Carbamazepine

Registered South African indications:

• Epilepsy with motor and psychic manifestations
• Bipolar affective disorder
• Neuralgia

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Known hypersensitivity to structurally related medicines e.g. tricyclic antidepressants
• Patients with atrioventricular block
• Patients with a history of bone-marrow depression
• Patients with a history of porphyria e.g. acute intermittent porphyria, variegate porphyria
• Mothers taking carbamazepine should not breastfeed their infants
• Previous Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)
• Coadministration with monoamine-oxidase inhibitors or within 2 weeks of discontinuation of MAOIs
• Neonates below 4 weeks of age for term babies or below 44 weeks post-menstrual age for pre-term babies or equivalent preterm age based on a local-specific premature corrected age calculator (due to the amount of propylene glycol (PG) contained in this formulation) (sus)

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Known hypersensitivity to structurally related medicines e.g. tricyclic antidepressants
• Patients with atrioventricular block
• Patients with a history of bone marrow depression
• Presence of bone marrow damage (srt)
• Hepatic porphyria (srt)
• Patients with a history of hepatic porphyrias e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda
• Coadministration with monoamine oxidase inhibitors

Cautions

• Pregnancy
• Breastfeeding (Recommendations in other jurisdictions)
• Severe renal impairment
• Hepatic impairment
• Elderly
• Males of reproductive potential
• HLA-B*1502 allele
• HLA-A*3101 allele
• Asian ethnic group
• Mixed seizures
• Abrupt withdrawal
• Cardiovascular disease
• Hypothyroidism
• Increased intraocular pressure
• Urinary retention
• Fructose intolerance
• May impair the ability to drive and operate machinery

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

South African registered indications and dosages

Epilepsy with motor and psychic manifestations
- Psychomotor or temporal-lobe epilepsy
- Generalised tonic-clonic seizure
- Mixed forms of seizures
- Complex or simple partial seizures (with or without loss of consciousness) with or without secondary generalisation

• Oral (srt, tab): Initial: 100-200mg, once or twice daily; Titrate slowly until an optimal effect is obtained, usually at a level of 400mg, 2-3 times daily; In some instances, up to 1600mg in 3-4 divided doses may be necessary
• Oral (sus): Initial: 100-200mg, once or twice daily; Titrate slowly until an optimal effect is obtained, usually at a level of 400mg, 2-3 times daily; In some instances, up to 1200mg in 3-4 divided doses may be necessary; Max: 1200mg/day

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Treatment should be initiated with low daily dosage, to be slowly increased until an optimal effect is obtained. Determination of plasma levels may help in establishing the optimum dosage

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Carbamazepine is preferably prescribed as monotherapy for epilepsy. When adding carbamazepine to existing anti-epileptic therapy, do it gradually while maintaining or adapting the dosage of other anti-epileptic(s)

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Carbamazepine is usually not effective in absences (petit mal) and myoclonic seizures

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Bipolar affective disorder
- Acute mania and maintenance treatment of bipolar affective disorders to prevent or attenuate recurrence

• Oral (srt, tab): Dosage range: Approx. 400-1600mg daily; Usual dose range: 400-600mg daily in 2-3 divided doses; In acute mania, increase the dosage quickly; For maintenance therapy of bipolar disorders, small dosage increments are recommended to ensure optimal tolerability
• Oral (sus): Dosage range: Approx. 400-1200mg daily; Usual dose range: 400-600mg daily in 2-3 divided doses; In acute mania, increase the dosage quickly; For maintenance therapy of bipolar disorders, small dosage increments are recommended to ensure optimal tolerability; Max: 1200mg/day

Idiopathic trigeminal neuralgia

• Oral (srt, tab): Initial: 200-400mg daily; Titrate slowly daily until freedom from pain is achieved, usually at 200mg, 3-4 times daily; In some instances, up to 1600mg daily may be necessary; Gradually reduce the dosage to the lowest possible maintenance level
• Oral (sus): Initial: 200-400mg daily; Titrate slowly daily until freedom from pain is achieved, usually at 200mg, 3-4 times daily; In some instances, up to 1200mg daily may be necessary; Gradually reduce the dosage to the lowest possible maintenance level; Max: 1200mg/day

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Carbamazepine is suitable for both monotherapy and combination therapy

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Directions for use: The tablets, slow-release tablets and suspension may be taken during, after, or between meals
Slow-release tablet: As a result of slow, controlled release of the active substance from the slow-release tablets, these are designed to be taken in a twice daily dosage regimen and should be swallowed whole with adequate amount of fluid
Suspension: The suspension is particularly suitable for elderly patients as the liquid form affords easier and more flexible dosage. Since a given dose of the suspension produces higher peak levels than the same dose in tablet form, therapy should be started with low doses and should be increased slowly to avoid adverse reactions

