Indications:
Agicetam is indicated in adult patients:
Treatment of myoclonus of cortical origin, irrespective of aetiology, and should be used in combination with other anti-myoclonic therapies.
Adjuvant symptomatic treatment of chronic pathological cognitive and neurosensorial impairment in elderly (excluding Alzheimer’s disease and other dementia).
Improvement of vertigo symptoms.
Dosage and administration:
Administration: Piracetam is administered orally with a glass of water, and may be taken with or without food.
Dosage:
The recommended dosages as indicated are:
Treatment of myoclonus: The daily dosage should begin at 7.2 g increasing by 4.8 g every three to four days up to a maximum of 24 g, divided in two or three doses. Treatment with other anti-myoclonic medicinal products should be maintained at the same dosage. Depending on the clinical benefit obtained, the dosage of such medicinal products should be reduced, if possible.
Once started, treatment with piracetam should be continued for as long as the original cerebral disease persists. In patients with an acute episode, spontaneous evolution may occur over time and an attempt should be made every 6 months to decrease or discontinue the medicinal treatment. This should be done by reducing the dose of piracetam by 1.2 g every two days (every three or four days in the case of a Lance and Adams syndrome, in order to prevent the possibility of sudden relapse or withdrawal seizures).
Adjuvant symptomatic treatment of chronic pathological cognitive and neurosensorial impairment in elderly and vertigo: 1 tablet, 3 times daily (breakfast, lunch and dinner).
Special population:
Elderly:
Adjustment of the dose is recommended in elderly patients with compromised renal function (see ‘Dosage adjustment in patients with renal impairment’ below).
For long term treatment in the elderly, regular evaluation of the creatinine clearance is required to allow dosage adaptation if needed.
Patients with renal impairment:
Piracetam is contraindicated in patients with severe renal impairment (renal creatinine clearance less than 20 ml/min) (see section Contraindications, Warnings).
The daily dose must be individualized according to renal function. Refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient’s creatinine clearance (Clcr) in ml/min is needed. The Clcr in ml/min may be estimated from serum creatinine (mg/dl) determination using the following formula:
Clcr = {[140 – age (years)] x weight (kg) / [72 x serum creatinine (mg/dl)]} (x 0.85 for women)
| Group | Creatinine clearance (ml/min) | Posology and frequency |
| Normal | > 80 | Usual daily dose, divided in 2 to 4 doses |
| Mild | 50 – 79 | 2/3 usual daily dose, divided in 2 or 3 doses |
| Moderate | 30 – 49 | 1/3 usual daily dose, divided in 2 doses |
| Severe | < 30 | 1/6 usual daily dose, 1 single intake |
| End-stage renal disease | – | Contraindicated |
Patients with hepatic impairment:
No dose adjustment is needed in patients with solely hepatic impairment. In patients with hepatic impairment and renal impairment, adjustment of dose is recommended (see ‘Dosage adjustment in patients with renal impairment’ above).
Some special attention on the handling of the medicine before and after use:
There are no special requirements for handling this medicine after use.
Contraindications:
Hypersensitivity to any of the excipients of the drug.
Patients with severe renal failure (creatinine clearance < 20 ml/minute).
Patients with Huntington’s chorea.
Patients with cerebral haemorrhage.
Pregnant women and breastfeeding mothers.
Warnings and precautions for use:
Effects on platelet aggregation: Due to the effect of piracetam on platelet aggregation, caution is recommended in patients with severe haemorrhage, patients at risk of bleeding such as gastrointestinal ulcer, patients with underlying disorders of haemostasis, patients with history of haemorrhagic cerebro-vascular accident (CVA), patients undergoing major surgery including dental surgery, and patients using anticoagulants or platelet antiaggregant drugs including low dose aspirin.
Renal insufficiency: Piracetam is eliminated via the kidneys and care should thus be taken in cases of renal insufficiency (see Dosage and administration).
