Piracetam

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PIRACETAM (PIRACETAM)

Composition:

Active substance: piracetam;

1 ml of solution contains 200 mg of piracetam;

Excipients: sodium acetate trihydrate, glacial acetic acid, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Psychostimulants and nootropic agents.

ATC code N06B X03.

Pharmacological Properties

Pharmacodynamics

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

Piracetam is a nootropic agent acting on the brain and 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: modification of the rate of excitation propagation in the brain; enhancement of metabolic processes in nerve cells; improvement of microcirculation by influencing the rheological properties of blood, without vasodilatory effects. Piracetam improves interhemispheric connections and synaptic conduction in neocortical structures. It inhibits platelet aggregation, restores erythrocyte membrane elasticity, and reduces erythrocyte adhesion. Piracetam exerts protective and restorative effects on impaired brain function due to hypoxia, intoxication, and electroconvulsive therapy. Piracetam reduces the intensity and duration of vestibular nystagmus.

Piracetam is used either as a monotherapy or as part of combination therapy for cortical myoclonus, as an agent to reduce the impact of triggering factors—specifically vestibular neuronitis.

Pharmacokinetics

After administration of 2 g of the drug, Cmax in plasma is reached within 30 minutes, and in cerebrospinal fluid within 2–8 hours, reaching 40–60 mcg/mL. The volume of distribution of piracetam is approximately 0.6 L/kg. The elimination half-life from plasma is 4–5 hours and 6–8 hours from cerebrospinal fluid. This half-life may be prolonged in renal impairment. Piracetam does not bind to plasma proteins and is not metabolized in the body. 80–100% of piracetam is excreted unchanged by the kidneys via glomerular filtration. Renal clearance of piracetam in healthy volunteers is 86 mL/min. The pharmacokinetics of piracetam are not altered in patients with hepatic insufficiency. Piracetam crosses the blood-brain barrier, placental barrier, and membranes used during hemodialysis. Animal studies have shown that piracetam selectively accumulates in cerebral cortical tissues, predominantly in the frontal, parietal, and occipital regions, as well as in the cerebellum and basal ganglia.

Clinical characteristics.

Indications.

Adults:

• symptomatic treatment of pathological conditions associated with impaired memory and cognitive disorders, excluding diagnosed dementia;
• treatment of cortical myoclonus as part of monotherapy or combination therapy.

Contraindications.

Hypersensitivity to piracetam or pyrrolidone derivatives, as well as to other components of the medicinal product.

Acute cerebral circulation disorders (hemorrhagic stroke).

Terminal stage of renal failure.

Huntington's chorea.

Interaction with other medicinal products and other types of interactions.

Thyroid hormones.

Concomitant use with thyroid hormones may lead to increased irritability, disorientation, and sleep disturbances.

Acenocoumarol.

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

Pharmacokinetic interactions.

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

In vitro, piracetam does not inhibit the main human cytochrome P450 isoforms 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 sufficiently high to exceed 1422 µg/mL. Therefore, metabolic interaction with drugs undergoing biotransformation by these enzymes is unlikely.

Antiepileptic medicinal products.

Administration of piracetam at a dose of 20 g daily for 4 weeks or longer did not alter the concentration-time curve or maximum concentration (Cmax) of antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, sodium valproate) in serum of epileptic patients receiving stable doses.

Alcohol.

Concomitant intake with alcohol did not affect plasma concentrations of piracetam, and alcohol concentrations were not altered following administration of 1.6 g of piracetam.

Special precautions for use.

Effect on platelet aggregation.

Since piracetam reduces platelet aggregation, the drug should be administered with caution to patients with coagulation disorders, conditions that may be associated with bleeding (e.g. peptic ulcer of the gastrointestinal tract), during major surgical procedures (including dental interventions), patients with signs of severe hemorrhage, or those with a history of hemorrhagic stroke; and to patients receiving anticoagulants, platelet antiaggregants, including low-dose acetylsalicylic acid. The drug is excreted by the kidneys; therefore, special attention should be given to patients with renal impairment.

Elderly patients. During long-term therapy in elderly patients, renal function parameters should be monitored regularly, and the dose should be adjusted as necessary based on creatinine clearance test results (see section "Dosage and administration").

When treating patients with cortical myoclonia, abrupt discontinuation of therapy should be avoided due to the risk of generalized myoclonus or seizure occurrence.

The drug contains 1 mmol (23 mg) of sodium per 24 g of piracetam. This should be taken into account for patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

The medicinal product should not be used during pregnancy or breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Caution should be exercised when driving or operating machinery.

