Carbamazepin

Pharmaceutical

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Antiepileptic

Pharmaceuticals

log Kow = 2.45

2.3

Crystals from absolute ethanol and benzene

White to off-white powder

Sol in alcohol, acetone, propylene glycol; practically insol in water

Soluble in chloroform, dimethylformamide, ethylene glycol monomethyl ether, or methanol; only slightly soluble in ethanol or glacial acetic acid

1.52e-01 g/L

>35.4 [ug/mL] (The mean of the results at pH 7.4)

Breast Feeding; Lactation; Milk, Human; Anticonvulsants; Antimanic Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Antiseizure medicines

189-192

190.2 °C

190.2 °C

To study the photostability of carbamazepine polymorphs, the pure materials on the tablet surface were evaluated without physical damage by means of Fourier-transform infrared reflection-absorption infrared spectrometry (FT-IR-RAS) and colorimetric measurement of the carbamazepine polymorphs I, II, and III, after photodegradation at 2 irradiation intensities under a near-UV fluorescent lamp. The surface of sample pellets of all crystalline forms turned gradually from white to yellow-orange upon exposure to light, and the discoloration rate of form II was faster than that of forms I and III, indicating that form II was the most unstable of the three. The semilogarithmic plots of the photodegradation profiles of the various polymorphs were straight lines, including the induction period, indicating that degradation of the drug on the surface followed first-order kinetics. The induction periods of all forms were not significantly different. However, the degradation rate constant of form II was 5.1 and 1.5 times larger than those of forms I and III, respectively.

Positive

2.4

2.7

Agilent XCT

Electrospray ionization

formic acid (5.3nM)

This chemical does not meet GHS hazard criteria for 0.5% (1 of 210) of reports.

Danger

H302 (96.2%): Harmful if swallowed [Warning Acute toxicity, oral]

P233, P260, P261, P264, P270, P271, P272, P280, P284, P301+P317, P302+P352, P304+P340, P321, P330, P333+P317, P342+P316, P362+P364, P403, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 210 reports by companies from 24 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Hazard Traits - Developmental Toxicity

Carbamazepine: Does not have an individual approval but may be used under an appropriate group standard

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl carbamazepine approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Carbamazepine tablets, extended-release tablets, and chewable tablets should be stored in tight, light-resistant containers at temperatures not exceeding 30 °C. Carbamazepine extended-release capsules should be stored in tight, light-resistant containers at 15-25 °C. Because dissolution characteristics and associated oral bioavailability of carbamazepine tablets may be affected substantially by moisture, patients should be cautioned to keep containers of the tablets tightly closed and in a dry location, away from areas with excessive moisture (e.g., showers, bathrooms, humidifiers). Carbamazepine tablets may lose one-third or more of their oral bioavailability when exposed to excessive moisture. Tablets continuously exposed to 97% relative humidity at room temperature for 2 weeks become hardened and dissolve poorly.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote. (L1712)

Various combinations of carbamazepine, felbamate, and phenytoin were evaluated in mice (ip) for anticonvulsant activity (maximal electroshock seizure test) and minimal neurotoxicity (rotarod test). The results obtained from these studies were analyzed using response surface methodologies. The outcomes of these analyses in regard to anticonvulsant activity suggest that, under these experimental study conditions, at 0.5 hr post treatment there is a significant carbamazepine/phenytoin synergism even though none of the drugs has a significant dose-response by that time when given alone, and that at l.0 hr post treatment, the combination dose-response is additive. Thus, there appears to be an important dose/time relationship. In regard to the neurotoxic response, the results suggest a significant carbamazepine/phenytoin synergism at 0.25 hr post treatment and an additive neurotoxic effect due to the combination of felbamate/carbamazepine/phenytoin at 0.5, l.0 and 2.0 hr post exposure.

Risk of hepatotoxicity with single toxic doses or prolonged use of high doses of acetaminophen may be increased, and therapeutic effects of acetaminophen may be decreased, in patients taking hepatic enzyme-inducing agents such as carbamazepine.

Concurrent use /of aminophylline, oxtriphylline, or theophylline/ with carbamazepine may stimulate hepatic metabolism of the xanthines (except dyphylline), resulting in increased theophylline clearance.

