Oxcarbazepine

Registered South African indications:

• Partial seizures with or without secondary generalised seizures
• Generalised tonic-clonic seizures

Contraindications

Registered South African contraindications & Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or eslicarbazepine or to any of its excipients
• Porphyria

Cautions

• Previous hypersensitivity reactions to carbamazepine
• Pregnancy 
• Breastfeeding 
• Severe renal impairment 
• Severe hepatic impairment 
• Presence of HLA-B*1502 allele
• Presence of HLA-A*3101 allele 
• Risk factors for hyponatraemia 
• Fluid retention 
• Cardiac insufficiency
• Secondary cardiac failure
• Cardiac conduction disturbance 
• Abrupt withdrawal

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

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Partial seizures with or without secondary generalization
- Monotherapy and adjunctive therapy
Generalised tonic-clonic seizures
- Monotherapy and adjunctive therapy

• Oral (fct, tab): Initial: 600mg/day (8-10mg/kg/day), in 2 divided doses; Titrate by up to 600mg/day at intervals of 1 week from the starting dose to achieve the desired clinical response; Maintenance: 600-2400mg/day; Most adult patients are controlled on dosages of 900-1200mg/day; Max: 2400mg/24hrs

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Doses up to 2400mg/day have been achieved over 48 hours in a controlled hospital setting. Daily doses from 600 to 2400mg/day have been shown to be effective in a controlled adjunctive therapy trial, although most patients were not able to tolerate the 2400mg/day dose without reduction of concomitant anti-epileptic drugs, mainly because of CNS-related adverse events. Daily doses above 2400mg/day have not been studied systematically in clinical trials

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When other antiepileptic medicinal products (AEMPs) are replaced by oxcarbazepine, the dose of the concomitant AEMP(s) should be reduced gradually on initiation of oxcarbazepine therapy. In adjunctive therapy, as the total antiepileptic medicinal products load of the patient is increased, the dose of concomitant AEMP(s) may need to be reduced and/or the oxcarbazepine dose increased more slowly

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Method of administration: Oxcarbazepine can be taken with or without food

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

Paed. dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Partial seizures with or without secondary generalization
- Monotherapy or adjunctive therapy
Generalised tonic-clonic seizures
- Monotherapy or adjunctive therapy

Younger than 1 month

• Not established for use

Between 1 month - less than 4 years

• Oral (fct, tab): Initial: 8-10mg/kg/day, in 2 divided doses; Maintenance: 30-46mg/kg/day, achieved over 2 weeks. In a clinical trial, the intention was to reach a target daily dose of 60mg/kg/day, 56% of patients reached a final dose of at least 55mg/kg/day; Max: If clinically indicated, the dose can be increased by a maximum of 10mg/kg/day increments at approximately weekly intervals from the starting dose to a maximum daily dose of 60mg/kg/day, to achieve the desired clinical response

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Due to the decreased apparent clearance when normalized by body weight, these children may require twice the oxcarbazepine dose per body weight compared to adults. If on enzyme-inducing antiepileptic medications, about 60% higher oxcarbazepine dose per body weight may be required for adjunctive therapy relative to monotherapy or adjunctive therapy with non-enzyme-inducing antiepileptic medicinal products

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Between 4-12 years

• Oral (fct, tab): Initial: 8-10mg/kg/day, in 2 divided doses; Maintenance: 30-46mg/kg/day, achieved over 2 weeks; Max: If clinically indicated, the dose can be increased by a maximum of 10mg/kg/day increments at approximately weekly intervals from the starting dose to a maximum daily dose of 60mg/kg/day, to achieve the desired clinical response

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These children may require a 50% higher oxcarbazepine dose per body weight compared to adults. If on enzyme-inducing antiepileptic medications, only a slightly higher dose per body weight may be required than their counterparts on monotherapy

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Between 12-17 years

• Oral (fct, tab): Initial: 8-10mg/kg/day, in 2 divided doses; Maintenance: 30-46mg/kg/day, achieved over 2 weeks. In a clinical trial with the intention to reach a target daily dose of 46mg/kg/day, the median daily dose was 31mg/kg/day with a range of 6-51mg/kg/day; Max: If clinically indicated, the dose can be increased by a maximum of 10mg/kg/day increments at approximately weekly intervals from the starting dose to a maximum daily dose of 60mg/kg/day, to achieve the desired clinical response

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If on enzyme-inducing antiepileptic medications, only a slightly higher dose per body weight may be required than their counterparts on monotherapy

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Method of administration: Oxcarbazepine can be taken with or without food

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Oxcarbazepine has not been studied in controlled clinical trials in children below 1 month of age

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When other antiepileptic medicinal products (AEMPs) are replaced by oxcarbazepine, the dose of the concomitant AEMP(s) should be reduced gradually on initiation of oxcarbazepine therapy. In adjunctive therapy, as the total antiepileptic medicinal products load of the patient is increased, the dose of concomitant AEMP(s) may need to be reduced and/or the oxcarbazepine dose increased more slowly

