Piracetam

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PIRACETAM (pIracetam)

Composition:

Active ingredient: piracetam;

1 tablet contains 200 mg of piracetam calculated as 100 % substance;

Excipients: microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate;

film-coating: hypromellose, copovidone, polyethylene glycol, medium-chain triglycerides, polidextrose, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex tablets, film-coated, yellow to brownish-yellow in color.

Pharmacotherapeutic group. Psychostimulants and nootropic agents. Piracetam. ATC code N06B X03.

Pharmacological properties.

Pharmacodynamics.

The active component of the drug is piracetam, a cyclic derivative of gamma-aminobutyric acid.

Piracetam is a nootropic agent acting on the brain, improving cognitive functions such as learning ability, memory, attention, and mental performance. The mechanisms of the drug's action on the central nervous system are likely multiple: alteration of the rate of excitation propagation in the brain; enhancement of metabolic processes in nerve cells; improvement of microcirculation by influencing blood rheological properties without vasodilatory effects. Prolonged or single-dose administration of piracetam to patients with cerebral dysfunction leads to significant changes in electroencephalogram, demonstrating increased alertness and improved cognitive function (increased α- and β-activity and decreased δ-activity).

Piracetam inhibits hyperaggregation of activated platelets. In case of pathological erythrocyte rigidity, piracetam increases their filterability and elasticity. Piracetam exerts protective and restorative effects in impaired brain function due to hypoxia and intoxication, as well as electroshock therapy.

Piracetam is used as a monotherapy or as part of combination therapy for cortical myoclonus to reduce the severity of the triggering factor—vestibular neuronitis.

Pharmacokinetics.

Absorption

After oral administration, piracetam is rapidly and almost completely absorbed from the gastrointestinal tract. Bioavailability is nearly 100%.

After a single 2 g dose, Cmax is reached in plasma within 30 minutes and in cerebrospinal fluid within 2–8 hours, reaching 40–60 μg/mL.

Distribution

Piracetam does not bind to plasma proteins, and its apparent volume of distribution is approximately 0.6 L/kg. Piracetam distributes throughout all tissues and crosses the blood-brain barrier, placental barrier, and membranes used during hemodialysis. Piracetam accumulates in brain cortex tissues, predominantly in frontal, parietal, and occipital regions, as well as in the cerebellum and basal ganglia.

Biotransformation

Piracetam is active in its unchanged form and is not metabolized in animals.

Elimination

The elimination half-life of the drug from blood is 4–5 hours and 6–8 hours from cerebrospinal fluid. This period may be prolonged in renal impairment. Piracetam is excreted by the kidneys. It is almost completely excreted in urine (over 95%) within 30 hours. Renal clearance of piracetam in healthy volunteers is 86 mL/min.

Clinical characteristics.

Indications.

In adults:

• Symptomatic treatment of pathological conditions associated with impaired memory and cognitive disorders, excluding diagnosed dementia;
• Treatment of cortical myoclonus: as monotherapy or as part of combination therapy. To assess sensitivity to piracetam, a trial treatment course over a limited period of time may be conducted.

Contraindications.

• Hypersensitivity to piracetam, to other pyrrolidone derivatives, or to any of the excipients of the drug.
• End-stage renal failure (creatinine clearance < 20 mL/min).
• Acute cerebral circulation disorders (hemorrhagic stroke).
• Huntington's chorea.

Interaction with other medicinal products and other types of interactions.

Thyroid hormones.

When used concomitantly with thyroid hormones (T3+T4), increased irritability, disorientation, and sleep disturbances may occur.

Acenocoumarol.

Clinical studies have shown that high doses of piracetam (9.6 g/day) in patients with severe recurrent venous thrombosis did not affect the dosing of acenocoumarol required to achieve an international normalized ratio (INR) of 2.5–3.5. However, when administered concomitantly, a significant reduction in platelet aggregation, fibrinogen levels, release of β-thromboglobulin, von Willebrand factor (coagulation activity (VIII:C); ristocetin cofactor (VIII:vW:Rco) and plasma protein (VIII:vW:Ag)), whole blood and plasma viscosity was observed.

Pharmacokinetic interactions.

The likelihood of changes in piracetam pharmacokinetics due to other medicinal products is low, as approximately 90% of the drug is excreted unchanged in urine.

In vitro, piracetam does not inhibit the major human liver cytochrome P450 isoenzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A9/11 at concentrations of 142, 426, and 1422 µg/mL.

At a concentration of 1422 µg/mL, slight inhibition of CYP2A6 (21%) and 3A4/5 (11%) was observed. However, the Ki value for inhibition of these two CYP isoenzymes is sufficient only when exceeding a concentration of 1422 µg/mL. Therefore, metabolic interactions with drugs metabolized by these enzymes are unlikely.

Antiepileptic drugs.

Administration of piracetam at a dose of 20 mg/day for 4 weeks or longer did not alter the maximum concentration (Cmax) or serum concentration-time curves of antiepileptic drugs (carbamazepine, clonazepam, phenytoin, phenobarbital, sodium valproate) in patients with epilepsy receiving stable doses.

Alcohol.