Concurrent use /of hydantoin anticonvulsants, succinimide anticonvulsants, barbiturates, benzodiazepines metabolized via hepatic microsomal enzymes, especially clonazepam, primidone, or valproic acid/ with carbamazepine may result in increased metabolism, leading to decreased serum concentrations and reduced elimination half-lives of these medications because of induction of hepatic microsomal enzyme activity; monitoring of blood concentrations as a guide to dosage is recommended, especially when any of these medications or carbamazepine is added to or withdrawn from an existing regimen. Valproic acid may prolong the half-life and reduce the protein-binding of carbamazepine; the concentration of the active 10,11-epoxide metabolite may be increased. In addition, use of carbamazepine in combination with other anticonvulsants has been reported to be associated with an increased risk of congenital defects and with an alteration of thyroid function.

For more Interactions (Complete) data for CARBAMAZEPINE (41 total), please visit the HSDB record page.

Prospective studies indicate that a sizeable proportion of patients taking carbamazepine have transient serum aminotransferase elevations (ranging from 1% to 22%). These elevations are usually benign, not associated with liver histological abnormalities and usually resolve even with drug continuation. In addition, most patients on carbamazepine develop mild-to-moderate elevations in gamma glutamyltranspeptidase (GGT) levels, probably indicative of hepatic enzyme induction rather than liver injury. Marked aminotransferase elevations (more than 5 fold elevated) occur less frequently.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 520(SRC), determined from a log Kow of 2.45(2) and a regression-derived equation(3), indicates that carbamazepine is expected to have moderate mobility in soil(SRC). Volatilization of carbamazepine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.1X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Carbamazepine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.8X10-7 mm Hg(SRC), determined from a fragment constant method(5). A 7% removal rate in sewage treatment plants(8) suggests that biodegradation is not an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 510(SRC), determined from a log Kow of 2.45(2) and a regression-derived equation(3), indicates that carbamazepine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.1X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). The compound is susceptible to direct photolysis in water(5). Applying carbamazepine to natural river water and subjecting this to solar radiation resulted in a half-life of 907 hours(9). According to a classification scheme(6), an estimated BCF of 15(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Carbamazepine was fairly persistent when tested in a field experiment using epilimnion lake water, exhibiting an overall elimination rate constant of 0.11 1/day; this corresponds to a half-life of 63 days(8).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), carbamazepine, which has an estimated vapor pressure of 1.8X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase carbamazepine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 4 hours(SRC), calculated from its rate constant of 8.1X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Carbamazepine absorbs light at wavelengths >290 nm(4) and therefore may be susceptible to direct photolysis by sunlight(SRC).

The most common side effects of carbamazepine include dizziness, drowsiness, ataxia, nausea, and vomiting. Although rarer in occurrence, this comes with a black box warning for several severe dermatologic reactions. In patients of Han Chinese ancestry, studies have indicated a strong association between the HLA-B*1502 gene and Steven Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Studies have shown no increased risk with this gene and SJS/TEN in Iranian patients. A meta-analysis of 11 studies with 343 cases of carbamazepine-induced SJS/TEN showed HLB-B*4001, HLB*4601, and HLB*5801 genes were strong protective factors. Patients of Han Chinese ancestry should undergo testing for the HLA-B*1502 gene. Up to 90 % of patients on carbamazepine who have this reaction experience it within the first few months of treatment. Another important allele to consider with this medication is HLA*3101. This allele is present in Japanese, Korean, and European ancestry. Retrospective studies show a significantly increased incidence of dermatologic reactions such as Stevens-Johnson syndrome, toxic epidemic necrolysis, maculopapular eruptions, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Oral. In clinical studies, carbamazepine suspension, conventional tablets, and extended-release tablets delivered equivalent amounts of drug to the systemic circulation. However, it has been observed that the suspension is somewhat faster absorbed. Furthermore, the extended-release tablet is slightly slower than the conventional tablet. The bioavailability of the extended-release tablet is 89%, compared to the suspension. Plasma levels of carbamazepine are variable. The time to peak concentration for the different formulations are as follows: Suspension = 1.5 hours; Conventional tablets = 4-5 hours; Extended-release tablets = 3-12 hours.

