Indications:
Pitamsol is indicated in adult patients suffering from myoclonus of cortical origin, irrespective of aetiology, and should be used in combination with other anti-myoclonic therapies.
Administration, dosage:
Administration:
Piracetam should be administered orally, and may be taken with or without food. The dose should be divided into 2 – 4 times daily. It is advisable to follow each dose with a drink of water or a soft drink to reduce the bitter taste of the solution.
Or use pre-divided sachets of 7.2 ml (equivalent to 2.4 g piracetam) and 24 ml (equivalent to 8 g).
Dosage:
The initial daily dose is 7.2 g, divided into 2 – 3 times (7.2 ml sachet x 3 times/day can be used) and then increase by 4.8 g every 3 – 4 days up to a maximum dose of 24 g/day, divided into 2 – 3 times (24 ml sachet x 3 times/day can be used). Treatment with other antimyoclonic drugs should be maintained at the same dosage. Depending on the clinical benefit obtained, the dosage of these drugs should be reduced, if possible.
Once started, treatment with piracetam should be continued as long as the initial brain disease persists. In patients with an acute episode, spontaneous improvement may occur over time and will require try to decrease or stop medication every six months. For this case, the dose of piracetam will have to be reduced by 1.2 g every other day (every three or four days in the case of Lance and Adams syndrome), to prevent the risk of sudden recurrence of myoclonus or withdrawal convulsions.
Elderly:
Dose adjustment is recommended in elderly patients with impaired renal function (see “Warnings and precautions for use, patients with renal impairment”). During long-term treatment in the elderly, creatinine clearance should be regularly assessed to adjust the dose appropriately when necessary.
Patients with renal impairment:
The daily dose is adjusted for individual patient 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)] * weight (kg) | (* 0.85 for women) | ||||
| 72 * serum creatinine (mg/dl)) | ||||||
| Group | Clearance of the
creatinine (ml/min) |
Dosage and frequency | ||||
| Normal kidney function | > 80 | Usual daily dose, divided into 2 to 4 doses | ||||
| Mild renal failure | 50 ‒ 79 | 2/3 of the usual daily dose, divided into 2 or 3 doses | ||||
| Moderate renal failure | 30 ‒ 49 | 1/3 of the usual daily dose, divided into 2 doses | ||||
| Severe renal failure | < 30 | 1/6 usual daily dose, 1 single intake | ||||
| End stage renal disease | ‒ | Contraindication | ||||
Patients with hepatic impairment:
No dose adjustment is needed in patients with solely hepatic impairment. Dosage adjustment is recommended in patients with hepatic and renal impairment (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 the drug after use.
Contraindications:
Hypersensitivity to piracetam, other pyrrolidone derivatives or any ingredient of the drug.
Patients with severe renal failure (renal creatinine clearance of less than 20 ml per minute).
Cerebral hemorrhage.
Huntington’s chorea.
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 hemorrhage, patients at risk for bleeding such as a gastrointestinal ulcer, patients with hemostatic disorders, patients with history of hemorrhagic cerebro-vascular accident, patients undergoing major surgery including dental surgery, patients using anticoagulants or platelet antiaggregant drug including low dose acetylsalicylic acid.
Renal failure:
Piracetam is eliminated via the kidneys, therefore caution should be exercised in patients with renal impairment.
In mild to moderate renal impairment, doses will be decreased and/or spaced if the clearance of creatinine is less than 80 ml/min.
Elderly:
In case of long-term treatment, creatinine clearance should be regularly assessed to adjust the dose, if necessary.
Discontinuation:
Abrupt discontinuation of treatment should be avoided as this may induce myoclonic or generalised seizures in some myoclonic patients.
Warnings related to the excipients:
Each ml of the medicine contains 25 mg of betadex. Due to limited safety information in children under 2 years of age, the medicine should not be used for this group unless directed by a doctor.
Each ml of the medicine contains 200 mg of sorbitol. Due to sorbitol is a source of fructose, if you have an intolerance to some sugars or a rare hereditary fructose intolerance, where you cannot break down fructose, you should inform your doctor before taking it. In addition, sorbitol may cause gastrointestinal upset or a mild laxative effect.
The medication contains methylparaben and propylparaben, which may cause allergic reactions.
The medication contains glycerin, which can cause headache, stomach upset, and diarrhea.
Each ml of the drug contains 4 mg propylene glycol, concomitant use with any alcohol dehydrogenase substrate such as ethanol may cause serious adverse reactions in newborns.
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 or foetal development, parturition or post-natal development.
Piracetam crosses the placental barrier. Drug concentrations in the newborn are approximately 70% to 90% of maternal concentrations. Piracetam is not recommended during pregnancy unless there is a real need, when the expected benefit for the mother is greater than the potential risks.
Lactation:
Piracetam is excreted in breast milk. Therefore, piracetam should not be used while breastfeeding or breastfeeding should be discontinued during treatment with piracetam. A decision whether to discontinue breast-feeding or to discontinue piracetam should be made taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility:
Animal studies indicate that piracetam has no effect on fertility in male or female rats.