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Dosage should be as low as is consistent with a satisfactory effect. Blood plasma levels can be used to help establish the optimum dose. Usually the optimum therapeutic plasma levels range between 4-12µg/ml (16-50µmol/l). When the patient is transferred from another anticonvulsant medicine to carbamazepine, the dosage of the first should be reduced gradually

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Switching patients between dosage forms of carbamazepine
From tablets to suspension: Administer the same daily dose in smaller, more frequent doses
From conventional tablets to slow-release tablets: Clinical experience indicates that dosage may need to be increased in some patients

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Important Medicine Safety Information
Change in the maximum daily dose for carbamazepine oral suspension to 1200mg/day due to the potential risks associated with ethylene glycol, which is a by-product of sorbitol (an excipient used in the product)
Click here for details

Paed. forms avail. in SA and covered in this monograph: sus

South African registered indications and dosages

Epilepsy with motor and psychic manifestations
- Psychomotor or temporal-lobe epilepsy
- Generalised tonic-clonic seizure
- Mixed forms of seizures
- Complex or simple partial seizures (with or without loss of consciousness) with or without secondary generalisation

Neonates <4 weeks of age for term babies or below 44 weeks post-menstrual age for pre-term babies or equivalent preterm age based on a local-specific premature corrected age calculator

• Contraindicated

Between ≥4 weeks to 4 years of age

• Oral (sus): Initial: 20-60mg, dly; Increase by 20-60mg, every second day; Maintenance: 10-20mg/kg body weight, dly in divided doses (see table below)

Older than 4 years

• Oral (sus): Initial: 100mg, dly; Increase by 100mg at weekly intervals; Maintenance: 10-20mg/kg body weight, dly in divided doses (see table below)

Age band	Dosage: Oral (sus)
Between ≥4 weeks to 1 year	100–200mg, dly
Between 1-5 years	200–400mg, dly
Between 6-10 years	400–600mg, dly
Between 11-15 years	600–1000mg, dly

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Treatment should be initiated with low daily dosage, to be slowly increased until an optimal effect is obtained. Determination of plasma levels may help in establishing the optimum dosage

---

Carbamazepine is preferably prescribed as monotherapy for epilepsy. When adding carbamazepine to existing anti-epileptic therapy, do it gradually while maintaining or adapting the dosage of other anti-epileptic(s)

---

Carbamazepine is usually not effective in absences (petit mal) and myoclonic seizures

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Directions for use
The suspension is particularly suitable for infants and small children as the liquid form affords easier and more flexible dosage. It may be taken during, after, or between meals. Since a given dose of the suspension produces higher peak levels than the same dose in tablet form, therapy should be started with low doses and should be increased slowly to avoid adverse reactions

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Important Medicine Safety Information
Change in the maximum daily dose for carbamazepine oral suspension due to the potential risks associated with ethylene glycol, which is a by-product of sorbitol (an excipient used in the product)
Click here for details

Updated limitation of use for carbamazepine oral suspension due to the risk associated with the excipient propylene glycol (PG)
Click here for details

Pregnancy

South African recommendations

• Caution; positive evidence of risk
• Offspring of epileptic mothers are more prone to developmental disorders, including malformations
• Developmental disorders and malformations, such as spina bifida, craniofacial defects, cardiovascular malformations, hypospadias, and other body system anomalies, have been associated with carbamazepine use
• Patients should be informed about the increased risk of malformations and offered antenatal screening
• Pregnant women with epilepsy require special attention
• If women taking carbamazepine become pregnant or plan to, or if the need arises to start carbamazepine during pregnancy, the benefits and risks of the medication should be carefully considered, especially in the first 3 months
• Carbamazepine should ideally be prescribed as monotherapy to women of childbearing potential. The risk of congenital abnormalities is higher with combination antiepileptic therapy, especially combinations that include valproate
• Use the minimum effective dose and monitor plasma levels. The risk of malformation with carbamazepine may be dose-dependent. Lower doses (<400mg/day) have lower malformation rates than higher doses
• Effective antiepileptic treatment should not be interrupted during pregnancy, as worsening of the condition can harm both the mother and foetus
• Animal studies have shown reproductive toxicity with carbamazepine
• Women of childbearing potential / Contraception in males and females: Carbamazepine may reduce the effectiveness of oral contraceptives containing oestrogen and/or progesterone due to enzyme induction. Women of childbearing potential should use alternative contraceptive methods while on treatment with carbamazepine
• Monitoring and Prevention
  • Antiepileptic medications, including carbamazepine, can exacerbate folic acid deficiency during pregnancy, increasing the risk of birth defects. Folic acid supplementation is recommended before and during pregnancy
  • To prevent bleeding disorders in the newborn, vitamin K1 should be administered to the mother in the last weeks of pregnancy and to the neonate
  • Neonatal seizures, respiratory depression, vomiting, diarrhoea, and decreased feeding have been associated with maternal carbamazepine use, potentially indicative of a neonatal withdrawal syndrome

