CARBAMAZEPINE- carbamazepine_capsule, extended release

CLINICAL PHARMACOLOGY
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. 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 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. 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. 5 µg/mL and the time to reach the peak was 5. 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 14 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. 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. 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 max A high fat meal diet increased the rate of absorption of a single 300 mg dose (mean T max max max 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 C max 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.
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
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. 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. 5 µg/mL and the time to reach the peak was 5. 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 14 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. 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. 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 max A high fat meal diet increased the rate of absorption of a single 300 mg dose (mean T max max max.

INDICATIONS AND USAGE
Carbamazepine extended-release capsules are indicated for use as an anticonvulsant drug. Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types: Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvements than those with other types. Generalized tonic-clonic seizures (grand mal). 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 (see PRECAUTIONS, General Carbamazepine extended-release capsules are indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia. This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
Epilepsy
Carbamazepine extended-release capsules are indicated for use as an anticonvulsant drug. Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types: Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvements than those with other types. Generalized tonic-clonic seizures (grand mal). 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 (see PRECAUTIONS, General
Trigeminal Neuralgia
Carbamazepine extended-release capsules are indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia. This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
Epilepsy
(see INDICATIONS AND USAGE 200 mg twice daily. Increase at weekly intervals by adding up to 200 mg/day until the optimal response is obtained. Dosage generally should not exceed 1000 mg per day in children 12-15 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. Adjust dosage to the minimum effective level, usually 800-1200 mg daily. Children taking total daily dosages of immediate-release carbamazepine of 400 mg or greater may be converted to the same total daily dosage of carbamazepine extended-release capsules, using a twice daily regimen. 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 extended-release for use at doses above 35 mg/kg/24 hours can be made. Carbamazepine extended-release capsules 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 (see PRECAUTIONS, Drug Interactions Pregnancy Category D.
Trigeminal Neuralgia
(see INDICATIONS AND USAGE On the first day, start with one 200 mg capsule. This daily dose may be increased by up to 200 mg/day every 12 hours only as needed to achieve freedom from pain. Do not exceed 1200 mg daily. Control of pain can be maintained in most patients with 400-800 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 AND ADMINISTRATION
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS, Laboratory Tests Carbamazepine extended-release capsules are an extended-release formulation for twice a day administration. When converting patients from immediate release carbamazepine to carbamazepine extended-release capsules, the same total daily mg dose of carbamazepine should be administered. Following conversion to carbamazepine extended-release capsules, patients should be closely monitored for seizure control. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions. (see INDICATIONS AND USAGE 200 mg twice daily. Increase at weekly intervals by adding up to 200 mg/day until the optimal response is obtained. Dosage generally should not exceed 1000 mg per day in children 12-15 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. Adjust dosage to the minimum effective level, usually 800-1200 mg daily. Children taking total daily dosages of immediate-release carbamazepine of 400 mg or greater may be converted to the same total daily dosage of carbamazepine extended-release capsules, using a twice daily regimen. 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 extended-release for use at doses above 35 mg/kg/24 hours can be made. Carbamazepine extended-release capsules 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 (see PRECAUTIONS, Drug Interactions Pregnancy Category D (see INDICATIONS AND USAGE On the first day, start with one 200 mg capsule. This daily dose may be increased by up to 200 mg/day every 12 hours only as needed to achieve freedom from pain. Do not exceed 1200 mg daily. Control of pain can be maintained in most patients with 400-800 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.
Adults and children over 12 years of age
200 mg twice daily. Increase at weekly intervals by adding up to 200 mg/day until the optimal response is obtained. Dosage generally should not exceed 1000 mg per day in children 12-15 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. Adjust dosage to the minimum effective level, usually 800-1200 mg daily.
Initial
200 mg twice daily. Increase at weekly intervals by adding up to 200 mg/day until the optimal response is obtained. Dosage generally should not exceed 1000 mg per day in children 12-15 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.
Maintenance
Adjust dosage to the minimum effective level, usually 800-1200 mg daily.
Initial
On the first day, start with one 200 mg capsule. This daily dose may be increased by up to 200 mg/day every 12 hours only as needed to achieve freedom from pain. Do not exceed 1200 mg daily.
Maintenance
Control of pain can be maintained in most patients with 400-800 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.

Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with carbamazepine treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Carbamazepine extended-release capsules should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.
Hypersensitivity Reactions and HLA-A*3101 Allele
Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a moderate association between the risk of developing hypersensitivity reactions and the presence of HLA-A*3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine. These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity HLA-A*3101 is expected to be present in the following approximate frequencies: greater than 15% in patients of Japanese and Native American ancestry; up to about 10% in patients of Han Chinese, Korean, European, and Latin American ancestry; and up to about 5% in African-Americans and patients of Indian, Thai, Taiwanese, and Chinese (Hong Kong) ancestry. The risks and benefits of carbamazepine therapy should be weighed before considering carbamazepine in patients known to be positive for HLA-A*3101.
Aplastic Anemia and Agranulocytosis
Aplastic anemia and agranulocytosis have been reported in association with the use of carbamazepine. (See BOXED WARNING
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, have occurred with carbamazepine. Some of these events have been fatal or lifethreatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e. , fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Carbamazepine extended-release capsules should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin, primidone, and phenobarbital. A history of hypersensitivity reactions should be obtained for patients and their immediate family members. If such history is present, benefits and risks should be carefully considered, and, if carbamazepine is initiated, the signs and symptoms of hypersensitivity should be carefully monitored. In patients who have exhibited hypersensitivity reactions to carbamazepine, approximately 25 to 30% may experience hypersensitivity reactions with oxcarbazepine.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive patient with epilepsy may lead to seizures or even status epilepticus with its life-threatening hazards. The most severe adverse reactions previously observed with carbamazepine were reported in the hemopoietic system and skin (see BOXED WARNING The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the lowest dosage recommended. The following additional adverse reactions were previously reported with carbamazepine: Hemopoietic System: Skin: BOXED WARNING Cardiovascular System: Liver: Pancreatic: Respiratory System: Genitourinary System: Testicular atrophy occurred in rats receiving carbamazepine orally from 4-52 weeks at dosage levels of 50-400 mg/kg/day. Additionally, rats receiving carbamazepine in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg/day and higher. Relevance of these findings to humans is unknown. Nervous System: There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established. Isolated cases of neuroleptic malignant syndrome have been reported with concomitant use of psychotropic drugs. Digestive System: Eyes: Musculoskeletal System: Metabolism: Other: A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
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: Cardiovascular System: Nervous System and Muscles: Gastrointestinal Tract: Kidneys and Bladder: Laboratory Findings: Combined Poisoning:
Respiratory Depression
Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, and administration of oxygen.
Convulsions
Diazepam or barbiturates.

CONTRAINDICATIONS
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 and nortriptyline. Likewise, on theoretical grounds its use with monoamine oxidase 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. Coadministration of carbamazepine is contraindicated with delavirdine due to the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.
Hypersensitivity
Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin, primidone, and phenobarbital. A history of hypersensitivity reactions should be obtained for patients and their immediate family members. If such history is present, benefits and risks should be carefully considered, and, if carbamazepine is initiated, the signs and symptoms of hypersensitivity should be carefully monitored. In patients who have exhibited hypersensitivity reactions to carbamazepine, approximately 25 to 30% may experience hypersensitivity reactions with oxcarbazepine.

