Levetiracetam Biotech 250 mg / 750 mg / 1 000 mg FC tablets

LEVETIRACETAM BIOTECH is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in patients from 16 years of age with newly diagnosed epilepsy. LEVETIRACETAM BIOTECH is indicated as adjunctive therapy:

• in the treatment of partial onset seizures with or without secondary generalisation in adults and children over 16 years of age with epilepsy
• in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy
• in the treatment of primary generalised tonic-clonic seizures in adults and children from 16 years of age with idiopathic generalised epilepsy.

Posology

Monotherapy

Adults and adolescents from 16 years of age: The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum daily dose is 1 500 mg twice daily.

Add-on therapy

Adults (u2265 18 years) and adolescents (12 to 17 years) weighing 50 kg or more, when indicated (see section 4.1): The initial therapeutic dose is 500 mg twice daily. The dose can be started on the first day of treatment. Depending upon the clinical response and tolerability, the daily dose can be increased up to 1 500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decreases every two to four weeks.

Elderly (65 years and older): Adjustment of the dose is recommended in elderly patients with compromised renal function (see u201cPatients with renal impairmentu201d below).

Adolescents (12 to 17 years) weighing less than 50 kg, when indicated (see section 4.1): The initial therapeutic dose is 10 mg/kg twice daily. This dose can be started on the first day of treatment. Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used. Dosage in children 50 kg or greater is the same as in adults. The physician should prescribe the most appropriate pharmaceutical form and strength according to weight and dose.

Recommended dosage for children and adolescents with normal renal function:

• Weight Starting dose 10 mg/kg twice daily Maximum dose 30 mg/kg twice daily
• 15 kg (1) 150 mg twice daily 450 mg twice daily
• 20 kg (1) 200 mg twice daily 600 mg twice daily
• 25 kg 250 mg twice daily 750 mg twice daily
• From 50 kg (2) 500 mg twice daily 1 500 mg twice daily

(1) Children 20 kg or less should preferably start treatment with an oral solution of levetiracetam.

(2) Dosage in children and adolescents 50 kg or more is the same as in adults.

Special populations

Infants and children less than 12 years: There are insufficient data to recommend the use of levetiracetam in children under 12 years of age.

Patients with renal impairment: The LEVETIRACETAM BIOTECH daily dose must be individualised according to renal function. For adult patients refer to the following table and adjust the dose as indicated. To use this dosing table, calculate creatinine clearance (eClcr) according to the following formula:

For males: eClcr (mL/minute) = [140 u2013 age] x Wt (kg) / S cr (u03bcmol/L)

For females: The above formula x 0,85

Dosing adjustment for patients with impaired renal function:

Group Creatinine clearance (mL/min) Dosage and frequency

• Normal > 80 500 to 1 500 mg twice daily
• Mild 50 u2013 79 500 to 1 000 mg twice daily
• Moderate 30 u2013 49 250 to 750 mg twice daily
• Severe < 30 250 to 500 mg twice daily
• End-stage renal disease patients undergoing dialysis (1) -- 500 to 1 000 mg once daily (2)

(1) A 750 mg loading dose is recommended on the first day of treatment with LEVETIRACETAM BIOTECH.

(2) Following dialysis, a 250 mg to 500 mg supplemental dose is recommended.

Patients with hepatic impairment: No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 70 mL /min.

Method of administration

The film-coated tablets must be taken orally, swallowed with liquid and may be taken with or without food. The daily dose is administered in two equally divided doses.

Do not use LEVETIRACETAM BIOTECH if you are:

• Hypersensitive to levetiracetam or other pyrrolidone derivatives or any of the excipients of LEVETIRACETAM BIOTECH listed in section 6.1.
• Pregnant and lactating (see section 4.7).

Suicide: Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic medicines (including levetiracetam as in LEVETIRACETAM BIOTECH). Patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge (see section 4.8).

Acute kidney injury: The use of levetiracetam has been infrequently associated with acute kidney injury, with a time to onset ranging from a few days to several months.

Blood cell counts: Infrequent cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with levetiracetam administration, generally at the beginning of the treatment. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders (section 4.8).

Abnormal and aggressive behaviours: LEVETIRACETAM BIOTECH may cause psychotic symptoms and behavioural abnormalities including irritability and aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric signs suggesting important mood and/or personality changes. If such behaviours are noticed, treatment adaptation or gradual discontinuation should be considered. If discontinuation is considered, please refer to u201cDiscontinuationu201d below.

Worsening of seizures: As with other types of antiepileptic medicines, LEVETIRACETAM BIOTECH may infrequently exacerbate seizure frequency or severity. This paradoxical effect was mostly reported within the first month after levetiracetam initiation or increase of the dose and was reversible upon discontinuation or dose decrease. Patients should be advised to consult their treating doctor immediately in case of aggravation of epilepsy.

Electrocardiogram QT interval prolongation: A few cases of ECG QT interval prolongation have been observed during the post-marketing surveillance. LEVETIRACETAM BIOTECH should be used with caution in patients with QTc-interval prolongation, in patients concomitantly treated with medicines affecting the QTc-interval, or in patients with relevant pre-existing cardiac disease or electrolyte disturbances.

Renal impairment: Patients with renal impairment may require dose adaptation. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection (see sections 4.2 and 5.2).

Discontinuation: If LEVETIRACETAM BIOTECH has to be discontinued, it is recommended to withdraw it gradually (e.g. 500 mg twice daily decrements every two to four weeks).

