Carbamazepine Capsules

In controlled clinical trials, carbamazepine has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia.

Mechanism of Action

Carbamazepine has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Carbamazepine greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in cats. Carbamazepine is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown.

The principal metabolite of carbamazepine, carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been postulated, the significance of its activity with respect to the safety and efficacy of carbamazepine has not been established.

Pharmacokinetics

Taken every 12 hours, carbamazepine extended-release capsules provide steady state plasma levels comparable to immediate-release carbamazepine tablets given every 6 hours, when administered at the same total mg daily dose.

Following a single 200 mg oral extended-release dose of carbamazepine, peak plasma concentration was 1.9 ± 0.3 µg/mL and the time to reach the peak was 19 ± 7 hours. Following chronic administration (800 mg every 12 hours), the peak levels were 11.0 ± 2.5 µg/mL and the time to reach the peak was 5.9 ± 1.8 hours. The pharmacokinetics of extended-release carbamazepine is linear over the single dose range of 200-800 mg.

Carbamazepine is 76% bound to plasma proteins. Carbamazepine is primarily metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide. Since carbamazepine induces its own metabolism, the half-life is also variable. Following a single extended-release dose of carbamazepine, the average half-life range from 35-40 hours and 12-17 hours on repeated dosing. The apparent oral clearance following a single dose was 25 ± 5 mL/min and following multiple dosing was 80 ± 30 mL/min.

After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged carbamazepine.

Carbamazepine-10,11-epoxide is considered to be an active metabolite of carbamazepine. Following a single 200 mg oral extended-release dose of carbamazepine, the peak plasma concentration of carbamazepine-10,11-epoxide was 0.11 ± 0.012 µg/mL and the time to reach the peak was 36 ± 6 hours. Following chronic administration of a extended-release dose of carbamazepine (800 mg every 12 hours), the peak levels of carbamazepine-10,11-epoxide were 2.2 ± 0.9 µg/mL and the time to reach the peak was 14 ± 8 hours. The plasma half-life of carbamazepine-10,11-epoxide following administration of carbamazepine is 34 ± 9 hours. Following a single oral dose of extended-release carbamazepine (200-800 mg) the AUC and Cmax of carbamazepine-10,11-epoxide were less than 10% of carbamazepine. Following multiple dosing of extended-release carbamazepine (800-1600 mg daily for 14 days), the AUC and Cmax of carbamazepine-10,11-epoxide were dose related, ranging from 15.7 µg.hr/mL and 1.5 µg/mL at 800 mg/day to 32.6 µg.hr/mL and 3.2 µg/mL at 1600 mg/day, respectively, and were less than 30% of carbamazepine. Carbamazepine-10,11-epoxide is 50% bound to plasma proteins.

A high fat meal diet increased the rate of absorption of a single 400 mg dose (mean Tmax was reduced from 24 hours, in the fasting state, to 14 hours and Cmax increased from 3.2 to 4.3 µg/mL) but not the extent (AUC) of absorption. The elimination half-life remains unchanged between fed and fasting state. The multiple dose study conducted in the fed state showed that the steady-state Cmax values were within the therapeutic concentration range. The pharmacokinetic profile of extended-release carbamazepine was similar when given by sprinkling the beads over applesauce compared to the intact capsule administered in the fasted state.

Special Populations

The effect of hepatic impairment on the pharmacokinetics of carbamazepine is not known. However, given that carbamazepine is primarily metabolized in the liver, it is prudent to proceed with caution in patients with hepatic dysfunction.

The effect of renal impairment on the pharmacokinetics of carbamazepine is not known.

No difference in the mean AUC and Cmax of carbamazepine and carbamazepine-10,11-epoxide was found between males and females.

Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide in young children than adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age.

No information is available on the effect of race on the pharmacokinetics of carbamazepine.

Acute Toxicity

Lowest known lethal dose: adults, >60 g (39-year-old man). Highest known doses survived: adults, 30 g (31-year-old woman); children, 10 g (6-year-old boy); small children, 5 g (3-year-old girl).

Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.

Signs and Symptoms

The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (>60 g) have been ingested.

Respiration: Irregular breathing, respiratory depression.

Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.

Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia.

Gastrointestinal Tract: Nausea, vomiting.

Kidneys and Bladder: Anuria or oliguria, urinary retention.

Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. ECG may show dysrhythmias.

Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with carbamazepine may be aggravated or modified.

Treatment

For the most up to date information on management of carbamazepine overdose, please contact the poison center for your area by calling 1-800-222-1222. The prognosis in cases of carbamazepine poisoning is generally favorable. Of 5,645 cases of carbamazepine exposures reported to US poison centers in 2002, a total of 8 deaths (0.14% mortality rate) occurred. Over 39% of the cases reported to these poison centers were managed safely at home with conservative care. Successful management of large or intentional carbamazepine exposures requires implementation of supportive care, frequent monitoring of serum drug concentrations, as well as aggressive but appropriate gastric decontamination.

The primary method for gastric decontamination of carbamazepine overdose is use of activated charcoal. For substantial recent ingestions, gastric lavage may also be considered. Administration of activated charcoal prior to hospital assessment has the potential to significantly reduce drug absorption. There is no specific antidote. In overdose, absorption of carbamazepine may be prolonged and delayed. More than one dose of activated charcoal may be beneficial in patients that have evidence of continued absorption (e.g., rising serum carbamazepine levels).

The data on use of dialysis to enhance elimination in carbamazepine is scarce. Dialysis, particularly high flux or high efficiency hemodialysis, may be considered in patients with severe carbamazepine poisoning associated with renal failure or in cases of status epilepticus, or where there are rising serum drug levels and worsening clinical status despite appropriate supportive care and gastric decontamination. For severe cases of carbamazepine overdose unresponsive to other measures, charcoal hemoperfusion may be used to enhance drug clearance.

Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, and administration of oxygen.

Keep the patient's legs raised and administer a plasma expander. If blood pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.

Diazepam or barbiturates.

Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week).

Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary reflexes, and kidney and bladder function should be monitored for several days.

If evidence of significant bone marrow depression develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency to monitor recovery.

Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels.

A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought.

NDC 66993-409-32

PRASCO

Carbamazepine
Extended-Release Capsules

Should not be used with other
carbamazepine containing products.

120 Capsules
Rx Only

300 mg

Dispense the accompanying
Medication Guide to each patient.