NEUPAX

Carbamazepine, also known as Tegretol, is an anticonvulsant drug and analgesic drug used to control seizures and to treat pain resulting from trigeminal neuralgia.

It was initially approved by the

FDA in 1965.

Aside from the above uses, this drug is also given to control the symptoms of bipolar 1.

Interestingly, carbamazepine was the first anticonvulsant used to treat individuals with bipolar disorder.

Carbamazepine is indicated for the treatment of epilepsy and pain associated with true trigeminal neuralgia.

In particular, carbamazepine has shown efficacy in treating mixed seizures, partial seizures with complex symptoms, and generalized tonic-clonic seizures. 3, 16 Carbamazepine is also indicated for the treatment of manic episodes and mixed manic-depressive episodes caused by bipolar I disorder.

Some off-label, unapproved uses of carbamazepine include the treatment of alcohol withdrawal syndrome and restless leg syndrome. 9,

General effects

Carbamazepine treats seizures and the symptoms of trigeminal neuralgia by inhibiting sodium channels.

In bipolar 1 disorder, carbamazepine has been found to decrease mania symptoms in a clinically significant manner according to the Young Mania Rating Scale (YMRS).

Carbamazepine has a narrow therapeutic index.

A note on genetic variation and carbamazepine use In studies of Han Chinese ancestry patients, a pronounced association between the HLA-B*1502 genotype and Steven Johnson syndrome and/or toxic epidermal necrolysis (SJS/TEN) resulting from carbamazepine use was observed.

The bioavailability of carbamazepine is in the range of 75-85% of an ingested dose.

After one 200 mg oral extended-release dose of carbamazepine in a pharmacokinetic study, the Cmax carbamazepine was measured to be 1.9 ± 0.3 mcg/mL.

Tmax was 19 ± 7 hours.

After several doses of 800 mg every 12 hours, the peak concentrations of carbamazepine were measured to be 11.0 ± 2.5 mcg/mL.

Tmax was reduced to 5.9 ± 1.8 hours.

Extended-release carbamazepine demonstrated linear pharmacokinetics over a range of 200–800 mg.

Effect of food on absorption

A meal containing high-fat content increased the rate of absorption of one 400 mg dose but not the AUC of carbamazepine.

The elimination half-life remained unchanged between fed and fasting state.

The pharmacokinetics of an extended-release carbamazepine dose was demonstrated to be similar when administered in the fasted state or with food.

Based on these findings, food intake is unlikely to exert significant effects on carbamazepine absorption.

The volume of distribution of carbamazepine was found to be 1.0 L/kg in one pharmacokinetic study.

Another study indicates that the volume of distribution of carbamazepine ranges between 0.7-1.4 L/kg. 11.

Carbamazepine crosses the placenta, and higher concentrations of this drug are found in the liver and kidney as opposed to lung and brain tissue.

Carbamazepine crosses variably through the blood-brain barrier.

Carbamazepine is largely metabolized in the liver.

CYP3A4 hepatic enzyme is the major enzyme that metabolizes carbamazepine to its active metabolite, carbamazepine-10,11-epoxide 12, which is further metabolized to its trans-diol form by the enzyme epoxide hydrolase.

Other hepatic cytochrome enzymes that contribute to the metabolism of carbamazepine are CYP2C8, CYP3A5, and CYP2B6.

Carbamazepine also undergoes hepatic glucuronidation by

UGT2B7 enzyme and several other metabolic reactions occur, resulting in the formation of minor hydroxy metabolites and quinone metabolites.

Interestingly, carbamazepine induces its own metabolism.

This leads to enhanced clearance, reduced half-life, and a reduction in serum levels of carbamazepine. 3, 16 Hover over products below to view reaction partners Carbamazepine 10,11-Epoxycarbamazepine 10,11-Dihydroxycarbamazepine 3-hydroxycarbamazepine 2,3-Dihydroxycarbamazepine Carbamazepine-o-quinione Carbamazepine 2,3-epoxide 2-hydroxycarbamazepine 2-hydroxyiminostilbene Iminoquinone.

After an oral dose of radiolabeled carbamazepine, 72% of the administered radioactive dose was detected in the urine and the remainder of the ingested dose was found in the feces.

Carbamazepine is mainly excreted as hydroxylated and conjugated metabolites, and minimal amounts of unchanged drug.

The mean elimination half-life of carbamazepine was 35-40 hours after one dose of carbamazepine extended-release formulations.

The half-life ranged from 12-17 hours after several doses of carbamazepine.

One pharmacokinetic study determined the elimination half-life of carbamazepine to range between 27-36.8 hours in healthy volunteers.

In a pharmacokinetic study, the apparent oral clearance of carbamazepine was 25 ± 5 mL/min 11, 16 after one dose of carbamazepine and 80 ± 30 mL/min after several doses.

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LDLO (female): 1920 mg/kg/17W (intermittent); Oral LDLO (male): 54 mg/kg/9D (intermittent) 18 Oral LD50 (rat): 1957 mg/kg 18 Overdose information The initial signs of carbamazepine overdose occur 1-3 hours post ingestion.

These signs and symptoms may vary in case of an overdose between carbamazepine and other drugs.

Carbamazepine may cause various cardiovascular, neurological, respiratory, urinary symptoms as well as laboratory abnormalities including leukocytosis, reduced leucocytes, acetonuria, and glycosuria.

Neuromuscular symptoms may occur initially, followed by mild cardiac symptoms such as tachycardia, hypertension, or hypotension.

Higher doses of carbamazepine may cause more severed cardiovascular effects.

Restlessness, muscular twitching, tremor, dilated pupils, nystagmus, psychomotor disturbances, and other neurological symptoms may occur.

Hyperreflexia in the initial stages of overdose may be followed by hyporeflexia.