In adults, doses of carbamazepine exceeding 24 grams have correlated with fatal outcomes. Acute toxicity appears after 1 to 3 hours of intake and presents with neuromuscular disturbances. Patients have impaired consciousness leading to coma, tremor, restlessness, athetoid movements, psychomotor disturbances, dizziness, drowsiness, mydriasis, and nystagmus. Initially, patients experience hyperreflexia, but during intoxication, they progress into a state of hyporeflexia. Cardiac, vascular signs are generally mild with low toxicity, but with doses higher than 60 grams, severe cardiac dysfunction can occur. In cases of acute toxicity, respiratory depression, ECG abnormalities, tachycardia, shock, and urinary retention require monitoring and management to avoid end-organ damage. Treatment of an overdose focuses on eliminating the drug by inducing vomiting, gastric lavage, activated charcoal, and forced diuresis. Gastric lavage is indicated even after 4 hours of indigestion. Seizures caused by carbamazepine poisoning should receive treatment with benzodiazepines such as diazepam.

Carbamazepine inhibits sustained repetitive firing by blocking use-dependent sodium channels. Pain relief is believed to be associated with blockade of synaptic transmission in the trigeminal nucleus and seizure control with reduction of post-tetanic potentiation of synaptic transmission in the spinal cord. Carbamazepine also possesses anticholinergic, central antidiuretic, antiarrhythmic, muscle relaxant, antidepressant (possibly through blockade of norepinephrine release), sedative, and neuromuscular-blocking properties.

/AQUATIC SPECIES/ The effects of the antiepileptic drug carbamazepine were studied in three freshwater invertebrate species representing different taxonomic groups, life histories, and habitats in aquatic ecosystems. The oligochaete Lumbriculus variegatus was exposed by way of carbamazepine-spiked sediments at nominal concentrations between 0.625 and 10 mg/kg dry weight (dw) for 28 days. At the end of the test, reproduction and biomass were monitored as end points. The non-biting midge Chironomus riparius was exposed to carbamazepine in a series of tests at nominal carbamazepine concentrations in sediment ranging from 0.16 to 100 mg/kg dw at 20 degrees C and 23 degrees C. Emergence and gender ratio were monitored at the end of the test. The freshwater snail Potamopyrgus antipodarum as the third test species was used in a chronic reproduction test for 28 days at aqueous carbamazepine concentrations from 0.4 to 250 mg/L. Whereas for the oligochaete and the snail no effects were observed, C. riparius exhibited a significant and concentration-dependent decrease of emergence in all test series. No observed effect concentrations and 10% effect concentrations were in the range of 33 to 140 and 70 to 210 microg/kg dw, respectively, based on measured carbamazepine concentrations in sediments. These low values indicate that carbamazepine may pose a potential threat for the survival of C. riparius and probably also for other aquatic insect populations in the field.

/AQUATIC SPECIES/ In this study, the four most abundantly used pharmaceuticals in Korea, namely acetaminophen, carbamazepine, cimetidine, and diltiazem, and six sulfonamide related antibiotics, ... were examined for their acute aquatic toxicity employing a marine bacterium (Vibrio fischeri), a freshwater invertebrate (Daphnia magna), and the Japanese medaka fish (Oryzias latipes). In general, Daphnia was the most susceptible among the test organisms. The most acutely toxic among the chemicals tested in this study was diltiazem, with a median lethal concentration of 8.2 mg/L for D. magna. ...

/AQUATIC SPECIES/ The effects of the antiepileptic, analgesic drug carbamazepine on the growth, morphology, and life-history characteristics of Daphnia pulex were examined at nominal concentrations of 0, 0.1, 1, 10, 100, and 200 ug L(-1). At 1 microg carbamazepine L(-1), Daphnia matured and reproduced slightly earlier than did controls, and at a given body length females produced more offspring than did controls or those receiving other treatments. In combination with a relatively high juvenile somatic growth rate and highest total number of progeny produced per female, carbamazepine at 1ug L(-1) seemed to exert a stimulatory effect. The rates of population growth of the 100 and 200 ug L(-1) treatment groups was 9% and 32% lower, respectively, than the rates of growth of the controls and the Daphnia receiving treatments of up to 10 microg carbamazepine L(-1). At the highest dose, retardation of juvenile somatic growth resulted in delayed maturity and consequently in a lower rate of population growth. Adult somatic growth, spine length, reproductive output, and size of newborns were similar among treatments. Male offspring were only produced in the third broods, with broods that were 8% and 28% male at 1 and 10 ug L(-1), respectively. Neck teeth were never observed in Daphnia. Chronic adverse effects of carbamazepine on nontarget Daphnia were detected at 200 ug carbamazepine L(-1), but stimulatory effects might occur at environmentally realistic concentrations. However, additional studies of chronic toxicity investigating various combinations of pharmaceuticals and various environmental stresses, such as food condition, temperature, and kairomones, are needed to fully explore potential long-term adverse effects and to assess the environmental risk of common pharmaceuticals.

