Levetiracetam

Registered South African indications: 

• Partial onset seizures with or without secondary generalisation in patients with epilepsy
• Myoclonic seizures
• Primary generalised tonic-clonic seizures in patients with idiopathic generalised epilepsy

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to other pyrrolidine derivatives
• Pregnancy (fct, tab, XR tab)
• Lactation (fct, tab, XR tab)
• Patients with rare hereditary problems of fructose intolerance (sol)

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to other pyrrolidine derivatives

• Pregnancy (sol) (South African recommendations)
• Pregnancy (Recommendations in other jurisdictions)
• Breastfeeding (sol) (South African recommendations)
• Breastfeeding (Recommendations in other jurisdictions)
• Renal impairment
• Severe hepatic impairment (CrCl<70ml/min) (South African recommendations)
• Severe hepatic impairment (CrCl<60ml/min) (Recommendations in other jurisdictions)
• Children 
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: fct, sol, tab, XR tab

South African registered indications and dosages

Film-coated tablet, tablet, XR tab

Partial onset seizures with or without secondary generalisation in patients with newly diagnosed epilepsy

Monotherapy

• Oral (fct, tab): Initial: 250mg, twice daily; THEN increase to initial therapeutic dose: 500mg, twice daily after 2 weeks; Titrate by 250mg, twice daily every 2 weeks depending on the clinical response; Max: 1500mg, twice daily
• Oral (XR tab): Initial: 500mg, once daily; THEN increase to initial therapeutic dose: 1000mg, once daily after 2 weeks; Titrate by 500mg, once daily every 2 weeks depending on the clinical response; Max: 1500mg, once daily

Partial onset seizures with or without secondary generalisation in patients with epilepsy
Myoclonic seizures
Primary generalised tonic-clonic seizures in patients with idiopathic generalised epilepsy

Adjunctive therapy

• Oral (fct, tab): Initial: 500mg, twice daily started on 1st day of treatment; Titrate by 500mg, twice daily in increments or decrements every 2-4 weeks; Daily dose can be increased to 1500mg, twice daily depending upon the clinical response and tolerance; Max: 3000mg/24hrs
• Oral (XR tab): Initial: 1000mg, once daily, which can be started on the 1st day of treatment; Titrate by 1000mg, once daily in increments or decrements every 2-4 weeks; Daily dose can be increased to 3000mg, once daily depending upon the clinical response and tolerability; Max: 3000mg/24hrs

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

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XR tablets must be taken orally, swallowed with liquid and may be taken with or without food. The daily dose is administered once daily

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Missed dose: If a dose is missed, the tablet should be taken as soon as the missed dose is remembered. Two tablets should not be taken to make up for the missed dose

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Oral solution

Partial onset seizures with or without secondary generalisation in patients with epilepsy

Adjunctive therapy

• Oral (sol): Initial: 1st day: 500mg, twice daily; Titrate by 500mg, twice daily increments or decrements every 2-4 weeks; Daily dose can be increased up to 1500mg, twice daily depending upon the clinical response and tolerance; Max: 3000mg/24hrs

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The oral solution may be diluted in a glass of water and may be taken with or without food. After oral administration the bitter taste of levetiracetam may be experience

Paed. forms avail. in SA and covered in this monograph: sol, fct, tab, XR tab

South African registered indications and dosages

Film-coated tablet, tablet, XR tab

Partial onset seizures with or without secondary generalisation in patients with newly diagnosed epilepsy

Monotherapy

• Younger than 16 years: Not established for use
• 16 years and older: ≥50kg: See adult dosage

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The safety and efficacy of levetiracetam in children and adolescents below 16 years as monotherapy treatment has not been established

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Myoclonic seizures in patients with juvenile myoclonic epilepsy

Adjunctive therapy

• Younger than 12 years: Insufficient data to recommended use
• 12 years and older: ≥50kg: See adult dosage

Partial onset seizures with or without secondary generalisation in patients with epilepsy
Primary generalised tonic-clonic seizures in patients with idiopathic generalised epilepsy