Recommendations in other jurisdictions

• Caution; positive evidence of risk
• Women of childbearing potential taking antiepileptic treatment should receive specialist medical advice about the risks to a foetus from seizures and antiepileptic treatment
• Sudden discontinuation of antiepileptic drug (AED) therapy can lead to seizures with potential harm to the mother and unborn child
• Monotherapy is recommended during pregnancy as multiple AEDs can increase the risk of congenital malformations compared to monotherapy
• Carbamazepine crosses the placenta in humans
• Children born to mothers with epilepsy treated with carbamazepine during the first trimester have an increased risk of major congenital malformations
• Common malformations associated with carbamazepine include neural tube defects, craniofacial defects, cardiovascular malformations, genitourinary tract defects, skeletal malformations, and other body system anomalies
• Around 4.93% of children exposed to carbamazepine monotherapy during the first trimester have congenital malformations, higher than the general population rate of 2-3%
• Specialized antenatal surveillance for these malformations is recommended
• Carbamazepine use during pregnancy doesn't negatively impact intelligence, developmental outcomes, or symptoms/diagnoses of autism spectrum disorders in the child
• Carbamazepine should only be used during pregnancy if the benefits outweigh the risks, with the patient fully informed of the risks
• The risk of malformation with carbamazepine may be dose-dependent. Lower doses (<400mg/day) have lower malformation rates than higher doses
• If carbamazepine is continued, use monotherapy and the lowest effective dose with monitoring of plasma levels
• Carbamazepine and other antiepileptic drugs can decrease serum folate levels, potentially increasing birth defect risks. Folic acid supplementation is recommended before and during pregnancy
• Vitamin K1 should be given to the mother in the last weeks of pregnancy and to the neonate to prevent bleeding disorders in the offspring
• If planning a pregnancy, consider switching to an alternative treatment before conception
• If a woman becomes pregnant while on carbamazepine, a specialist should reassess the treatment and consider alternative options

Breastfeeding

South African recommendations

• Contraindicated
• Carbamazepine passes into the breast milk (about 25-60% of plasma concentration). Mothers taking carbamazepine should not breastfeed their infants

Recommendations in other jurisdictions

• Caution
• Carbamazepine and its active metabolite are excreted in breast milk (milk/plasma concentration ratios of 0.24 to 0.69). However, the benefits of breastfeeding should be weighed against the small risk of side effects in the infant
• Carbamazepine may be taken during breastfeeding, provided the breastfed infant is observed for possible adverse effects (decreased weight gain, sedation, allergic skin reactions). If such effects occur, breastfeeding should be discontinued. There have been a few reports of cholestatic hepatitis in neonates exposed to carbamazepine prenatally or during breastfeeding. Therefore, breast-fed infants whose mothers are being treated with carbamazepine should be carefully monitored for adverse hepatobiliary side effects

Fertility

South African recommendations

• There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis

Recommendations in other jurisdictions

• There have been isolated cases of sexual dysfunction, such as impotence or decreased libido. There have been very rare reports of decreased male fertility and/or abnormal spermatogenesis

• Caution; dose adjustment recommended

CrCl (ml/min)	Oral Dose
> 10	No adjustment necessary
< 10	Administer 75% of the recommended dose
Haemodialysis	Administer 75% of the recommended dose; After dialysis

 

GFR (ml/min)	IV Dose
≥ 60	No adjustment necessary; monitor closely
15-59	Avoid use
< 15	Has not been studied

• Caution; no information available

• Caution; dose adjustment recommended
  Trigeminal neuralgia: Initial: 100mg, 12hrly; Up-titrate slowly at intervals of 24hrs to a dosage of 200mg, 6-8hrly; Down-titrate gradually to the lowest possible maintenance level; Max: 1200mg/24hrs
  When pain relief has been obtained, attempts should be made to gradually discontinue therapy, until another attack occurs
  Manic depressive disorders: Initial: 400mg, dly in divided doses; Up-titrate gradually until symptoms are controlled; Maintenance (usual dosage range): 400-600mg, dly; Max: 1600mg/24hrs