/AQUATIC SPECIES/ ... Carbamazepine, an anticonvulsant commonly present in surface and groundwater, was studied, using six ecotoxicological model systems with eighteen endpoints evaluated at different exposure time periods. The battery included the immobilization of Daphnia magna, bioluminescence inhibition in the bacterium Vibrio fischeri, growth inhibition of the alga Chlorella vulgaris, and micronuclei induction and root growth inhibition in the plant Allium cepa. Cell morphology, neutral red uptake, total protein content, MTS metabolization, lactate dehydrogenase leakage and activity and glucose-6-phosphate dehydrogenase activity were studied in the salmonid fish cell line RTG-2. The total protein content, LDH activity, neutral red uptake and MTT metabolization in Vero monkey kidney cells were also investigated. The most sensitive system to carbamazepine was the Vero cell line, followed by Chlorella vulgaris, Vibrio fischeri, Daphnia magna, Allium cepa, and RTG-2 cells. EC50 values from 19 microM in Vero cells at 72 h to more than 1200 microM in other systems, were obtained. Comparing the concentrations in water and the toxicity quantified in our assay systems, carbamazepine is not expected to produce acute toxic effects in the aquatic biota under these circumstances, but chronic and synergistic effects with other chemicals cannot be excluded.

Carbamazepine has been reported in sewage treatment plant and environmental samples(1). A median concentration of 2.1 ug/L has been reported in German sewage treatment plant effluents(2) with concentrations in these effluents as high as 6.3 ug/L(3). The maximum carbamazepine concentrations in waste water treatment plant effluents in Switzerland sampled for a period of 3 months reached 0.95 ug/L(4). A concentration of 0.27 ug/L was reported in an Asgard Norway sewer sample collected on April 18, 2002(5).

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl carbamazepine approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

N03AF01

N03AF01

N - Nervous system

QN - Nervous system

N03AF01

**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.

Carbamazepine's mechanism of action is not fully elucidated and is widely debated. One major hypothesis is that carbamazepine inhibits sodium channel firing, treating seizure activity. Animal research studies have demonstrated that carbamazepine exerts its effects by lowering polysynaptic nerve response and inhibiting post-tetanic potentiation. In both cats and rats, carbamazepine was shown to decrease pain caused by infraorbital nerve stimulation. A decrease in the action potential in the nucleus ventralis of the thalamus in the brain and inhibition of the lingual mandibular reflex were observed in other studies after carbamazepine use. Carbamazepine causes the above effects by binding to voltage-dependent sodium channels and preventing action potentials, which normally lead to stimulatory effects on nerves. In bipolar disorder, carbamazepine is thought to increase dopamine turnover and increase GABA transmission, treating manic and depressive symptoms. A common issue that has arisen is resistance to this drug in up to 30% of epileptic patients, which may occur to altered metabolism in patients with variant genotypes. A potential therapeutic target to combat carbamazepine resistance has recently been identified as the EPHX1 gene promoter, potentially conferring resistance to carbamazepine through methylation.

Anticonvulsant: Exact mechanism unknown; may act postsynaptically by limiting the ability of neurons to sustain high frequency repetitive firing of action potentials through enhancement of sodium channel inactivation; in addition to altering neuronal excitability, may act presynaptically to block the release of neurotransmitter by blocking presynaptic sodium channels and the firing of action potentials, which in turn decreases synaptic transmission.

Antineuralgic: Exact mechanism unknown; may involve gamma-aminobutyric acid (GABAB) receptors, which may be linked to calcium channels.

Antimanic; antipsychotic: Exact mechanism is unknown; may be related to either the anticonvulsant or the antineuralgic effects of carbamazepine, or to tis effects on neurotransmitter modulator systems.

Antidiuretic: Exact mechanism unknown; may exert a hypothalamic effect on the osmoreceptors mediated via secretion of antidiuretic hormone (ADH), or may have a direct effect on the renal tubule.

For more Mechanism of Action (Complete) data for CARBAMAZEPINE (8 total), please visit the HSDB record page.

The mean elimination half-life of carbamazepine was 35 to 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 to 36.8 hours in healthy volunteers.

Initial single dose: May range from 25 to 65 hours. Chronic dosing: May decrease to 8 to 29 hours (average 12 to 17 hours) because of autoinduciton of metabolism.