There are no available clinical data on the effect of piracetam on fertility.
Effects on ability to drive, use machines:
In clinical studies, at dosages between 1.6 – 15 grams per day, hyperkinesia, somnolence, nervousness and depression were reported more frequently in patients on piracetam than on placebo. There is no experience on driving ability in dosages between 15 and 20 grams daily. Therefore, caution should be exercised by patients intending to drive or use machinery whilst taking piracetam.
Interactions, incompatibilities of medicine:
Interaction of the drug with other drugs and other types of interactions:
Pharmacokinetic 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 did not inhibit 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 a concentration of 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 disorders 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/d did not modify the doses of acenocoumarol necessary to reach INR 2.5 to 3.5. However, 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 of drug incompatibility, do not mix this drug with other drugs.
Undesirable effects:
Undesirable effects are classified 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); not known (cannot be estimated from the available data).
Blood and lymphatic system disorders:
Not known: Haemorrhagic disorder.
Immune system disorders:
Not known: Anaphylactoid reaction, hypersensitivity.
Psychiatric disorders:
Common: Nervousness.
Uncommon: Depression.
Not known: Agitation, anxiety, confusion, hallucination.
Nervous system disorders:
Common: Hyperkinesia.
Uncommon: Somnolence.
Not known: Ataxia, balance impaired, epilepsy aggravated, headache, insomnia, drowsiness.
Ear and labyrinth disorders:
Not known: Vertigo.
Gastrointestinal disorders:
Not known: Abdominal pain, abdominal pain upper, diarrhoea, nausea, vomiting.
Skin and subcutaneous tissue disorders:
Not known: Angioneurotic oedema, dermatitis, pruritus, urticaria.
General disorders and administration site conditions:
Uncommon: Asthenia.
Investigations:
Common: Weight increased.
Overdose and management:
Overdose:
Symptoms: The highest reported overdose with piracetam was oral intake of 75 g, bloody diarrhea with abdominal pain appeared, was most probably related to the extreme high dose of sorbitol contained in the used formulation.
No additional adverse reactions related to overdose have been reported with piracetam.
Management:
In case of significant, acute overdose, 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:
Pharmacological group: Other psychostimulants and nootropics.
ATC code: N06BX03.
Action mechanism:
The action mechanism of the therapeutic effects is unknown.
Pharmacodynamic effects:
Piracetam exerts its haemorrheological effects on the platelets, red blood cells, and vessel walls by increasing erythrocyte deformability and by decreasing platelet aggregation, erythrocyte adhesion to vessel walls and capillary vasospasm.
Effects on the red blood cells:
In patients with sickle cell anemia, piracetam improves the deformability of the erythrocyte membrane, decreases blood viscosity, and prevents rouleaux formation.
Effects on platelets:
In open studies in healthy volunteers and in patients with Raynaud’s phenomenon, increasing doses of piracetam up to 12 g was associated with a dose-dependent reduction in platelet functions compared with pre-treatment values (tests of aggregation induced by ADP, collagen, epinephrine and ßTG release), without significant change in platelet count. In these studies, piracetam prolonged bleeding time.
Effects on blood vessels:
In animal studies, piracetam inhibited vasospasm and counteracted the effects of various spasmogenic agents. It lacked any vasodilatory action and did not induce “steal” phenomenon, nor low or no reflow, nor hypotensive effects. In healthy volunteers, piracetam reduced the adhesion of RBCs to vascular endothelium and possessed also a direct stimulant effect on prostacycline synthesis in healthy endothelium.
Effects on coagulation factors:
In healthy volunteers, compared with pre-treatment values, piracetam up to 9.6 g reduced plasma levels of fibrinogen and von Willebrand’s factors (VIII: C; VIII R: AG; VIII R: vW) by 30 to 40 %, and increased bleeding time.
In patients with both primary and secondary Raynaud phenomenon, piracetam 8 g/day during 6 months reduced plasma levels of fibrinogen and von Willebrand’s factors (VIII: C; VIII R: AG; VIII R: vW (RCF)) by 30 to 40 %, reduced plasma viscosity, and increased bleeding time compared with pre-treatment values.
Pharmacokinetics:
Absorption:
Piracetam is rapidly and almost completely absorbed. Peak plasma levels are reached within 1.5 hours after
administration. The extent of oral bioavailability, assessed from the Area Under Curve (AUC), is close to 100% for capsules, tablets and solution. Peak levels and AUC are proportional to the dose given.
Distribution:
The volume of distribution of piracetam is 0.7 L/kg. Piracetam crosses the blood-brain, the placental barrier and diffuses across membranes used in renal dialysis.
Metabolism:
Up to now, no metabolite of piracetam has been found.
Elimination:
Piracetam is excreted almost completely in urine and the fraction of the dose excreted in urine is independent of the dose given. Excretion half-life values are consistent with those calculated from plasma/blood data. The plasma half-life is 5 hours, in young adult men. Clearance of the compound is dependent on the renal creatinine clearance and would be expected to diminish with renal insufficiency.
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. Once opened, the medicine can be stored under the same conditions and used within 28 days.
Quality specification: In house.
