February 23, 2017
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Mechanism Of Action

Although numerous pharmacological effects of carbamazepine have been described in the published literature (e.g., modulation of ion channels [sodium and calcium], receptor-mediated neurotransmission [GABAergic, glutamatergic, and monoaminergic], and intracellular signaling pathways in experimental preparations), the contribution of these effects to the efficacy of carbamazepine in acute manic or mixed episodes associated with bipolar disorder is unknown.


Carbamazepine (CBZ)


Following a single 200 mg oral extended-release dose of carbamazepine, peak plasma concentration was 1.9 ± 0.3 mcg/mL and the time to reach the peak was 19 ± 7 hours. Following repeat dose administration (800 mg every 12 hours), the peak levels were 11.0 ± 2.5 mcg/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. The average half-life ranged from 35 to 40 hours following a single extended-release dose of carbamazepine and from 12 to 17 hours following repeated dosing. The apparent oral clearance was 25 ± 5 mL/min following a single dose and 80 ± 30 mL/min following multiple dosing.

Carbamazepine-10,11-epoxide (CBZ-E)

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 mcg/mL and the time to reach the peak was 36 ± 6 hours. Following chronic administration of an extended-release dose of carbamazepine (800 mg every 12 hours), the peak levels of carbamazepine-10,11-epoxide were 2.2 ± 0.9 mcg/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 mcg.hr/mL and 1.5 mcg/mL at 800 mg/day to 32.6 mcg.hr/mL and 3.2 mcg/mL at 1600 mg/day, respectively, and were less than 30% those of carbamazepine. Carbamazepine-10,11-epoxide is 50% bound to plasma proteins.

Food Effect

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 mcg/mL) but not the extent (AUC) of absorption. The elimination half-life remained 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.


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


In vitro data indicate carbamazepine is metabolized mainly by cytochrome P450 (CYP) 3A4 to the active carbamazepine-10,11-epoxide, which is further metabolized to the trans-diol by epoxide hydrolase. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11-epoxide.

Renal Impairment

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

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of carbamazepine is not known. Consider reducing the dosage in patients with hepatic impairment.

Effect Of Age

Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide in young children than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age. The safety and effectiveness of EQUETRO® in pediatric and adolescent patients have not been established.

Effect Of Gender

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

Clinical Studies

Bipolar I Disorder (Acute Manic Or Mixed Episodes)

The efficacy of EQUETRO in the acute treatment of manic or mixed symptoms associated with bipolar I disorder was established in two 3-week, multicenter, randomized, double-blind, placebo-controlled, flexible-dose studies (Studies 1 and 2) in adult patients who met the DSM-IV criteria for bipolar I disorder, manic or mixed episode. In both studies, patients must have had a history of at least one previous manic or mixed episode. They must have had a Young Mania Rating Scale (YMRS) baseline score of at least 20. The YMRS is an 11-item instrument, ranging from 0 to 60 (greater score indicates a more severe manic disorder) that measures symptoms associated with a manic state: elevated mood, increased motor activity/energy, sexual interest, sleep, irritability, speech, language-thought disorder, content, disruptive/aggressive behavior, appearance, and insight.

In Studies 1 and 2, patients were hospitalized for at least one week. They received placebo during a 5-day lead-in period and subsequently were randomized to receive placebo or EQUETRO, initially at a dose of 200 mg twice daily (400 mg per day). If tolerated, the total daily dose could be increased by 200 mg once daily to a maximum dose of 800 mg twice daily (1600 mg/day). The mean EQUETRO dose during the last week was 952 mg/day in Study 1 and 726 mg/day in Study 2.

Patients were permitted to receive lorazepam for agitation or insomnia (up to 6 mg/day during the placebo-lead in period, up to 4 mg/day during the first week of controlled treatment, and up to 2 mg/day during the second week of treatment; no lorazepam was permitted during the third week of treatment. They were permitted to continue their routine psychotherapy. Patients were not allowed to use antipsychotics, lithium, antidepressants, or sedatives/hypnotics (other than lorazepam) during the studies. There were no significant differences in lorazepam use between the EQUETRO and placebo groups in both studies.

In Studies 1 and 2, the primary endpoint was the mean change from baseline in the YMRS total score at Day 21. In both studies, treatment with EQUETRO was statistically significantly superior to placebo, as measured by the mean decrease in YMRS score at Day 21 (Table 3)

The key secondary efficacy endpoint in both trials was the change in Clinical Global Impression-Severity (CGI-S) Scale score. The CGI-S an investigator-rated global assessment of symptom severity that is scored on a 7-point scale (1 = normal, not ill); 7 = severely ill). In both studies, there was a statistically significant decrease from baseline in the mean CGI-S score at Day 21, compared to placebo (Table 3).

Table 3.Efficacy Results in the 2 Trials in Patients with Bipolar I Disorder – Change in mean YMRS score from baseline to Week 3 and change in mean CGI-S from baseline to Week 3

  Study 1 Study 2
Young Mania Rating Scale (YMRS)
Baseline YMRS 26.6 27.3 28.5 27.9
Week 3 YMRS 17.9 22.1 13.4 20.8
LS mean change -7.8 -4.8 -14.8 -7.0
LS mean difference from placebo* -3.5 - -8.0 -
p-value P= 0.033   (< 0.0001  
Clinical Global Impression-Severity Scale (CGI-S)
Baseline CGI-S 4.4 4.4 4.5 4.5
Week 3 CGI-S 3.7 4.1 3 3.9
Change from Baseline at Week 3 -0.7 -0.3 -1.5 -0.6
Difference (p-value) -0.4 (0.025)_ - -0.9 (< 0.0001_ -
* Least squares mean for the difference defined as the change from baseline at Week 3 in the EQUETRO group minus that in the placebo group.


Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types:

  1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvements than those with other types.
  2. Generalized tonic-clonic seizures (grand mal).
  3. Mixed seizure patterns which include the above, or other partial or generalized seizures.

Absence seizures (petit mal) do not appear to be controlled by carbamazepine.

Last reviewed on RxList: 11/14/2016
This monograph has been modified to include the generic and brand name in many instances.

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