4.1. Therapeutic indications

Nootropil 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.

4.2. Posology and method of administration

Posology

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 other 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).

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

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:

Group

Creatinine Clearance (ml/min)

Posology and frequency

Normal

> 80

usual daily dose, divided in 2 to 3 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).

Method of administration

Piracetam should be administered orally, and may be taken with or without food. The tablet(s) should be swallowed with liquid. It is recommended to take the daily dose in two to three sub-doses.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or other pyrrolidone derivatives.

Piracetam is contra-indicated in patients with severe renal impairment (renal creatinine clearance of less than 20 ml per minute). It is also contraindicated in patients with cerebral haemorrhage and in patients suffering from Huntington's Chorea.

4.4. Special warnings and precautions for use

Effects on platelet aggregation

Due to the effect of piracetam on platelet aggregation (see section 5.1), 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 acetylsalicylic acid.

Renal insufficiency

Piracetam is eliminated via the kidneys and care should thus be taken in cases of renal insufficiency (see section 4.2).

Elderly

For long-term treatment in the elderly, regular evaluation of the creatinine clearance is required to allow dosage adaptation if needed (see section 4.2).

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

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'. When the used dose is greater than 10 tablets/day (12.6 g), it cannot be considered 'sodium-free' and it should be taken into consideration by patients on a controlled sodium diet. At maximum daily dose (20 tablets (24 g)) this medicine contains 43.8 mg of sodium. This is equivalent to 2.19% of the recommended maximum daily dietary intake of sodium for an adult.

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4.5. 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/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.

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.

4.6. Fertility, 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 (see section 5.3).

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.

Breast-feeding

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 woman.

Fertility

There are no available clinical data on the effect of piracetam on fertility. Animal studies indicate that piracetam has no effect on fertility in male or female rats.

4.7. Effects on ability to drive and 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. Caution should therefore be exercised by patients intending to drive or use machinery whilst taking piracetam.

4.8. Undesirable effects

a. Summary of safety profile

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.

b. Tabulated list of adverse reactions

Undesirable effects reported in clinical studies and from post-marketing experience are listed in the following table per System Organ Class and per frequency. The 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).

Data from post-marketing experience are insufficient to support an estimate of their incidence in the population to be treated.

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,

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard

4.9. Overdose

Symptoms

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 diarrhoea 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 of overdose

In acute, significant overdosage, the stomach may be emptied by gastric lavage or 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.