Nausea, vomiting, urinary retention, dizziness or drowsiness may also occur.

In cases of overdose, contact the local poison control center.

Ensure to provide supportive and symptomatic treatment, which may include monitoring and careful supervision by a medical professional.

The possibility of overdose with multiple drugs must be considered in the case of carbamazepine overdose.

Maintain an adequate airway, oxygen, in addition to ventilation.

Carbamazepine should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc.

Likewise, on theoretical grounds its use with monoamine oxidase (MAO) inhibitors is not recommended.

Before administration of carbamazepine, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits.

Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect.

Coadministration of carbamazepine with nefazodone is contraindicated.

Carbamazepine suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation, and, in the case of chlorpromazine, there has been a report of patient passing an orange rubbery precipitate in the stool following coadministration of the two drugs.

Because the extent to which this occurs with other liquid medications is not known, Carbamazepine suspension should not be administered simultaneously with other liquid medications or diluents.

Monitoring of blood levels has increased the efficacy and safety of anticonvulsants.

Dosage should be adjusted to the needs of the individual patient.

A low initial daily dosage with a gradual increase is advised.

As soon as adequate control is achieved, the dosage may be reduced very gradually to the minimum effective level.

Medication should be taken with meals.

Since a given dose of

Carbamazepine suspension will produce higher peak levels than the same dose given as the tablet, it is recommended to start with low doses (children to 12 years: ½ teaspoon four times a day and to increase slowly to avoid unwanted side effects. Conversion of patients from oral Carbamazepine tablets to Carbamazepine suspension: Patients should be converted by administering the same number of mg per day in smaller, more frequent doses (i.e., twice a day tablets to three times a day suspension).

Tegretol-XR is an extended-release formulation for twice a day administration.

When converting patients from Carbamazepine conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be administered.

Tegretol-XR tablets must be swallowed whole and never crushed or chewed.

Tegretol-XR tablets should be inspected for chips or cracks.

Damaged tablets, or tablets without a release portal, should not be consumed.

Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be noticeable in the stool.

Adults and children over 12 years of age-Initial: Either 200 mg twice a day for tablets and XR tablets, or 1 teaspoon four times a day for suspension (400 mg/day).

Increase at weekly intervals by adding up to 200 mg/day using a twice a day regimen of Tegretol-XR or a three times a day or four times a day regimen of the other formulations until the optimal response is obtained.

Dosage generally should not exceed 1000 mg daily in children to 15 years of age, and 1200 mg daily in patients above 15 years of age.

Doses up to 1600 mg daily have been used in adults in rare instances.

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

Children to 12 years of age-Initial: Either 100 mg twice a day for tablets or XR tablets, or ½ teaspoon four times a day for suspension (200 mg/day).

Increase at weekly intervals by adding up to 100 mg/day using a twice a day regimen of Tegretol-XR or a three times a day or four times a day regimen of the other formulations until the optimal response is obtained.

Dosage generally should not exceed 1000 mg daily.

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

Children under 6 years of age-Initial: 10 to 20 mg/kg/day twice a day or three times a day as tablets, or four times a day as suspension.

Increase weekly to achieve optimal clinical response administered three times a day or four times a day. Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range.

No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be made.

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.

On the first day, either 100 mg twice a day for tablets or XR tablets or ½ teaspoon four times a day for suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours for tablets or XR tablets, or 50 mg (½ teaspoon) four times a day for suspension, only as needed to achieve freedom from pain.

Do not exceed 1200 mg daily.

Control of pain can be maintained in most patients with to 800 mg daily.

However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 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.

Dosage Information Initial Dose Subsequent Dose MaximumDaily Dose Indication Tablet XR † Suspension Tablet XR † Suspension Tablet XR † Suspension Epilepsy Under 6 yr 10-20 mg/kg/day twice a day or 3 times of day 10-20 mg/kg/day 4 times a day Increase weekly to achieve optimal clinical response, 3 times a day or 4 times a day Increase weekly to achieve optimal clinical response, 3 times a day or 4 times a day 35mg/kg/24hr [See Dosage and Administration section above](#dosage_and_administration) 35 mg/kg/24 hr [See Dosage and Administration section above](#dosage_and_administration) 6-12 yr 100 mg twice a day (200 mg/day) 100 mg twice a day (200 mg/day) ½ tsp 4 times a day (200 mg/day) Add up to 100 mg/day at weekly intervals 3 times a day or 4 times a day Add 100 mg/day at weekly intervals, twice a day Add up to 1 tsp (100 mg)/day at weekly intervals, 3 times a day or 4 times a day 1000mg/24 hr Over 12 yr 200 mg twice a day(400 mg/day) 200 mg twice a day (400 mg/day) 1 tsp 4 times a day (400 mg/day) Add up to 200 mg/day at weekly intervals, 3 times a day or 4 times a day Add up to 200 mg/day at weekly intervals, twice a day Add up to 2 tsp (200 mg)/day at weekly intervals, 3 times a day or 4 times a day 1000 mg/24 hr (12-15 yr) 1200 mg/24 hr (>15 yr) 1600 mg/24 hr (adults, in rare instances) Trigeminal Neuralgia 100 mg twice a day(200 mg/day) 100 mg twice a day (200 mg/day) ½ tsp 4 times a day (200 mg/day) Add up to 200 mg/day in increments of 100 mg every 12 hr Add up to 200 mg/day in increments of 100 mg every 12 hr Add up to 2 tsp (200 mg)/day in increments of 50 mg (½ tsp) 4 times a day 1200mg/24 hr Tablet = conventional tablets † XR = Tegretol-XR extended-release tablets.

50090-5740 NDC: 50090-5740-0 100 TABLET in a BOTTLE NDC: 50090-5740-3 28 TABLET in a BOTTLE.