieved approximately 0.5 to 1 hour post-dose.
The absolute bioavailability of nicergoline following oral administration is approximately 5% of the administered dose, because of its first-pass metabolism.
The pharmacokinetics of nicergoline in healthy volunteers following oral doses of 30-60 mg were found to be linear based on measurement of its principal metabolite MDL.
There was no relevant food effect on the pharmacokinetics of MDL and MMDL when nicergoline was given as a single oral dose of 30 mg tablet.
Distribution: Nicergoline distribution to tissues is rapid and extensive, as reflected by the short distribution phase of plasma radioactivity. The nicergoline volume of distribution in central compartment (roughly estimated by dividing the dose by nicergoline plasma concentration at the first PK sampling time after IV administration of nominal 2 mg dose) is fairly high (224 L), which possibly reflects nicergoline distribution into blood cells and/or tissues.
Nicergoline is extensively bound to human plasma proteins, with 4-fold higher affinity for α-acid glycoprotein than for serum albumin. The percentage binding is relative constant when nicergoline concentration is increased from 1 μg/mL to 500 μg/mL. Both nicergoline metabolites, MDL and MMDL, have low protein binding values of approximately 14.7% and 34.7% in a concentration range of 50-200 ng/mL, respectively.
Metabolism and Elimination: Urinary excretion is the main elimination route. Within 120 hours post-dose, average of 82% of the total radiolabelled nicergoline dose is excreted via the kidney and 10% via feces. Nicergoline is extensively metabolized. Its main metabolic route is via hydrolysis of the ester bond, producing MMDL, and then by the formation of MDL via demethylation. The demethylation process occurs through the catalytic action of the isoenzyme CYP2D6. Therefore, pharmacokinetics of nicergoline and its metabolites are affected in subjects with a genetic deficit of cytochrome CYP2D6. The resulting active metabolites (MMDL and MDL) are conjugated with glucoronic acid. The main metabolite MDL accounts for 51% of the total dose and 76% of radioactivity recovered from urine following an oral dose of 15 mg. The mean value of terminal half-life for MDL ranged approximately 11-20 hours.
Special Population: The effect of renal impairment on the pharmacokinetics of nicergoline was evaluated in patients with mild (Clcr 60-80 mL/min), moderate (Clcr 30-50 mL/min), and severe (Clcr 10-25 mL/min) renal impairment. In the 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 a 30 mg oral dose of nicergoline (38.1%, 42.6%, and 25.7% of the dose, respectively); for MMDL, the corresponding values were 1.7, 0.6, and 0.2%, respectively. Patients with severe renal impairment exhibited a significant decrease in urinary MDL excretion compared to the other two groups. In addition, patients with mild, moderate, and severe renal impairment showed an average decrease in MDL urinary excretion (0-72 hours) of 32%, 32%, and 59% compared with the subjects with normal renal function in another study with 30 mg tablet.
The pharmacokinetics of nicergoline has not been studied in patients with hepatic impairment.
The pharmacokinetics of nicergoline has not been studied in children.
The influence of age (geriatric) on the pharmacokinetics of nicergoline has not been fully studied.
Toxicology: Preclinical safety data: Carcinogenicity studies have not been conducted. Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, genotoxicity, and embryo-fetal, and peri- and postnatal development. In a fertility study, nicergoline had no effect on male fertility at doses of up to 50 mg/kg/day (8 times the maximum recommended human dose of 60 mg/day on a mg/m² basis). In female rats administered 50 mg/kg/day, there was a significantly reduced pregnancy rate and at the Gestation Day 13 cesarean section, there was a significantly lower number of corpora lutea and lower number of implants and embryos. However, there were no effects on litters of treated females that delivered in this study.
30 mg film-coated tablet: Acute, subacute and chronic toxicity studies in various animal species (rat, dog and rabbit) have shown that the drug is well tolerated. In addition, nicergoline has no teratogenic and embryotoxic effects and is not mutagenic. Numerous controlled clinical studies carried out with appropriate methodologies in patients affected by cerebral deterioration have shown that nicergoline is effective in ameliorating the cognitive, affective behavioral and somatic disturbances associated with this disease.

10 mg sugar-coated tablet: Acute or chronic, peripheral and cerebral vasculo-metabolic disorders with signs and symptoms of cerebral insufficiency or dementia, such as impaired memory and concentration, dizziness, depressed mood, impaired self-care, impaired sleep-waking cycle, disorientation in time and place, tinnitus, blurred vision, performance insufficiency, headache and fatigue (also those due to cerebral thrombosis, cerebral embolism, cerebral arteriosclerosis in its different manifestations). Obliterative arteriopathies of the limbs: Raynaud's syndrome and all syndromes due to altered peripheral flow. Headache in geriatric arteriosclerotic subjects. As an adjuvant to therapy of arterial hypertension.
30 mg film-coated tablet: Signs and symptoms of mental deterioration, such as cognitive, affective, behavioral and somatic disturbances associated with cerebral deterioration (chronic cerebrovascular insufficiency and/or senile and pre-senile dementia, Parkinson's disease): impaired memory, decreased vigilance and impaired concentration, mood depression, apathy, interpersonal relationships, lack of self-care, asthenia, anorexia, tinnitus, dizziness; as co-adjuvant in the rehabilitative treatment of hemiplegic patients with ictus sequelae.