Pregnancy 

• Caution
• Risk related to epilepsy and antiepileptic medicinal products in general: In the treated population, an increase in malformations has been noted with polytherapy, particularly in polytherapy including valproate. Moreover, effective anti-epileptic therapy must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus
• Risk related to oxcarbazepine: There is moderate amount of data on pregnant women (300-1000 pregnancy outcomes). However, the data on oxcarbazepine associated with congenital malformation is limited. There is no increase in the total rate of malformations with oxcarbazepine as compared with the rate observed in the general population (2-3%). Nevertheless, with this amount of data, a moderate teratogenic risk cannot be completely excluded
• If women receiving oxcarbazepine become pregnant or plan to become pregnant, the use of this product should be carefully re-evaluated. Minimum effective doses should be given, and monotherapy whenever possible should be preferred at least during the first three months of pregnancy
• During pregnancy, an effective antiepileptic oxcarbazepine treatment must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus
• Some antiepileptic medicinal products may contribute to folic acid deficiency, a possible contributory cause of foetal abnormality. Folic acid supplementation is recommended before and during pregnancy. As the efficacy of this supplementation is not proved, a specific antenatal diagnosis should be offered even for women with a supplementary treatment of folic acid
• Data from a limited number of women indicate that plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. It is recommended that clinical response should be monitored carefully in women receiving oxcarbazepine treatment during pregnancy to ensure that adequate seizure control is maintained. Determination of changes in MHD plasma concentrations should be considered. If dosages have been increased during pregnancy, postpartum MHD plasma levels may also be considered for monitoring
• Bleeding disorders in the newborn have been reported with hepatic inductor antiepileptic medicines. As a precaution, vitamin K1should be administered as a preventive measure in the last few weeks of pregnancy and to the newborn

Breastfeeding 

• Caution; not recommended
• Oxcarbazepine and its active metabolite (MHD) are excreted in human breast milk. A milk-to-plasma concentration ratio of 0.5 was found for both. The effects on the infant exposed to oxcarbazepine by this route are not known. Therefore, oxcarbazepine should not be used during breastfeeding

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; dose adjustment recommended 3,4

CrCl (ml/min)	Adult dosage	Children >6 years old
>30	No dose adjustment	No dose adjustment
<30	Reduce initial dose by 50% (300mg, dly), Up-tirate at intervals of at least 1 week to achieve desired clinical response	Commence therapy at lower doses; Initial dose may be reduced to 50%; Up-tirate at intervals of at least 1 week to achieve desired clinical response

Hepatic Impairment 

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended

Elderly 

• No dose adjustment recommended

Porphyria Information

• Probably porphyrinogenic (PRP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Agitation
• Lability
• Confusion
• Depression
• Apathy
• Fatigue 
• Somnolence
• Headache
• Dizziness
• Ataxia
• Tremor
• Nystagmus
• Disturbance in attention
• Amnesia
• Speech disorders
• Seizures
• Encephalopathy
• Depressed level of consciousness 

Cardiovascular Disorders

• Atrioventricular block
• Arrhythmia
• Hypertension

Gastrointestinal Disorders

• Nausea and vomiting 
• Diarrhoea
• Abdominal pain
• Constipation

Hepatobiliary Disorders

• Pancreatitis
• Increased lipase
• Increased amylase
• Increased hepatic enzymes

Endocrine and Metabolic Disorders

• Hypothyroidism
• Inappropriate antidiuretic hormone secretion like syndrome
• Hyponatraemia 

Musculoskeletal Disorders

• Systemic lupus erythematosus
• Decreased bone mineral density
• Osteopenia
• Osteoporosis
• Fractures

Skin and Subcutaneous Tissue Disorders

• Rash
• Alopecia
• Acne
• Urticaria
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Erythema multiforme
• Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)
• Acute Generalized Exanthematous Pustulosis

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Angioedema
• Anaphylactic reactions
• Leucopenia
• Thrombocytopenia
• Bone marrow depression
• Aplastic anemia
• Agranulocytosis
• Pancytopenia
• Neutropenia

Sensory Disorders

• Diplopia 
• Vertigo 
• Blurred vision 
• Visual disturbance

• CYP3A4 substrates
• CYP3A5 substrates 
• CYP2C19 substrates 
• Oral contraceptives 
• Lithium 
• Monoamine oxidase inhibitors 
• Carbamazepine
• Phenytoin
• Phenobarbitone
• Valproic acid

• Thyroid function 
• Full blood count 

Specific cases may require

• Serum sodium 
• Serum levels of concomitant antiepileptic agents 

Oxcarbazepine and its monohydroxy metabolite (MHD) block voltage-sensitive sodium channels. This stabilizes hyperexcited neuronal membranes, thereby inhibiting repetitive firing, and decreasing the propagation of synaptic impulses. Oxcarbazepine and MHD also increase potassium conductance and modulate the activity of high-voltage activated calcium channels.

Tablet 300mg

• Mylan-Oxcarbazepine fct (Xixia)
• Trileptal fct (Novartis) originator

Tablet 600mg

• Mylan-Oxcarbazepine fct (Xixia)
• Trileptal fct (Novartis) originator