Carbamazepine and Oxcarbazepine

• Carbamazepine is a drug of choice for simple and complex partial seizures and for tonic-clonic generalised seizures secondary to a focal discharge.
• It has a wider therapeutic index and usually has fewer side-effects than phenytoin.
• Controlled-release carbamazepine is better tolerated than the standard formulation and can be prescribed once or twice daily in all patients.

Indications

• Carbamazepine is indicated for partial and secondary generalised tonic-clonic seizures, and also some primary generalised seizures.
• It is not effective for patients with absences and myoclonic seizures.
• Carbamazepine is also indicated for trigeminal neuralgia and prophylaxis of bipolar disorder unresponsive to lithium.

Contraindications

• AV conduction abnormalities (unless paced)
• History of bone marrow depression
• Porphyria

Cautions

• Leucopenia (may be severe and progressive, and require withdrawal of the drug)
• Hepatic impairment (impaired metabolism in severe liver disease)
• Renal impairment
• Cardiac disease
• Skin reactions
• History of haematological reactions to other drugs
• Glaucoma
• Pregnancy:
  • First trimester: increased risk of neural tube and other defects
  • Third trimester: may cause vitamin K deficiency and risk of neonatal bleeding
• Avoid abrupt withdrawal

Patients or their carers should be told how to recognise signs of blood, liver, or skin disorders, and advised to seek immediate medical attention if symptoms such as fever, sore throat, rash, mouth ulcers, bruising, or bleeding develop.

Important interactions

• As well as inducing its own metabolism, carbamazepine can accelerate clearance of a number of other lipid-soluble drugs including the oral contraceptive pill, necessitating, for most women, a daily oestrogen dose of 50 mcg or more. Other affected drugs include sodium valproate, ethosuximide, corticosteroids, anticoagulants, antipsychotics and cyclosporin.
• Drugs that inhibit carbamazepine metabolism and which may result in toxicity include phenytoin, cimetidine, danazol, dextropropoxyphene, diltiazem, erythromycin, isoniazid, verapamil and viloxazine.
• The less common neurotoxic interaction with lithium (confusion, disorientation, drowsiness, ataxia, tremor, hyperreflexia) is not associated with altered concentrations of either drug.

Common problems

• Diplopia, rash, headache, dizziness, nausea and vomiting are the commonest side effects of carbamazepine.
• Peak levels often result in intermittent side effects occurring around two hours after dosing, necessitating administration three or four times daily in some patients. These problems can be overcome by prescribing the controlled-release formulation, which can be given once or twice daily.

Other side-effects

• Carbamazepine can cause a range of idiosyncratic reactions, the most common of which is a rash, occurring in up to 10% of patients. Slow dosage titration may reduce the risk. Rarely it may cause more severe skin eruptions including erythema multiforme and Stevens-Johnson syndrome.
• Reversible mild leucopenia often occurs but does not require discontinuation of therapy unless accompanied by evidence of infection or if the cell count is well below 2 x 109/L. Blood dyscrasias and toxic hepatitis occur very rarely.
• At high levels, the drug has an antidiuretic hormone-like action that can result in fluid retention in patients with cardiac failure and in the elderly.
• Mild hyponatraemia is usually asymptomatic, but if the serum sodium falls below 125 mmol/L the patient may present with confusion, peripheral oedema and worsening seizure control.
• Orofacial dyskinesias and cardiac arrhythmias are other occasional complications.

Initiation

• It is essential to initiate carbamazepine therapy at a low dose and build this up slowly with increments of 100-200 mg every two weeks. This allows tolerance to develop to its CNS side effects.
• The dose can then be increased in 1-2 weekly increments of 100-200mg/day to a maintenance amount that completely controls the seizure disorder.
• The usual dose is 0.4–1.2 g daily in divided doses. Maximum recommended dose is 1.6g daily but up to 2g daily may be required for epilepsy control.

Monitoring

• The dose of carbamazepine is a poor guide to serum levels, and so drug level monitoring can be helpful when complete seizure control is not readily obtained. Plasma concentration for optimum response is 4-12 mg/litre (20-50 micromol/litre).
• Steady-state blood levels are only achieved after 20 days.
• Due to substantial variation in blood levels, sampling should ideally be undertaken just before the next scheduled dose.
• In most patients, the dosage can be titrated adequately on clinical criteria alone. Exceptions include patients with learning disabilities, suspicion of poor compliance, and those taking more than one antiepileptic drugs which are likely to interact.
• Saliva drug concentrations have been observed to be very close to that of free plasma concentrations.

• Oxcarbazepine, the 10-keto analogue of carbamazepine, has a similar mechanism of action to carbamazepine.
• Indications are very similar to those of carbamazepine. Oxcarbazepine is licensed for the treatment of partial seizures with or without secondarily generalised tonic-clonic seizures.
• Oxcarbazepine may worsen absences and myoclonic seizures.
• Oxcarbazepine induces hepatic enzymes to a lesser extent than carbamazepine.
• Oxcarbazepine is approximately 40% bound to plasma proteins and is mainly eliminated by conjugation.
• Compared to carbamazepine, oxcarbazepine exhibits a smaller pharmacokinetic variability and a lower susceptibility to drug interactions. The metabolism of oxcarbazepine is enhanced by enzyme-inducing antiepileptic drugs.

• Oxcarbazepine is licensed for use in adults and children over the age of 6 with partial seizures, as monotherapy or alongside other antiepileptic drugs.

• Porphyria

Cautions

• Hypersensitivity to carbamazepine
• Avoid abrupt withdrawal
• Elderly
• Hyponatraemia (monitor plasma-sodium concentration in patients at risk)
• Heart failure (monitor body-weight)
• Cardiac conduction disorders
• Renal impairment (reduce dose in severe renal impairment)
• Pregnancy:
  • First trimester: increased risk of neural tube and other defects
  • Third trimester: may cause vitamin K deficiency and risk of neonatal bleeding

Patients or their carers should be told how to recognise signs of blood, liver, or skin disorders, and advised to seek immediate medical attention if symptoms such as lethargy, confusion, muscular twitching, fever, sore throat, rash, blistering, mouth ulcers, bruising, or bleeding develop.

Important interactions

• Oxcarbazepine only weakly induces hepatic enzymes, and so is likely to have fewer drug interactions than carbamazepine. In adjunctive therapy, the dose of concomitant antiepileptics may need to be reduced when using high doses of oxcarbazepine.
• A high dose of the oral contraceptive pill is advised to give protection against pregnancy.

Common problems

• Oxcarbazepine exhibits less autoinduction than carbamazepine.
• Its safety profile is very similar to that of carbamazepine apart from hyponatraemia, which is more pronounced with oxcarbazepine, and allergic skin reactions which are less common.
• Cross-sensitivity is seen in less than one-third of patients hypersensitive to carbamazepine.
• There are indications of teratogenicity in animal models, particularly at high doses, and caution should be used in humans.

Initiation

• The recommended dose is between 600 and 2400 mg/day divided into two doses.
• Oxcarbazepine should be started at 300 mg/day and increased by 300 mg/day each week, up to 900 mg/day in the first instance.

Monitoring

• The current target range is 50-110 mcmol/L.
• Oxcarbazepine is measurable in saliva but the relationship between plasma and saliva concentrations has not been established to date.