10 mg sugar-coated tablet: Orally 10 mg 3 times a day regular intervals. To improve absorption the drug should be taken on an empty stomach. The duration of treatment and the dosage vary with the clinical state. In certain cases, the symptoms may be relieved only after a period of treatment. Tolerance is optimum even for protracted treatment.
30 mg film-coated tablet: 60 mg per day in two administrations at regular intervals.

A transient reduction of blood pressure may occur when using nicergoline in a high dose. No specific treatment is usually needed, it is sufficient to lie down for a few minutes. In exceptional cases of serious deficiency of blood supply to the brain and the heart, it is advisable to administer sympathomimetics and to continuously monitor blood pressure.

Hypersensitivity to the active substance or to ergot alkaloids, or to any of the excipients; Recent myocardial infarction; Acute hemorrhage; Orthostatic hypotension; Severe bradycardia.

Studies with single or repeated doses of nicergoline have shown that nicergoline may lower systolic blood pressure and to a far lesser degree, diastolic blood pressure in normotensive patients and patients with elevated blood pressures. These effects can be variable, as other studies have not demonstrated changes in systolic or diastolic blood pressure.
Sympathomimetics agonists (alpha and beta) should be used with caution in patients receiving nicergoline (see Interactions).
It should be administered with caution to patients with hyperuricemia or a history of gout and/or during concomitant treatment with drugs that may influence the metabolism and excretion of uric acid (see Adverse Reactions).
Fibrosis (e.g., pulmonary, cardiac, cardiac valvular and retroperitoneal) has been associated with the use of some ergot alkaloids with agonist activity at the serotonin 5HT 2β receptor.
The symptoms of ergotism (including nausea, vomiting, diarrhea, abdominal pain and peripheral vasoconstriction) have been reported with the ingestion of some ergot alkaloids and their derivatives. Clinicians and prescribers should be aware of the signs and symptoms of ergot overdosing prior to prescribing this class of medications.
Effects on ability to drive and use machines: Although the clinical effects of nicergoline include an improvement of alertness and concentration, its effects on the ability to drive and operate machines have not been specifically studied. Caution should be used, considering the underlying disease of the patients. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or somnolence may occur (see Adverse Reactions).

Pregnancy: Nicergoline did not cause reproductive toxicity in pregnant rats and rabbits. Studies have not been conducted in pregnant women. Given the approved indications, the use of nicergoline in pregnant and lactating women is unlikely. Nicergoline should only be used during pregnancy if the potential benefit to the patient justifies the potential risk to the fetus.
30 mg film-coated tablet: Although nicergoline has shown no teratogenic activity in toxicological studies, it is recommended to use the drug in pregnancy only if strictly necessary.
Lactation: It is not known if nicergoline is excreted in breast milk in humans. Therefore, the use of nicergoline is not recommended during breastfeeding.
Fertility: Nicergoline did not affect fertility in a study in male rats. However, nicergoline decreased fertility in female rats administered 50 mg/kg/day (8 times the maximum recommended human dose of 60 mg/day on a mg/m² basis) (see Pharmacology: Toxicology: Preclinical safety data under Actions).
The clinical implications of the animal findings (at supratherapeutic doses) in human patients are not known.

The following table lists adverse drug reactions (ADRs) by system organ class (SOC) and CIOMS frequency category (i.e., very common, common, uncommon, rare, and very rare) and in order of decreasing medical seriousness within each frequency category and SOC.
ADRs by SOC and CIOMS frequency category listed in order of decreasing medical seriousness or clinical importance within each frequency category and SOC: See table.

Click on icon to see table/diagram/image

Nicergoline should be administered cautiously with drugs listed as follows: Antihypertensive drugs: Nicergoline may potentiate the effect of antihypertensive drugs. Nicergoline may potentiate the cardiac effect of beta blocking agents.
Sympathomimetic drugs (alpha and beta): Nicergoline may antagonize the vasoconstrictor effect of sympathomimetic drugs due to its alpha-adrenergic blocking effect (see Precautions).
Drugs metabolized by CYP 2D6: Since nicergoline is metabolized through CYP 2D6, an interaction with drugs undergoing the same pathway cannot be excluded.
Antiaggregant and anticoagulant drugs (e.g., acetylsalicylic acid): Increases the effect on hemostasis, therefore, bleeding period may be prolonged.
Drugs that influence uric acid metabolism: Since nicergoline may increase asymptomatic increase of serum uric acid levels. Caution should be used in administering the drug in patients with hyperuricemia or with a history of gout and/or under treatment with drugs that might be able to interfere with the metabolism and excretion of uric acid.

Neurodegenerative Disease Drugs / Peripheral Vasodilators & Cerebral Activators / Antivertigo Drugs

C04AE02 - nicergoline ; Belongs to the class of ergot alkaloids. Used as peripheral vasodilators.

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