Equetro (Carbamazepine) - Description and Clinical Pharmacology

Before prescribing EQUETRO^TM, the physician should be thoroughly familiar with the details of this prescribing information, particularly regarding use with other drugs, especially those which accentuate toxicity potential.

DESCRIPTION

EQUETRO^TM is available for oral administration as 100 mg, 200 mg and 300 mg extended-release capsules of carbamazepine, USP. Carbamazepine is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27. Its chemical name is 5H-dibenz[b,f]azepine-5-carboxamide, and its structural formula is:

EQUETRO^TM is a multi-component capsule formulation consisting of three different types of beads: immediate-release beads, extended-release beads, and enteric-release beads. The three bead types are combined in a specific ratio to provide twice daily dosing of EQUETRO^TM.

Inactive ingredients: citric acid, colloidal silicon dioxide, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, povidone, sodium lauryl sulfate, talc, triethyl citrate and other ingredients.

The 100 mg capsule shells contain gelatin-NF, FD&C Blue #2, Yellow Iron Oxide, Titanium Dioxide and are imprinted with white ink; the 200 mg capsule shells contain gelatin-NF, Yellow Iron Oxide, FD&C Blue #2, and Titanium Dioxide, and are imprinted with white ink; and the 300 mg capsule shells contain gelatin-NF, FD&C Blue #2, Yellow Iron Oxide, and Titanium Dioxide, and are imprinted with white ink.

CLINICAL PHARMACOLOGY

In controlled clinical trials, carbamazepine has been shown to be effective in the treatment of Bipolar I Disorder.

Mechanism of Action

The mechanism(s) of action of carbamazepine in the treatment of bipolar disorder has not been elucidated. 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 bipolar disorder is unknown.

Pharmacokinetics

Carbamazepine (CBZ): 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 repeat dose 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 ranged from 35-40 hours and 12-17 hours following 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 (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 μg/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 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 C_max 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 C_max 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.

Food Effect: A high fat meal diet increased the rate of absorption of a single 400 mg dose (mean T_max was reduced from 24 hours, in the fasting state, to 14 hours and C_max increased from 3.2 to 4.3 μg/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 C_max 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

Hepatic Dysfunction: 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.

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

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

Age: 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. The safety and effectiveness of EQUETRO^TM in pediatric and adolescent patients have not been established.

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

CLINICAL STUDIES

The effectiveness of EQUETRO^TM in the acute treatment of manic and mixed symptoms in patients with Bipolar I Disorder was established in 2 (3 week) multicenter, randomized, double-blind, flexible dose, placebo controlled studies in adult patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episode. In both studies, patients were titrated to a dose range from 400 mg/day to 1600 mg/day, given in divided doses, twice daily. The mean carbamazepine ER dose during the last week was 952 mg/day in the first study, and 726 mg/day in the second.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the YMRS total score.

EQUETRO^TM was significantly more effective than placebo in reduction of the YMRS total score for both studies