Elderly: For long-term treatment in the elderly, regular evaluation of the creatinine clearance is required to allow dosage adaptation if needed (see Dosage and administration).
Discontinuation: Abrupt discontinuation of treatment should be avoided as this may induce myoclonic or generalised seizures in some myoclonic patients.
Pregnancy and lactation:
Pregnancy:
There are no adequate data from the use of piracetam in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or post-natal development.
Piracetam crosses the placental barrier. Drug levels in the newborn are approximately 70% to 90% of maternal levels.
Piracetam should not be used during pregnancy unless clearly necessary, when benefit exceeds the risks and the clinical condition of the pregnant mother requires treatment with piracetam.
Women who are likely to become pregnant or are taking contraceptives should consult their doctor carefully before starting treatment with this medication.
Lactation:
Piracetam is excreted in human breast milk. Therefore, piracetam should not be used during breastfeeding or breastfeeding should be discontinued, while receiving treatment with piracetam. A decision must be made whether to discontinue breast-feeding or to discontinue piracetam therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.
Effects on ability to drive and use machines:
Piracetam almost does not affect the ability to drive and operate machinery. However, the risk of dizziness has been also reported, therefore depending on specific case the doctor may recommend the patients whether to drive or use machinery or not.
Interactions, incompatibilities of medicine:
Interaction with other medicinal products and other forms of interaction:
Pharmacokinetics interactions:
The drug interaction potential resulting in changes of piracetam pharmacokinetics is expected to be low because approximately 90% of the dose of piracetam is excreted in the urine as unchanged drug.
In vitro, piracetam does not inhibit the human liver cytochrome P450 isoforms CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 4A9/11 at concentrations of 142, 426 and 1422 µg/ml.
At 1422 µg/ml, minor inhibitory effects on CYP 2A6 (21%) and 3A4/5 (11%) were observed. However, the Ki values for inhibition of these two CYP isoforms are likely to be well in excess of 1422 µg/ml. Therefore, metabolic interaction of piracetam with other drugs is unlikely.
Thyroid hormones: Confusion, irritability and sleep disorder have been reported during concomitant treatment with thyroid extract (T3 + T4).
Acenocoumarol: In a published single-blind study on patients with severe recurrent venous thrombosis, piracetam 9.6 g/day did not modify the doses of acenocoumarol necessary to reach INR 2.5 to 3.5, but compared with the effects of acenocoumarol alone, the addition of piracetam 9.6 g/day significantly decreased platelet aggregation, β-thromboglobulin release, levels of fibrinogen and von Willebrand’s factors (VIII:C; VIII: vW: Ag; VIII : vW : Rco) and whole blood and plasma viscosity.
Antiepileptic drugs: A 20 g daily dose of piracetam over 4 weeks did not modify the peak and trough serum levels of antiepileptic drugs (carbamazepine, phenytoin, phenobarbitone, valproate) in epileptic patients who were receiving stable doses.
Alcohol: Concomitant administration of alcohol had no effect on piracetam serum levels and alcohol levels were not modified by a 1.6 g oral dose of piracetam.
Incompatibilities:
Because there are no studies about the incompatibility of the medicine, it should not be mixed with other medicines.
Undesirable effects:
Adverse reactions are ranked according to frequency: Very common (ADR > 1/10), common (1/100 ≤ ADR < 1/10), uncommon (1/1,000 ≤ ADR < 1/100), rare (1/10,000 ≤ ADR < 1/1,000), very rare (ADR < 1/10,000), can not be estimated from the available data “Unknown”.
Common:
Whole body: Fatigue.
Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain, abdominal distention.
Neurological: Restlessness, irritability, headache, insomnia, drowsiness.
Uncommon:
Whole body: Dizziness, weight gain, asthenia.
Neurological: Tremor, sexual stimulation, nervousness, hyperanakinesia, depression.
Hematologic: Blood clotting disorders or severe haemorrhage.
Skin: Dermatitis, pruritus, urticaria.
