Carbamazepine

ADMINISTRATION ROUTES:

PO, NG

ALTERNATIVE NAMES:

Tegretol

ICU INDICATIONS:

1. Epilepsy

2. Trigeminal neuralgia and other neuropathic pain

Note: this medication is usually prescribed in ICU patients who were taking it for a pre-existing indication prior to admission. It may occasionally be commenced de novo in patients with new seizures or neurogenic pain but is not first line therapy for either of these conditions

PRESENTATION AND ADMINISTRATION:

PO / NG:

Tegretol 200 mg and 400 mg tablets (white) Tegretol CR tablets 200 mg (beige/orange) and 400 mg (brown/orange) Tegretol syrup 100 mg/5 mL (white)

Tegretol liquid is available for NG administration – it should be diluted in equal parts with water to prevent possible adsorption

DOSAGE:

PO/NG:

Epilepsy

Initial:

Either 200 mg BD for tablets and extended-release tablets or 100 mg QID for suspension

Increase at weekly intervals by adding up to 200 mg/day using a BD regimen of extended-release or TDS or QID regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1200 mg daily. Doses up to 1600 mg daily have been used in adults in rare instances

Maintenance:

Adjust dosage to the minimum effective level, usually 800-1200 mg daily

Trigeminal neuralgia and other neuropathic pain

Initial:

On first day 100 mg BD for tablets or extended-release tablets or 50 mg QID for suspension. Total daily dose 200 mg

Daily dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours for tablets or extended-release tablets or 50 mg QID for suspension, only as needed to achieve freedom from pain. Do not exceed 1200 mg/daily

Maintenance:

Control of pain can be maintained in most patients with 400-800 mg daily

Some patients may be maintained on as little as 200 mg daily, others may require up to 1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level, or even to discontinue the drug.

Carbamazepine suspension produces higher peak levels than the same dose given as the tablet. It is recommended that patients given suspension be dosed in lower doses, given more frequently.

For conversion of patients from oral carbamazepine tablets to carbamazepine suspension, administer the same number of mg/day in smaller, more frequent doses (change dosing from twice daily to three times daily).

When converting patients from carbamazepine conventional tablets to carbamazepine extended-release tablets, the same total daily mg dose of carbamazepine extended-release should be administered.

DOSAGE IN RENAL FAILURE AND RENAL REPLACEMENT THERAPY:

Dose as in normal renal function

DOSAGE IN PAEDIATRICS:

2 mg/kg TDS. May increase over 2-4 weeks to 5-10 mg/kg TDS

CLINICAL PHARMACOLOGY:

Carbamazepine is an anticonvulsant and mood-stabiliser. It stabilises the inactivated state of voltage-gated sodium channels, meaning less are subsequently available to open. The affected cells are then less excitable until the drug dissociates

CONTRAINDICATIONS:

1. History of previous bone marrow depression,

2. Hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc.

WARNINGS:

The most serious complications of carbamazepine are those of bone marrow depression including aplastic anaemia, agranulocytosis, & pancytopaenia. Patients with a history of adverse haematologic reaction to any drug may be particularly at risk. Severe dermatologic reactions including toxic epidermal necrolysis and Stevens- Johnson syndrome, have been reported with carbamazepine.

Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.

PRECAUTIONS:

General:

Carbamazepine suspension produces higher peak levels than the same dose given as the tablet, therefore it is recommended that patients given the suspension be dosed in lower doses more given more frequently

Hyponatraemia has been reported in association with carbamazepine use, either alone or in combination with other drugs.

Cessation of carbamazepine may lead to seizures.

Laboratory Tests:

Carbamazepine levels (collect in red or yellow tube). Measure levels if there is concern about non-compliance or toxicity.

Induces its own metabolism so following initiation of therapy takes 2-4 weeks to reach steady state.

Measure trough levels (i.e. immediately pre-dose). Therapeutic range is 16-50 micmol/L

Potentially toxic levels and associated clinical features:

Drug/Laboratory Test Interactions :

Interference with some pregnancy tests has been reported

IMPORTANT DRUG INTERACTIONS IN ICU:

Carbamazepine may be used alone or with other anticonvulsants. When added to existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased, except phenytoin, which may have to be increased.

Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following:

CYP 3A4 inhibitors inhibit carbamazepine metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include diltiazem, erythromycin, clarithromycin, fluoxetine, loratadine, terfenadine, isoniazid, verapamil, & valproate.

CYP 3A4 inducers can increase the rate of carbamazepine metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include cisplatin, doxorubicin, rifampin, phenobarbital, phenytoin, & theophylline.

ADVERSE REACTIONS:

The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimise the possibility of such reactions, therapy should be initiated at the low dosage recommended

Body as a whole:

Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopaenia, eosinophilia, hepato-splenomegaly and abnormal liver function tests

Haemopoietic System:

Aplastic anaemia, agranulocytosis, pancytopaenia, bone marrow depression, thrombocytopaenia, leukopaenia, leukocytosis, eosinophilia, acute intermittent porphyria

Skin:

Pruritic and erythematous rashes, urticaria, toxic epidermal necrolysis, Stevens- Johnson syndrome, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, and diaphoresis

Cardiovascular System:

Congestive heart failure, oedema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism, and adenopathy or lymphadenopathy

Gastrointestinal System:

Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of hepatic failure, pancreatitis, nausea, vomiting, gastric distress and abdominal pain, diarrhoea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis

Musculoskeletal System:

Aching joints and muscles, and leg cramps

Respiratory System:

Pulmonary hypersensitivity characterised by fever, dyspnoea, pneumonitis or pneumonia

Genitourinary System:

Renal failure

Nervous System:

Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paraesthesias, depression with agitation, talkativeness, tinnitus, and hyperacusis