Nootropil Tablets 1200 mg

Nootropil Tablets 800 mg

Nootropil Solution 33%

Piracetam - 1200 mg per tablet

Piracetam - 800 mg per tablet

Piracetam – 33% w/v

Tablet for oral administration.

Solution for oral administration.

NOOTROPIL is indicated for patients suffering from myoclonus of cortical origin, irrespective of aetiology, and should be used in combination with other anti-myoclonic therapies.

Adults :

The dosage regime shows important interindividual variability, requiring an individualised dose finding approach. A reasonable protocol would be to introduce piracetam at a dosage of 7.2 g/day, increasing by 4.8 g/day every 3 to 4 days up to a maximum of 20g/day, given in either 2 or 3 divided doses while keeping other antimyoclonic drugs unchanged at their optimal dosage. If possible, depending on clinical benefit, an attempt should be made to subsequently reduce the dosage of other antimyoclonic drugs.

Piracetam is contra-indicated in patients with severe renal impairment (renal creatinine clearance of less than 20 ml per minute), hepatic impairment and to those under 16 years of age. It is also contraindicated in patients with cerebral haemorrhage and in those with hypersensitivity to piracetam, other pyrrolidone derivatives or any of the excipients .

Due to the effect of piracetam on platelet aggregation (see section 5.1. Pharmacodynamic Properties), caution is recommended in patients with underlying disorders of haemostasis, major surgery or severe haemorrhage.

Abrupt discontinuation of treatment should be avoided as this may induce myoclonic or generalised seizures in some myoclonic patients.

As piracetam is almost exclusively excreted by the kidneys caution should be exercised in treating patients with known renal impairment. In renally impaired and elderly patients an increase in terminal half-life is directly related to renal function as measured by creatinine clearance.

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:

In a single case, confusion, irritability and sleep disorders were reported in concomitant use with thyroid extract (T3 + T4). At present although based on a small number of patients, no interaction has been found with the following anti-epileptic medications: clonazepam, carbamazepine, phenytoin, phenobarbitone and sodium valproate.

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, but compared with the effects of acenocoumarol alone, the addition of piracetam 9.6 g/d 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.

To date, there are no known interactions with other drugs.

In animal studies piracetam was not teratogenic and had no effect on fertility at the maximal tested dose of 2.7 /g/kg/day for the rabbit and 4.8 g/kg/day for rats and mice.

Piracetam readily crosses the placental barrier. Since the safety of use in human pregnancy is not established, piracetam is to be avoided during pregnancy.

Piracetam is excreted in human breast milk. Therefore, piracetam should be avoided during breastfeeding or breastfeeding should be discontinued, while receiving treatment with piracetam.

Young women using the product should be taking adequate contraceptive precautions.

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. Caution should therefore be exercised by patients intending to drive or use machinery whilst taking piracetam.

A. Clinical studies

Double-blind placebo-controlled clinical or pharmacoclinical trials, of which quantified safety data are available (extracted from the UCB Documentation Data Bank on June 1997), included more than 3000 subjects receiving piracetam, regardless of indication, dosage form, daily dosage or population characteristics.

When adverse events are grouped together according to WHO System Organ Classes, the following classes were found to be related to a statistically significantly higher occurrence under treatment with piracetam: psychiatric disorders, central and peripheral nervous system disorders, metabolic and nutritional disorders, body as a whole - general disorders.

Following adverse experiences were reported for piracetam with a statistically significantly higher incidence than placebo. Incidences are given for piracetam versus placebo treated patients.

B. Post-marketing experience

From the post-marketing experience, the following adverse drug reactions have been reported (sorted according to MedDRA System Organ Classes). Data are insufficient to support an estimate of their incidence in the population to be treated.