Adjunctive therapy

• Younger than 16 years: Insufficient data to recommended use
• 16 years and older: ≥50kg: See adult dosage

Adolescents 12-17 years weighing <50kg, when indicated (indications above)

Film-coated tablet, tablet

• Between 12-17 years: <50kg: Initial: 10mg/kg, twice daily, which can be started on the 1st day of treatment; Titrate by 10mg/kg, twice daily in increments or decrements every 2 weeks; Increase daily dose up to 30mg/kg, twice daily depending upon clinical response and tolerability; The lowest effective dose should be used

Recommended dosage for children and adolescents with normal renal function (fct, tab)

Weight	Starting dose 10mg/kg twice daily	Maximum dose 30mg/kg twice daily
15kg	150mg, twice daily	450mg, twice daily
20kg	200mg, twice daily	600mg, twice daily
25kg	250mg, twice daily	750mg, twice daily
From 50kg	500mg, twice daily	1500mg, twice daily

For 15kg and 20kg use oral solution

XR tab

• Between 12-17 years: <50kg: Initial: 20mg/kg, once daily, which can be started on the 1st day of treatment; Titrate by 20mg/kg, once daily in increments or decrements every 2 weeks; Increase daily dose up to 60mg/kg, once daily depending upon clinical response and tolerability; The lowest effective dose should be used

Recommended dosage for children and adolescents with normal renal function (XR tab)

Weight	Starting dose 20mg/kg once daily	Maximum dose 60mg/kg once daily
15kg	300mg, once daily	900mg, once daily
20kg	400mg, once daily	1200mg, once daily
25kg	500mg, once daily	1500mg, once daily
From 50kg	1000mg, once daily	3000mg, once daily

Children 20kg or less should preferably start treatment with a levetiracetam containing oral solution (100mg/mL; twice daily formulation)

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

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XR tablets must be taken orally, swallowed with liquid and may be taken with or without food. The daily dose is administered once daily

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Missed dose: If a dose is missed, the tablet should be taken as soon as the missed dose is remembered. Two tablets should not be taken to make up for the missed dose

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Oral solution

Partial onset seizures with or without secondary generalisation in patients with epilepsy

Adjunctive therapy

• Younger than 4 years: Insufficient data to recommended use
• Between 4-11 years: Oral (sol): 10mg/kg, twice daily can be started on 1st day of treatment; Titrate by 10mg/kg, twice daily increments or decrements every 2 weeks; Increase daily dose up to 30mg/kg, twice daily depending upon clinical response and tolerance
• Adolescents between 12-17 years OR children ≥50kg: See adult dosage

Recommended dosage for children and adolescents with normal renal function

Weight	Starting dose 10mg/kg twice daily	Maximum dose 30mg/kg twice daily
15kg	150mg (1.5ml), twice daily	450mg (4.5ml), twice daily
20kg	200mg (2ml), twice daily	600mg (6ml), twice daily
25kg	250mg, twice daily	750mg, twice daily
From 50kg	500mg, twice daily	1500mg, twice daily

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Children 20kg or less should preferably start treatment with a levetiracetam 100mg/ml oral solution

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The medical practitioner should prescribe the most appropriate pharmaceutical form and strength according to age, weight and dose. Levetiracetam oral solution is the preferred formulation for use in in children under the age of 6 years. In addition, the available dose strengths of the tablets are not appropriate for initial treatment in children weighing less than 25kg, for patients unable to swallow tablets or for the administration of doses below 250mg. In all the above cases, levetiracetam oral solution should be used

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The oral solution may be diluted in a glass of water and may be taken with or without food. After oral administration the bitter taste of levetiracetam may be experienced. The daily dose is administered in two equal divided doses