Monitoring: There is no need for plasma level monitoring of levetiracetam. Due to the complete and linear absorption, plasma levels can be predicted from the oral dose of LEVETIRACETAM BIOTECH expressed as mg/kg bodyweight.

Anti-epileptic medicines: Evidence indicates that LEVETIRACETAM BIOTECH does not influence the serum concentrations of existing anti-epileptic medicines (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these anti-epileptic medicines do not influence the pharmacokinetics of LEVETIRACETAM BIOTECH.

Probenecid: Probenecid (500 mg four times daily), a renal tubular secretion blocking medicine, has been shown to inhibit the renal clearance of the primary metabolite but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low. It is expected that other medicines excreted by active tubular secretion could also reduce the renal clearance of the metabolite. The effect of levetiracetam on probenecid was not studied and the effect of levetiracetam on other actively secreted medicines, e.g. NSAIDs and sulphonamides is unknown.

Methotrexate: Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two medicines.

Oral contraceptives and other pharmacokinetic interactions: Co-administration of LEVETIRACETAM BIOTECH with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.

Laxatives: There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxative macrogol has been concomitantly administered with oral levetiracetam. Therefore, macrogol should not be taken orally for one hour before and for one hour after taking LEVETIRACETAM BIOTECH.

Antacids: No data on the influence of antacids on the absorption of LEVETIRACETAM BIOTECH are available.

Food and alcohol: The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced. No data on the interaction of LEVETIRACETAM BIOTECH with alcohol are available.

Women of childbearing potential: Specialist advice should be given to women who are of childbearing potential. Treatment with LEVETIRACETAM BIOTECH should be reviewed when a woman is planning to become pregnant. As with all antiepileptic medicines, sudden discontinuation of levetiracetam should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child. Monotherapy should be preferred whenever possible because therapy with multiple antiepileptic medicines could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated antiepileptics.

Pregnancy: LEVETIRACETAM BIOTECH is contraindicated in pregnancy.

Breastfeeding: Levetiracetam is excreted in human breast milk. Patients using LEVETIRACETAM BIOTECH should not breastfeed their infants.

Fertility: No impact on fertility was detected in animal studies (see section 5.3). No clinical data are available, potential risk for human is unknown.

At the beginning of treatment or following a dosage increase patients might experience, somnolence or other CNS related symptoms. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles, or operating machines.

The most frequently reported side effects are somnolence, headache, asthenia, dizziness and nasopharyngitis. Undesirable effects are listed in the table below.

Tabulated list of adverse reactions

System organ class Frequency: Side effect

Infections and infestations Frequent: Nasopharyngitis Less frequent: Infection

Blood and lymphatic system disorders Less frequent: Thrombocytopenia, leukopenia, pancytopenia, neutropenia, agranulocytosis

Immune system disorders Less frequent: Drug reaction with eosinophilia and systemic symptoms (DRESS), hypersensitivity (including angioedema and anaphylaxis)

Metabolism and nutrition disorders Frequent: Anorexia Less frequent: Weight decreased, weight increase, hyponatraemia

Psychiatric disorders Frequent: Depression, hostility/aggression, anxiety, insomnia, nervousness/irritability Less frequent: Suicide attempt, suicidal ideation, psychotic disorder, abnormal behaviour, hallucination, anger, confusional state, panic attack, affect lability/mood swings, agitation, completed suicide, personality disorder, thinking abnormal, delirium

Nervous system disorders Frequent: Somnolence, headache, convulsion, balance disorder, dizziness, lethargy, tremor Less frequent: Amnesia, memory impairment, coordination abnormal/ataxia, paraesthesia, disturbance in attention, choreoathetosis, dyskinesia, hyperkinesia, gait disturbance, encephalopathy, seizures aggravated

Eye disorders Less frequent: Diplopia, vision blurred

Ear and labyrinth disorders Frequent: Vertigo

Cardiac disorders Less frequent: Electrocardiogram QT prolonged

Respiratory, thoracic and mediastinal disorders Frequent: Cough

Gastrointestinal disorders Frequent: Abdominal pain, diarrhoea, dyspepsia, vomiting, nausea Less frequent: Pancreatitis

Hepatobiliary disorders Less frequent: Liver function test abnormal, hepatic failure, hepatitis

Renal and urinary disorders Less frequent: Acute kidney injury

Skin and subcutaneous tissue disorders Frequent: Rash Less frequent: Alopecia, eczema, pruritus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme

Musculoskeletal and connective tissue disorders Less frequent: Muscular weakness, myalgia, rhabdomyolysis, blood creatine phosphokinase increased

General disorders and administration site conditions Frequent: Asthenia, fatigue

Injury, poisoning and procedural complications Less frequent: Injury

Description of selected adverse reactions: The risk of anorexia is higher when levetiracetam is co-administered with topiramate. In several cases of alopecia, recovery was observed when levetiracetam was discontinued. Bone marrow suppression was identified in some of the cases of pancytopenia. Cases of encephalopathy generally occurred at the beginning of the treatment (few days to a few months) and were reversible after treatment discontinuation.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of LEVETIRACETAM BIOTECH is important. It allows continued monitoring of the benefit/risk balance of LEVETIRACETAM BIOTECH. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201cAdverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Symptoms of overdosage could include: somnolence, agitation, depressed level of consciousness, respiratory depression and coma. In acute, significant overdosage, the stomach may be emptied by induction of emesis. There is no specific antidote for levetiracetam. Treatment for an overdose will be symptomatic and may include haemodialysis.