- Ear and labyrinth disorders:

vertigo

- Gastrointestinal disorders:

abdominal pain, abdominal pain upper, diarrhoea, nausea, vomiting

- Immune system disorders:

anaphylactoid reaction, hypersensitivity

- Nervous system disorders:

ataxia, balance impaired, epilepsy aggravated, headache, insomnia, somnolence

- Psychiatric disorders:

agitation, anxiety, confusion, hallucination

- Skin and subcutaneous tissue disorders:

angioneurotic oedema, dermatitis, pruritus, urticaria, rash

Acute toxicological studies in animals showed lethal doses were obtained in mice (18.2 g/kg and higher) but not in rats and dogs dosed respectively at 21 g/kg or 10 g/kg.

No specific measure is indicated. The patient's general condition should be closely monitored. Close attention should be given to keeping the patient well hydrated and monitoring the urine flow.

Piracetam's mode of action in cortical myoclonus is as yet unknown.

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, compared with pre-treatment values, piracetam 8 g/d 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.

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. The volume of distribution of piracetam is 0.7 L/kg, and the plasma half-life is 5.0 hours, in young adult men. Piracetam crosses the blood-brain and the placental barrier and diffuses across membranes used in renal dialysis. Up to now, no metabolite of piracetam has been found. 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. Clearance of the compound is dependent on the renal creatinine clearance and would be expected to diminish with renal insufficiency.

Single doses of piracetam yielded LD 50 values at 26 g/kg in mice but LD 50 values were not reached in rats. In dogs, clinical signs after acute oral dosing were mild and lethality was not observed at the maximum tested dose of 10 g/kg.

Repeated oral treatment for up to 1 year in dogs (10 g/kg) and 6 months in rats (2 g/kg) was very well tolerated: no target organ toxicity or signs of (irreversible) toxicity were clearly demonstrated. Safe dose levels represent a multiple of the maximum intended human daily dose of 0.4 g/kg.

In terms of exposure (C max) safe levels obtained in the rat and the dog represent respectively 8 fold and 50 fold of the maximum human therapeutic level. AUC levels obtained in the same animals were a multiple of the human AUC level at the maximum intended daily dose.

The only change which might eventually be attributed to chronic treatment in male, but not in female, rats was an increase of the incidence over control animals of progressive glomerulonephrosis at the dose of 2.4 g/k/day given for 112 weeks.

Although piracetam crosses the placenta into the foetal circulation, no teratogenic effects were observed at dose levels up to 4.8 g/kg/day (mice, rats) and 2.7 g/kg/day (rabbits). Furthermore, the compound affects neither fertility nor the peri- or postnatal development of the pregnancy at doses up to 2.7 g/kg/day.

Piracetam was found to be devoid of any mutagenic or clastogenic activity and does not represent any genotoxic or carcinogenic risk to man.

Nootropil 800 and 1200 mg Tablets:

Polyethylene glycol 6000

Colloidal anhydrous silica

Magnesium stearate

Methocel

Titanium dioxide (E171)

Polyethylene glycol 400

Nootropil Solution 33%:

Glycerol

Methy parahydroxybenzoate

Propyl parahydroxybenzoate

Sodium acetate

Acetic acid

Purified water

None known.

Nootropil 800 and 1200 mg Tablets:

Four (4) years.

Nootropil Solution 33%:

Five (5) years.

Nootropil 800 and 1200 mg Tablets:

None.

Nootropil Solution 33%:

Do not store above 25°C.

Nootropil 800 mg Tablets - Blister pack in an outer cardboard carton (90 tablets per carton).

Nootropil 1200 mg Tablets – Blister pack in an outer cardboard carton (60 tablets per carton).

Nootropil Solution 33% - Glass bottle containing 125 ml or 300 ml solution.

Tablets – None.

Solution – Do not store above 25°C.

It is advisable to follow each dose with a drink of water or a soft drink to reduce the bitter taste of the solution.

UCB Pharma Ltd.,

208 Bath Road

Slough

Berkshire

SL1 3WE

Nootropil Tablets 800 mg : PL 00039/0535

Nootropil Tablets 1200 mg : PL 00039/0536

Nootropil Solution 33% : PL 00039/0534

14 December 1992/03 December 1998/18 November 2004

06 December 2006