Pregnancy

South African recommendations

Film-coated tablet, tablet, and XR tablet

• Contraindicated
• Levetiracetam is contraindicated in pregnancy

Oral Solution

• Caution
• Post-marketing data on more than 1800 pregnant women exposed to levetiracetam monotherapy, with over 1500 exposures during the first trimester, do not suggest an increased risk for major congenital malformations
• Limited evidence exists on the neurodevelopment of children exposed to levetiracetam monotherapy in utero, but current epidemiological studies on about 100 children do not indicate an increased risk of neurodevelopmental disorders or delays
• Physiological changes during pregnancy may affect levetiracetam concentration, and decreased concentrations during pregnancy have been reported
• Women of childbearing potential should receive specialist advice regarding levetiracetam
• Treatment with levetiracetam should be reviewed when planning pregnancy
• Sudden discontinuation of levetiracetam should be avoided to prevent breakthrough seizures, which could harm both the woman and the unborn child
• Monotherapy is preferred over polytherapy with antiepileptic drugs (AEDs) to reduce the risk of congenital malformations, as therapy with multiple AEDs could carry a higher risk depending on the specific medications used

Recommendations in other jurisdictions

• Caution
• A large amount of post-marketing data on pregnant women exposed to levetiracetam monotherapy (more than 1800, among which in more than 1500 exposure occurred during the first trimester) do not suggest an increase in the risk for major congenital malformations. Only limited evidence is available on the neurodevelopment of children exposed to levetiracetam monotherapy in utero. However, current epidemiological studies (on about 100 children) do not suggest an increased risk of neurodevelopmental disorders or delays
• Levetiracetam can be used during pregnancy if after careful assessment it is considered clinically needed. In such a case, the lowest effective dose is recommended. Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline concentration before pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam should be ensured
• Women of childbearing potential: Specialist advice should be given to women who are of childbearing potential. Treatment with levetiracetam 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 AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated antiepileptics

Breastfeeding

South African recommendations

Film-coated tablet, tablet, and XR tablet

• Contraindicated
• Levetiracetam is excreted in human breast milk. Patients using levetiracetam must not breastfeed

Oral solution

• Caution; not recommended

• Safety of levetiracetam during breastfeeding has not been established
• Levetiracetam is excreted in human breast milk
• Patients using levetiracetam are advised not to breastfeed their babies

Recommendations in other jurisdictions

• Caution; not recommended
• Levetiracetam is excreted in human breast milk. Therefore, breastfeeding is not recommended. However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breastfeeding

Fertility

South African recommendations

Film-coated tablets and tablets

• No adverse reactions on male or female fertility or reproduction performance were observed in rats at doses up to 1800mg/kg/day (x 6 the MRHD on a mg/m² or exposure basis) in parents and F1 generation

Oral solution

• No clinical data are available, potential risk for human is unknown

Recommendations in other jurisdictions

• No impact on fertility was detected in animal studies. No clinical data are available, potential risk for human is unknown

• Caution; dose adjustment recommended
  eGFR  50–80mL/min: Dosage should not exceed 2g/24hrs
  eGFR  30-50mL/min: Dosage should not exceed 1.5g/24hrs
  eGFR  <30mL/min: Dosage should not exceed 1g/24hrs

CrCl (ml/min)	Adults	Infants 1yr to < 6 months	Infants 6 - 23 months, children and adolescents weighing < 50 kg
≥ 80	500-1500mg every 12hrs	7-21mg/kg every 12hrs	10-30mg/kg every 12hrs
50-79	500-1000mg every 12hrs	7-14mg/kg every 12hrs	10-20mg/kg every 12hrs
30-49	250-750mg every 12hrs	3.5-10.5mg/kg every 12hrs	5-15mg/kg every 12hrs
< 30	250-500mg every 12hrs	3.5-7mg/kg every 12hrs	5-10mg/kg every 12hrs
End-stage renal disease	500-1000mg daily	7-14mg/kg daily	10-20mg/kg daily

*See additional prescribing points on dosing in end-stage renal disease

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; dose adjustment recommended
  In most subjects with severe hepatic impairment, the clearance of levetiracetam was reduced by more than 50% due to a concomitant renal impairment
  Therefore a 50% reduction of the daily maintenance dose is recommended when the creatinine clearance is <70ml/min