Concomitant intake with alcohol does not affect the serum concentration levels of piracetam; serum alcohol concentration was unchanged when 1.6 g of piracetam was administered.

Special precautions for use.

Effect on platelet aggregation.

Since piracetam reduces platelet aggregation (see section "Pharmacodynamics"), the drug should be administered with caution to patients:

• with disorders of hemostasis;
• with symptoms of severe bleeding;
• conditions that may be associated with bleeding (e.g., gastrointestinal ulcer);
• with pronounced liver function impairment;
• with a history of hemorrhagic stroke;
• when co-administered with anticoagulants, platelet antiaggregants, including low-dose acetylsalicylic acid;
• during major surgical procedures, including dental interventions.

Renal function impairment.

The drug is excreted by the kidneys; therefore, special attention should be paid to patients with impaired renal function (see section "Administration and dosage").

Elderly patients.

In elderly patients undergoing long-term treatment, regular monitoring of renal function is recommended; if necessary, the dose should be adjusted according to creatinine clearance values (see section "Administration and dosage").

Discontinuation of treatment.

In patients treated for cortical myoclonus, abrupt discontinuation of therapy should be avoided due to the high risk of seizure recurrence and generalization of myoclonus.

The drug penetrates through the filtering membranes of hemodialysis equipment.

Use during pregnancy or breastfeeding.

Do not use the drug during pregnancy or breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Caution should be exercised when driving or operating machinery, considering the possibility of adverse reactions affecting the nervous system.

Dosage and Administration

The drug can be taken regardless of food intake. The drug is administered orally, taken with a small amount of water.

Adults.

Treatment of conditions associated with impaired memory and cognitive disorders. The recommended daily dose is 2.4–4.8 g. The dose is usually divided into 2–3 doses.

Treatment of cortical myoclonia.

The initial daily dose is 7.2 g, which is increased by 4.8 g every three or four days up to the maximum dose of 24 g, divided into two or three doses. Treatment with other antimyoclonic agents should be maintained at previously prescribed doses. Depending on the therapeutic effect achieved, the dose of other antimyoclonic drugs should be reduced, if possible.

Treatment is continued until symptoms of the disease disappear. In patients with acute disease course, spontaneous improvement may occur over time; therefore, every 6 months an attempt should be made to reduce or discontinue the drug. For this purpose, the dose of piracetam should be reduced by 1.2 g every two days (every three or four days in the case of Landau–Adams syndrome, to prevent sudden relapse or occurrence of seizures associated with drug withdrawal).

Special patient groups.

Use in elderly patients. Dose adjustment is recommended for elderly patients with diagnosed or suspected renal function disorders (see "Renal function impairment"). In such patients undergoing long-term treatment, creatinine clearance should be monitored for appropriate dose adjustment.

Renal function impairment. Since the drug is excreted by the kidneys, caution is required when treating patients with renal insufficiency; in such patients, renal function should be monitored.

The increase in elimination half-life is directly related to impaired renal function and creatinine clearance. This also applies to elderly patients, in whom creatinine clearance is age-dependent. The dosing interval should be adjusted according to renal function.

Dose calculation in patients should be based on estimation of creatinine clearance using the following formula:

Treatment should be prescribed according to the degree of renal impairment, following these recommendations:

Dosage in patients with hepatic impairment.

Dose adjustment is not required for patients with hepatic impairment only. In cases of diagnosed or suspected hepatic and renal impairment, dose adjustment should be performed as indicated in the section "Renal impairment".

Children.

Not to be used.

Overdose.

Symptoms: intensification of adverse drug reactions. Symptoms of overdose have been observed following oral administration of 75 g of piracetam.

Treatment is symptomatic: gastric lavage, induction of emesis. There is no specific antidote; hemodialysis may be used (eliminates 50–60% of piracetam).

Adverse Reactions

Adverse reactions observed during clinical trials and post-marketing surveillance are listed by system organ classes and frequency.

Frequency is defined as follows: 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 not known (cannot be estimated from the available data).

Nervous system. Common: hyperkinesia; uncommon: somnolence; frequency not known: headache, insomnia, ataxia, increased frequency of epileptic seizures, loss of balance, tremor.

Psychiatric disorders. Common: nervousness; uncommon: depression; frequency not known: increased excitability, anxiety, confusion/disorientation, hallucinations.

Immune system. Frequency not known: hypersensitivity reactions, anaphylactoid reactions.

Gastrointestinal system. Frequency not known: abdominal pain, upper abdominal pain, nausea, diarrhea, vomiting.

Ear and labyrinth disorders. Frequency not known: vertigo.

Skin and subcutaneous tissue. Frequency not known: angioneurotic edema, dermatitis, pruritus, rash, urticaria.

Blood and lymphatic system. Frequency not known: coagulation disorders.

Reproductive system and breast. Frequency not known: increased sexual activity.

Other: weight gain, asthenia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System of Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. In the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 10 tablets in a blister; 6 blisters in a carton.

Prescription status.

Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Borshchagiv Chemical and Pharmaceutical Plant".

Manufacturer's address and location of operations.

17 Myru Street, Kyiv, 03134, Ukraine.