Central Nervous System Disorders

• Hallucinations
• Depression
• Aggression
• Agitation
• Restlessness
• Confusional state
• Activation of psychosis
• Ataxia
• Dizziness
• Somnolence
• Diplopia
• Headache
• Abnormal involuntary movements 
• Nystagmus
• Dyskinesia
• Eye movement disorder
• Speech disorders 
• Choreoathetosis
• Neuropathy peripheral
• Paraesthesia and paresis
• Neuroleptic malignant syndrome
• Aseptic meningitis with myoclonus and peripheral eosinophilia
• Dysgeusia
• Sedation
• Memory impairment

Cardiovascular Disorders

• Cardiac conduction disorders
• Arrhythmia
• Atrioventricular block with syncope
• Bradycardia
• Cardiac failure congestive
• Coronary artery disease aggravated
• Hypertension
• Hypotension
• Circulatory collapse
• Embolism 
• Thrombophlebitis

Respiratory Disorders

• Pulmonary hypersensitivity 

Gastrointestinal Disorders

• Nausea and vomiting
• Dry mouth
• Diarrhoea
• Constipation
• Abdominal pain
• Pancreatitis
• Glossitis 
• Stomatitis
• Colitis

Hepatobiliary Disorders

• Hepatitis of cholestatic, parenchymal or mixed type
• Vanishing bile duct syndrome
• Jaundice
• Hepatic failure
• Granulomatous liver disease

Genitourinary Disorders

• Tubulointerstitial nephritis
• Renal failure
• Renal impairment 
• Urinary retention
• Urinary frequency
• Sexual disturbances
• Erecticle dysfunction 
• Abnormal spermatogenesis 

Endocrine and Metabolic Disorders

• Oedema
• Fluid retention
• Increased weight 
• Hyponatraemia and decreased blood osmolarity due to an antidiuretic hormone-like effect
• Folate deficiency
• Decreased appetite
• Porphyria 

Musculoskeletal Disorders

• Muscular weakness
• Bone metabolism disorders 

Skin and Subcutaneous Tissue Disorders

• Urticaria
• Exfoliative dermatitis  
• Systemic lupus erythematosus
• Pruritus
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Photosensitivity reaction
• Erythema multiforme
• Erythema nodosum
• Pigmentation disorder
• Purpura
• Acne
• Hyperhydrosis
• Alopecia
• Hirsutism
• Acute generalized exanthematous pustulosis 
• Lichenoid keratosis
• Onychomadesis

Immune, Blood and Lymphatic System Disorders

• Leucopenia
• Thrombocytopenia
• Eosinophilia 
• Leucocytosis
• Lymphadenopathy
• Agranulocytosis
• Aplastic 
• Anaemia
• Pancytopenia 
• Pure red cell aplasia 
• Anaemia
• Megaloblastic anaemia 
• Reticulocytosis
• Haemolytic anaemia
• Bone marrow depression
• Delayed multi-organ hypersensitivity disorder 
• Anaphylactic reaction
• Oedema angioedema
• Hypogammaglobulinaemia
• Drug rash with eosinophilia and systemic symptoms (DRESS)

Sensory Disorders

• Accommodation disorders 
• Lenticular opacities
• Conjunctivitis
• Hearing disorders

• CYP3A4 inducers
• CYP3A4 inhibitors
• Monoamine oxidase inhibitors
• Oral contraceptives
• Levetiracetam
• Isoniazid
• Lithium
• Metoclopramide
• Major tranquillisers
• Diuretics
• Non-depolarising muscle relaxants
• Alcohol

None routine. Specific cases may require

• Full blood count
• Serum sodium levels
• Carbamazepine plasma levels
• Thyroid function
• Renal function
• Urinalysis

Carbamazepine stabilises hyperexcited nerve membranes, inhibits repetitive neuronal discharges, and reduces synaptic propagation of excitatory impulses. It inhibits repetitive firing of sodium-dependent action potentials in depolarised neurons, via use- and voltage-dependent blockade of sodium channels. Pain relief is associated with blockade of synaptic transmission in the trigeminal nucleus and seizure control with reduction of post-tetanic potentiation of synaptic transmission in the spinal cord. 

Tablet 200mg

• Carbamazepine 200 Unimed (Unimed Healthcare)
• Degranol (Pharmacare)
• Gulf Carbamazepine (Gulf)
• Sandoz Carbamazepine (Sandoz)
• Tegretol (Novartis) originator
• Zecarb 200 (Pharma-Q)
• Zeptol (Ranbaxy)

Tablet CR 200mg

• Sandoz Carbamazepine (Sandoz)
• Tegretol (Novartis) originator

Tablet CR 400mg

• Sandoz Carbamazepine (Sandoz)
• Tegretol (Novartis) originator

Suspension (per 5ml) 100mg

• Tegretol S (Novartis) originator