Method of administration and dosage.

The drug in the form of an injectable solution is used in acute cases or when oral forms of piracetam cannot be administered. The drug is administered intravenously (given slowly over several minutes) or by infusion (administered continuously over 24 hours).

The drug is intended for use in adults.

Treatment of conditions associated with impaired memory and cognitive disorders.

The recommended dose is from 2.4 g to 4.8 g, divided into 2 or 3 administrations.

Treatment of cortical myoclonus.

The initial daily dose is 7.2 g, which is increased by 4.8 g every 3–4 days up to a maximum dose of 24 g, divided into two or three administrations. Treatment with other antimyoclonic medicinal products should be continued at the same doses. Depending on the therapeutic effect achieved, if possible, the dose of other antimyoclonic medicinal products should be reduced.

Piracetam treatment should be continued until symptoms of the primary brain disorder disappear. In patients with acute disease, spontaneous improvement may occur over time; therefore, every 6 months an attempt should be made to reduce the dose or discontinue the drug. For this purpose, the piracetam dose should be reduced by 1.2 g every two days (every 3 or 4 days in cases of Langs–Adams syndrome, to prevent sudden relapse or occurrence of seizures associated with drug withdrawal).

Elderly patients.

Dosage adjustment is recommended for elderly patients with diagnosed or suspected renal impairment (see section "Patients with renal impairment"). During treatment, creatinine clearance should be monitored to ensure appropriate dose adjustment in these patients when necessary.

Patients with renal impairment.

Since the drug is eliminated by the kidneys, caution should be exercised when treating patients with renal insufficiency: renal function should be monitored in such patients.

Prolongation of the elimination half-life is directly related to the degree of renal impairment and creatinine clearance. This also applies to elderly patients, in whom creatinine excretion levels are age-dependent. The dosing interval should be adjusted based on the degree of renal function impairment.

Dosage calculation should be based on the patient's creatinine clearance, calculated using the following formula:

[140 – age (years)] × body weight (kg)
Creatinine clearance = ———————————————————— × 0.85 (for women)
72 × plasma creatinine concentration (mg/dL)

Treatment in such patients should be prescribed according to the severity of renal insufficiency, following the recommendations presented in Table 1.

Table 1

Patients with hepatic impairment.

Dose adjustment is not required for patients with hepatic impairment alone. In case of diagnosed or suspected concomitant hepatic and renal impairment, dose adjustment should be performed as specified in the section «Patients with renal impairment».

Children.

Not applicable.

Overdose.

Symptoms: intensification of adverse drug reactions. Overdose symptoms were observed following oral administration of the drug at a dose of 75 g.

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

Adverse reactions.

Adverse reactions were observed during clinical trials.

Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), not reported (frequency cannot be estimated from the available data).

Table 2

The adverse reactions observed during post-marketing surveillance are listed below by system organ classes.

Blood and lymphatic system disorders.

Rare: haemorrhagic disorders.

Immune system disorders.

Rare: hypersensitivity, anaphylactoid reactions.

Psychiatric disorders.

Frequent: nervousness.

Uncommon: depression.

Rare: increased excitability, anxiety, confusion, hallucinations.

Nervous system disorders.

Frequent: hyperkinesia.

Uncommon: somnolence.

Rare: ataxia, loss of coordination, increased frequency of epileptic seizures, headache, insomnia, tremor.

Ear and labyrinth disorders.

Rare: dizziness.

Gastrointestinal disorders.

Rare: abdominal pain, upper abdominal pain, diarrhoea, nausea, vomiting.

Skin and subcutaneous tissue disorders.

Rare: angioneurotic oedema, dermatitis, rash, urticaria, pruritus.

Reproductive system disorders.

Rare: increased sexual activity.

Vascular disorders.

Very rare: hypotension, thrombophlebitis.

General disorders and administration site conditions.

Uncommon: asthenia.

Very rare: injection site pain, chills.

Shelf life.

2 years.

Storage conditions.

Keep out of the reach and sight of children. Store in the original packaging at a temperature not exceeding 25 °C.

Incompatibilities.

Studies have not been conducted. Do not mix with other medicinal products.

Packaging.

5 ml in an ampoule; 10 or 100 ampoules in a carton; or 5 ampoules in a blister, 2 blisters in a carton.

Prescription status.

Prescription only.

Manufacturer.

Private Joint Stock Company "Lekhim-Kharkiv".

Manufacturer's address and place of business.

36 Severina Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.