Toracetam

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

Composition:

Active substance: piracetam;

1 ml of solution contains piracetam 200 mg;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly yellowish liquid.

Pharmacotherapeutic group. Psychostimulants and nootropic agents.

ATC code N06BX03.

Pharmacological Properties

Pharmacodynamics

Piracetam is a nootropic agent, i.e. a psychotropic drug that directly improves the efficiency of cognitive functions. 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 the rheological properties of blood, while lacking vasodilatory effects.

Repeated or single administration of piracetam to patients with cerebral dysfunction causes significant changes in electroencephalogram (EEG), demonstrating increased alertness and improved cognitive function (increased α- and β-activity and decreased δ-activity).

Piracetam inhibits hyperaggregation of activated platelets. In pathological rigidity of erythrocytes, piracetam enhances their filterability and elasticity. Piracetam exerts protective and restorative effects in cases of impaired brain function due to hypoxia, intoxication, and electroconvulsive therapy.

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

Pharmacokinetics

After a single 2 g dose, maximum plasma concentration (Cmax) is reached within 30 minutes, while in cerebrospinal fluid it is achieved within 2–8 hours and amounts to 40–60 μg/mL. Piracetam distributes throughout all tissues and penetrates the blood-brain barrier, placental barrier, and membranes used in hemodialysis. Piracetam does not bind to plasma proteins but accumulates in cerebral cortex tissues, predominantly in the frontal, parietal, and occipital regions, as well as in the cerebellum and basal ganglia. The volume of distribution of piracetam is approximately 0.6 L/kg.

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

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

Clinical characteristics.

Indications.

For use in adults:

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

Contraindications.

• Hypersensitivity to piracetam or pyrrolidone derivatives, or to any of the excipients;
• acute cerebral circulation disorders (hemorrhagic stroke);
• terminal stage of renal failure;
• Huntington's chorea.

Interaction with other medicinal products and other forms 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 piracetam at a dose of 9.6 g/day did not require adjustment of acenocoumarol dosage to achieve an INR [International Normalized Ratio] of 2.5–3.5. However, concomitant use was associated with a significant reduction in platelet aggregation, release of β-thromboglobulin, levels of fibrinogen, von Willebrand factor [coagulation activity (VIII:C), ristocetin cofactor activity (VIII:vW:Rco), and antigenic protein in blood plasma (VIII:vW:Ag)], as well as whole blood and plasma viscosity.

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 cytochrome P450 isoforms CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A9/11 at concentrations of 142, 426, and 1422 mcg/ml.

At a concentration of 1422 mcg/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 mcg/ml. Therefore, metabolic interaction with drugs metabolized 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 serum concentration-time curves or Cmax of antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, sodium valproate) in patients with epilepsy 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 (see section "Pharmacodynamics"), caution is required when prescribing the drug to patients with impaired hemostasis, conditions that may be associated with bleeding (e.g. gastrointestinal ulcer), during major surgical procedures (including dental interventions), in patients with signs of severe hemorrhage, or in patients with a history of hemorrhagic stroke, as well as in patients receiving anticoagulants or platelet antiaggregants, including low-dose acetylsalicylic acid.

The drug is excreted by the kidneys; therefore, special attention should be paid to patients with renal impairment.

Elderly patients. During long-term therapy in elderly patients, it is recommended to regularly monitor renal function parameters and, if necessary, adjust the dose according to creatinine clearance test results (see section "Dosage and administration").

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

The medicinal product contains 1 mmol (23 mg) of sodium per 24 g of piracetam. This should be taken into account if the patient is on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

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

Ability to influence reaction rate when driving or operating machinery.

Due to the adverse reactions observed with this medicinal product, an effect on the ability to drive vehicles or operate machinery is possible and should be taken into account.

Administration and Dosage

Piracetam as an injectable solution is used when oral formulations of the drug cannot be administered.

The medicinal product is administered by intravenous injection (given slowly over several minutes) or by infusion (continuously over 24 hours).

To be prescribed to adults.

Treatment of conditions associated with memory impairment and cognitive disorders

The recommended daily dose is 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, increased by 4.8 g every three or four 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, the dose of other antimyoclonic medicinal products should be reduced, if possible.

Piracetam treatment should be continued until symptoms of the underlying 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 dose of piracetam should be reduced by 1.2 g every two days (every three or four days in cases of Landau–Adams syndrome, to prevent sudden relapse or withdrawal-related seizures).

Elderly patients

Dosage adjustment is recommended for elderly patients with diagnosed or suspected renal impairment (see section «Patients with renal impairment» below). During treatment, creatinine clearance should be monitored to allow appropriate dose adjustment for these patients, if 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 elimination half-life is directly related to impaired renal function and creatinine clearance. This also applies to elderly patients, in whom creatinine excretion is age-dependent. The dosing interval should be adjusted based on renal function.

The dose should be calculated according to creatinine clearance using the following formula:

[140 – age (years)] × body weight (kg)

Creatinine clearance = ---------------------------------------------------------------------- (× 0.85 for women)

72 × serum creatinine concentration (mg/dL)

Treatment in such patients should be prescribed according to the severity of renal insufficiency, following these recommendations:

Patients with hepatic impairment

Dose adjustment is not required for patients with hepatic impairment alone. In cases of diagnosed or suspected hepatic and renal impairment, dosage adjustment should be performed as indicated in the section «Patients with renal impairment» above.

Children. The medicinal product is not intended for use in children.

Overdose

Symptoms: intensification of adverse reactions of the medicinal product. Symptoms of overdose have been observed following oral administration of piracetam at a dose of 75 g.

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

Adverse Reactions

Adverse reactions observed during clinical trials and post-marketing surveillance are listed below by system organ class 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 based on available data).

Post-marketing data are insufficient to determine the frequency of adverse reactions in the treated population.

Blood and lymphatic system disorders: frequency not known — haemorrhagic disorders.

Immune system disorders: frequency not known — hypersensitivity, anaphylactoid reactions.

Psychiatric disorders: common — nervousness; uncommon — depression; frequency not known — increased excitability, anxiety, confusion, hallucinations.

Nervous system disorders: common — hyperactivity; uncommon — somnolence; frequency not known — ataxia, loss of balance, increased frequency of epileptic seizures, headache, insomnia, tremor.

Ear and labyrinth disorders: frequency not known — dizziness.

Gastrointestinal disorders: frequency not known — abdominal pain, upper abdominal pain, diarrhoea, nausea, vomiting.

Skin and subcutaneous tissue disorders: frequency not known — angioneurotic oedema, dermatitis, urticaria, pruritus.

Reproductive system and breast disorders: frequency not known — increased sexual activity.

Vascular disorders: rare — hypotension, thrombophlebitis.

General disorders and administration site conditions: uncommon — asthenia; rare — injection site pain, chills.

Investigations: common — weight increased.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

Incompatibilities. Studies have not been conducted. The medicinal product should not be mixed with other medicinal products.

Packaging. 5 ml or 10 ml in a polyethylene ampoule. 10 ampoules per cardboard pack.

Prescription status. Prescription only.

Manufacturer. LLC "FARMASEL".

Manufacturer's address and location of its business activity.
3, Prorizna Street, Kvitneve, Brovary District, Kyiv Region, 07408, Ukraine.