Carbamazepine-10,11-epoxide: 5 to 8 hours. /Carbamazepine-10,11-epoxide/

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, 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.

The pharmacokinetics of a single oral dose of carbamazepine-10,11-epoxide, (100 mg) were compared in 10 patients on chronic monotherapy with lamotrigine, (200-300 mg/day) and in 10 drug-free healthy control subjects. Carbamazepine-10,11-epoxide pharmacokinetic parameters in lamotridge-treated patients were found to be similar to those observed in controls (half-life: 7.2 + or - 1.6 vs 6.1 + or - 0.9 hr; apparent oral clearance: 110.8 + or - 53.1 vs 120.5 + or - 29.9 ml/h/kg; apparent volume of distribution: 1.08 + or 0.37 vs 1.04 + or - 0.25 l/kg respectively; means + or - s.d.). These data indicate that, contrary to previous suggestions, lamotridge has no effect on the metabolic disposition of carbamazepine-10,11-epoxide.

Placental transfer and metabolism of carbamazepine was studied in a dual recirculating placental cotyledon perfusion system and was also evaluated in 16 pairs of maternal venous and cord blood samples. ... Carbamazepine added into the maternal circulation crosses the placenta in the beginning quicker than antipyrine which is in agreement with the different lipid solubilities of these compounds. Because the transfer rates of antipyrine and carbamazepine were about the same, the mechanism of transfer of carbamazepine is probably similar to that of antipyrine (passive diffusion). No metabolites of carbamazepine could be detected in the perfusate by high-performance liquid chromatography or gas chromatography/mass spectrometry. With the improved HPLC methodology for carbamazepine metabolites, six metabolites were detected in clinical samples, including 10-hydroxy-10,11-dihydro-carbamazepine (10-OH-CBZ), which has been described earlier in only 1 uremic patient. Relative levels of metabolites showed significant individual differences. Carbamazepine crosses perfused placenta rapidly, but this does not contribute to carbamazepine metabolites detected in maternal and fetal circulation.

The aim of this work was to study the transport across the blood-brain barrier, blood and liver distribution kinetics, metabolic interaction and local liver metabolism of carbamazepine in the rat, using microdialysis with the internal standard technique as in vivo calibration method. Carbamazepine and its major metabolite, carbamazepine-10,11-epoxide, are homogeneously distributed to hippocampus and cerebellum. The ratios of the areas under the concentration-time curve for both brain regions to blood areas under the concentration-time curve were not different from unity for carbamazepine; they were 0.46 + or - 0.08 (hippocampus) and 0.45 + or - 0.05 (cerebellum) for carbamazepine-10,11-epoxide. In addition, the disposition of carbamazepine and carbamazepine-10,11-epoxide in blood and liver, after a single dose of carbamazepine, was studied in control animals and in rats after pretreatment with clomipramine. A 2-fold increase in the blood areas under concentration curve of carbamazepine and a decrease to 33% of the blood areas under concentration curve of carbamazepine-10,11-epoxide in the pretreated group demonstrate the metabolic inhibition of carbamazepine-10,11-epoxide formation by clomipramine. The ratios of the areas under concentration curve carbamazepine-10,11-epoxide to the areas under the concentration curve carbamazepine, as a measure of carbamazepine-10,11-epoxide formation, were not different for blood and liver within the control and the clomipramine-pretreated groups, but the ratios were significantly lower for liver and blood in the clomipramine group compared with the control animals. In addition, carbamazepine was administered locally in the extracellular fluid of the liver via the microdialysis probe. The liver metabolic ratio, expressed as the ratio of the formed carbamazepine-10,11-epoxide concentration to the carbamazepine concentration administered, ranged from 18.2 + or - 1.2% to 19.6 + or - 1.6%.

Carbamazepine has known human metabolites that include 9-Hydroxycarbamazepine, Carbamazepine 10,11-epoxide, 2-Hydroxycarbamazepine, and 3-Hydroxycarbamazepine.

Hepatic. CYP3A4 is the primary isoform responsible for the formation of carbamazepine-10,11-epoxide. This metabolite is active and shown to be equipotent to carbamazepine as an anticonvulsant. Carbamazepine is more rapidly metabolized to the aforementioned metabolite in younger patients than in adults. It also undergoes glucuronidation via UGT2B7, however this finding has been disputed. Route of Elimination: 72% of the dose is in the urine while 28% is in the feces. Hydroxylated and conjugated metabolites are largely what was recovered in the urine. 3% of the dose is recovered as unchanged carbamazepine. Half Life: Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses.