Guidelines for ADRs management:
Adverse reactions may be decreased by reducing the dose.
Overdosage and management:
Overdose:
No additional adverse events specifically related to overdose have been reported with piracetam.
The highest reported overdose with piracetam was oral intake of 75 g. One case of bloody diarrhea with abdominal pain, associated with the oral intake of 75 g piracetam daily, was most probably related to the extreme high dose of sorbitol contained in the used formulation.
Management:
In acute, significant overdosage, the stomach may be emptied by induction of emesis.
There is no specific antidote for overdose with piracetam. Treatment for an overdose will be symptomatic treatment and may include hemodialysis. The extraction efficiency of the dialyser is 50 to 60% for piracetam.
Pharmacodynamics:
Pharmacotherapeutic group: Other psychostimulants and nootropics
ATC code: N06BX03
Piracetam (a cyclic derivative of gamma-aminobutyric acid (GABA) acts directly on the brain to improve the efficacy of the telencephalon (this area of the brain is involved in cognition, learning, memory, alertness and awareness). Piracetam acts on a number of neurotransmitters such as acetylcholine, noradrenaline, dopamine etc. This may explain the positive effects of piracetam on learning and improving the ability to perform memory test. It can alter neurotransmission within the brain, and can help improve the metabolic environment essential for good neuronal function.
In experimental studies, piracetam has a protective effect against metabolic disorders induced by ischemia due to the increase of cerebral resistance to hypoxic conditions. Piracetam increases the mobilization and utilization of glucose whereas it does not depend on the oxygen supply. This facilitates the pentose pathway and sustains brain energy synthesis. Piracetam enhances recovery rate after hypoxic brain injury by increasing the turnover of inorganic phosphate and decreasing glucose and lactic acid accumulation. In normal conditions as well as hypoxia, it is found that piracetam increases the amount of ATP in the brain by increasing the conversion of ADP to ATP, this could be a mechanism to explain some of the beneficial effects of the drug. The impact on the acetylcholine transmission may also contribute to the mechanism of piracetam activity formation. Piracetam also has the effect on the dopamine release and this may have a positive effect on the memory formation. Piracetam has no hypnotic, sedative, recovery, analgesic effect, neuroleptic or tranquilizing action as well as no effect of GABA.
Piracetam reduces platelet aggregation and in the conditions where there is abnormal rigidity of the red blood cell, it can improve the potential of deformability of the erythrocyte membrane and passing through capillaries. Piracetam has effect on cortical myoclonus.
Pharmacokinetics:
Absorption: Piracetam is for oral use, rapidly and almost completely absorbed from the gastrointestinal tract.
Bioavailability is approximately 100%. Peak plasma levels (40 – 60 micrograms/ml) are reached within 30 minutes after oral dose of 2 g. Peak cerebrospinal fluid concentrations are achieved 2-8 hours after oral administration. Long term use of piracetam does not change the absorption.
The volume of distribution is approximately 0.6 L/kg.
Distribution: Piracetam permeates all tissues, crosses the blood-brain and the placental barrier and diffuses across membranes used in renal dialysis. Piracetam accumulates highly in the cerebral cortex, frontal lobe, parietal lobe, occipital lobe, cerebellum and basal nuclei.
Transformation, elimination: Plasma half-life is 4-5 hours, half-life in the CSF is about 6-8 hours.
Piracetam does not bind to plasma proteins and is eliminated unchanged principally via the kidney. Renal clearance rate of piracetam in normal people is 86 ml/min. 30 hours after oral administration, over 95% of the drug is excreted in the urine. In case of renal failure, elimination half-life is increased: In patients with completely impaired and unrecovered kidney function, this time is 48-50 hours.
Presentation:
Box of 10 blisters x 10 film-coated tablets.
Storage conditions, shelf-life, quality specification of the medicine:
Storage conditions: Protect from humidity and light, below 300C.
Shelf-life: 36 months from the manufacture date.
Quality specification: In house.
D1402001502