Recommendations in other jurisdictions

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; dose adjustment recommended
  In most subjects with severe hepatic impairment, the clearance of levetiracetam was reduced by more than 50% due to a concomitant renal impairment
  Therefore a 50% reduction of the daily maintenance dose is recommended when the creatinine clearance is <60ml/min/1.73m²

• No dose adjustment recommended

Central Nervous System Disorders

• Vertigo 
• Depression
• Aggression
• Anxiety
• Insomnia
• Nervousness
• Irritability
• Suicide attempt
• Suicidal ideation
• Psychotic disorder
• Abnormal behaviour
• Halluciantion
• Anger
• Confusional state
• Panic attack
• Labile affect 
• Agitation
• Completed suicide
• Personality disorder
• Abnormal thinking 
• Somnolence
• Headache
• Seizures 
• Balance disorder
• Dizziness
• Lethargy
• Tremor
• Amnesia
• Asthenia 
• Abnormal coordination
• Ataxia
• Paraesthesia
• Disturbance in attention
• Choreoathetosis
• Dyskinesia
• Hyperkinesia

Respiratory Disorders

• Cough
• Nasopharyngitis

Gastrointestinal Disorders

• Abdominal pain
• Diarrhoea
• Dyspepsia
• Nausea and vomiting 

Hepatobiliary Disorders

• Pancreatitis
• Abnormal hepatic function tests
• Hepatic failure
• Hepatitis

Genitourinary Disorders

• Acute renal injury 

Endocrine and Metabolic Disorders

• Anorexia
• Decreased weight 
• Increased weight 
• Hyponatraemia

Musculoskeletal Disorders

• Muscular weakness
• Myalgia
• Rhabdomyolysis
• Increased blood creatine phosphokinase

Skin and Subcutaneous Tissue Disorders

• Rash
• Alopecia
• Eczema
• Pruritus
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Erythema multiforme

Immune, Blood and Lymphatic System Disorders

• Drug reaction with eosinophilia and systemic symptoms (DRESS)
• Thrombocytopenia
• Leukopenia
• Pancytopenia
• Neutropenia
• Agranulocytosis
• Sepsis 

Sensory Disorders 

• Diplopia
• Blurred vision 

• Methotrexate
• Macrogol

• Mental status 

Specific cases may require 

• Diastolic blood pressure (children)

End-stage renal disease patients undergoing dialysis:

Adults

• A 750mg loading dose is recommended on the first day of treatment with levetiracetam
• Following dialysis, a 250 - 500mg supplemental dose is recommended

Infants, children and adolescent patients weighing < 50 kg 

• A 10.5mg/kg loading dose is recommended on the first day of treatment with levetiracetam
• A 15mg/kg loading dose is recommended on the first day of treatment with levetiracetam
• Following dialysis, a 3.5 - 7 mg/kg supplemental dose is recommended
• Following dialysis, a 5 - 10mg/kg supplemental dose is recommended

The precise mechanism by which levetiracetam exerts its antiepileptic effect is unknown. It may involve inhibition of voltage-dependent N-type calcium channels, facilitation of gamma aminobutyric acid inhibitory transmission through displacement of negative modulators, reduction of delayed rectifier potassium current, and/or binding to synaptic proteins which modulate neurotransmitter release.

Tablet 250mg

• Dyna Levetiracetam (Pharma Dynamics)
• Epikepp (Cipla)
• Keppra (GSK) originator
• Levetiracetam Biotech (Biotech)
• Levetiracetam Unicorn (Unicorn)
• Redilev (Dr Reddy)
• Torcetam (Litha)

Tablet 500mg

• Dyna Levetiracetam (Pharma Dynamics)
• Epikepp (Cipla)
• Keppra (GSK) originator
• Redilev (Dr Reddy)
• Torcetam (Litha)

Tablet 750mg

• Dyna Levetiracetam (Pharma Dynamics)
• Epikepp (Cipla)
• Keppra (GSK) originator
• Levetiracetam Biotech (Biotech)
• Levetiracetam Unicorn (Unicorn)
• Redilev (Dr Reddy)
• Torcetam (Litha)

Solution (per ml) 100mg

• Keppra (GSK) originator