33CM23913M

CARBAMAZEPINE

Physiologic Effects [PE] - Decreased Central Nervous System Disorganized Electrical Activity

Established Pharmacologic Class [EPC] - Mood Stabilizer

Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inducers

Mechanisms of Action [MoA] - Cytochrome P450 1A2 Inducers

Drugs used to prevent SEIZURES or reduce their severity.

Agents that are used to treat bipolar disorders or mania associated with other affective disorders.

A subclass of analgesic agents that typically do not bind to OPIOID RECEPTORS and are not addictive. Many non-narcotic analgesics are offered as NONPRESCRIPTION DRUGS.

A class of drugs that act by inhibition of sodium influx through cell membranes. Blockade of sodium channels slows the rate and amplitude of initial rapid depolarization, reduces cell excitability, and reduces conduction velocity.

Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP3A.

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. The 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. The 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.

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 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 to 1.4 L/kg.. 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.

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

Absorption: Slow and variable, but almost completely absorbed from gastrointestinal tract.

Patients in whom carbamazepine monotherapy is discontinued for preoperative EEG/video monitoring often display toxicity if their previous maintenance dosage is resumed, even after a few days without carbamazepine. To determine whether this is due to rapid reversibility of autoinduction of carbamazepine metabolism, single-dose studies of carbamazepine pharmacokinetics were performed before and after discontinuation for monitoring in 6 adults receiving carbamazepine monotherapy. The carbamazepine-free period was 5.7 + or - 1.1 days (mean + or - SD). The pharmacokinetic parameters of carbamazepine before and after discontinuation were volume of distribution 1.28 + or - 0.29 versus 1.22 + or - 0.331/kg, elimination half-life (tl/2) 13.7 + or - 1.67 versus 22.2 + or - 2.36 hr (p < 0.001), and clearance 1.54 + or - 0.39 versus 0.92 + or - 0.32 L/kg/day (p = 0.012). Assuming that deinduction is a first-order process, a deinduction tl/2 of 3.84 days was obtained by log linear regression analysis. We showed that after carbamazepine discontinuation half of the enzymatic autoinduction is already lost after 3.84 days, indicating very rapid deinduction. Our results also provide the necessary information to predict clearance and appropriate dosage reduction for carbamazepine at time of reintroduction.

Analgesic/antiepileptic drug

In the treatment of pain associated with trigeminal neuralgia

THERAP CAT: Anticonvulsant

MEDICATION

Use (kg) in Switzerland (2009): >2500

For the treatment of epilepsy and pain associated with true trigeminal neuralgia.

(1977) PROBABLY GREATER THAN 4.54X10+5 GRAMS

(1979) PROBABLY GREATER THAN 4.54X10+5 GRAMS

Amount used per year in the UK: 40.348.75 kg

(1995) estimated prescription amount in Germany was calculated to be 80 tons

THERMAL DEAMMONIATION OF 2-(O-AMINOSTYRYL)ANILINE HYDROCHLORIDE TO FORM 5H-DIBENZ(B,F)AZEPINE FOLLOWED BY CONDENSATION WITH CARBAMOYL CHLORIDE IN THE PRESENCE OF SODAMIDE

Prepn: W. Schindler, US 2948718 (1960 to Geigy).

Iminostilbene + phosgene + ammonia (phosgenation/dehydrochlorination)

5H-dibenz(b,f)azepine is first reacted with phosgene and then with ammonia.

Oral: Capsules, extended-release: 200 mg Carbatrol (with povidone), (Shire US); 300 mg Carbatrol (with povidone), (Shire US). Suspension: 100 mg/5 mL Carbamazepine Suspension, (Actavis), Carbamazepine Suspension, (Morton Grove), Carbamazepine Suspension, (Taro); Tegretol ( with propylene glycol), (Novartis). Tablets: 200 mg Epitol (scored), (Teva), Tegretol (scored), (Novartis). Tablets, chewable: 100 mg Tegretol (scored), (Novartis). Tablets, extended-release: 100 mg Tegretol-XR (with mannitol), (Novartis); 200 mg Tegretol-XR (with mannitol), (Novartis); 400 mg Tegretol-XR (with mannitol), (Novartis).

Pharmaceuticals -> Nervous System -> Antiepileptics -> Carboxamide derivatives

Pharmaceuticals