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 C max 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.
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
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.
Race
No information is available on the effect of race on the pharmacokinetics of carbamazepine.
Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman. Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. The prescribing physician will wish to weigh the benefits of therapy against the risks in treating or counseling women of childbearing potential. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung. Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times the MHDD on a mg/m 2 Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. Tests to detect defects using current accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine. There have been a few cases of neonatal seizures and/or respiratory depression reported in association with maternal carbamazepine and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal carbamazepine use. These symptoms may represent a neonatal withdrawal syndrome. To provide information regarding the effects of in utero exposure to carbamazepine extended-release capsules, physicians are advised to recommend that pregnant patients taking carbamazepine extended-release capsules enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
Usage in Pregnancy
(See WARNINGS
Pregnancy Category D
(See WARNINGS
Nursing Mothers
Carbamazepine and its epoxide metabolite are transferred to breast milk and during lactation. The concentrations of carbamazepine and its epoxide metabolite are approximately 50% of the maternal plasma concentration. Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Substantial evidence of carbamazepine effectiveness for use in the management of children with epilepsy (see INDICATIONS in vitro Taken as a whole, this information supports a conclusion that the generally acceptable therapeutic range of total carbamazepine in plasma (i.e., 4-12 µg/mL) is the same in children and adults. The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer term data from clinical trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.
Children under 12 years of age
Children taking total daily dosages of immediate-release carbamazepine of 400 mg or greater may be converted to the same total daily dosage of carbamazepine extended-release capsules, using a twice daily regimen. 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 extended-release for use at doses above 35 mg/kg/24 hours can be made.

Drug Interactions
Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to the following: Carbamazepine is not highly bound to plasma proteins; therefore, administration of carbamazepine extended-release capsules to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. 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. Therefore, the potential exists for interaction between carbamazepine and any agent that inhibits CYP3A4 and/or epoxide hydrolase. Agents that are CYP3A4 inhibitors that have been found, or are expected, to increase plasma levels of carbamazepine extended-release capsules are the following: Acetazolamide, azole antifungals, cimetidine, clarithromycin also inhibits epoxide hydrolase resulting in increased levels of the active metabolite carbamazepine 10,11- epoxide Thus, if a patient has been titrated to a stable dosage of carbamazepine extended-release capsules, and then begins a course of treatment with one of these CYP3A4 or epoxide hydrolase inhibitors, it is reasonable to expect that a dose reduction for carbamazepine extended-release capsules may be necessary. Carbamazepine is metabolized by CYP3A4. Therefore, the potential exists for interaction between carbamazepine and any agent that induces CYP3A4. Agents that are CYP inducers that have been found, or are expected, to decrease plasma levels of carbamazepine extended-release capsules are the following: Cisplatin, doxorubicin HCl, felbamate, rifampin, phenobarbital, phenytoin Phenytoin plasma levels have also been reported to increase and decrease in the presence of carbamazepine, see below. Thus, if a patient has been titrated to a stable dosage on carbamazepine extended-release capsules, and then begins a course of treatment with one of these CYP3A4 inducers, it is reasonable to expect that a dose increase for carbamazepine extended-release capsules may be necessary. Carbamazepine is known to induce CYP1A2 and CYP3A4. Therefore, the potential exists for interaction between carbamazepine and any agent metabolized by one (or more) of these enzymes. Agents that have been found, or are expected to have decreased plasma levels in the presence of carbamazepine extended-release capsules due to induction of CYP enzymes are the following: Acetaminophen, alprazolam, amitriptyline, bupropion, buspirone, citalopram, clobazam, clonazepam, clozapine, cyclosporin, delavirdine, desipramine, diazepam, dicumarol, doxycycline, ethosuximide, felbamate, felodipine, glucocorticoids, haloperidol, itraconazole, lamotrigine, levothyroxine, lorazepam, methadone, midazolam, mirtazapine, nefazodone 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 (see CONTRAINDICATIONS). Concomitant use of carbamazepine extended-release capsules with hormonal contraceptive products (e. , oral and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported with carbamazepine. Alternative or back-up methods of contraception should be considered. Phenytoin has also been reported to increase in the presence of carbamazepine. Careful monitoring of phenytoin plasma levels following co-medication with carbamazepine is advised. Following co-administration of carbamazepine 400 mg/day with trazodone 100 mg to 300 mg daily, carbamazepine reduced trough plasma concentrations of trazodone (as well as metachlorophenylpiperazine [mCPP]) by 76 and 60% respectively, compared to precarbamazepine values. Warfarin''s anticoagulant effect can be reduced in the presence of carbamazepine. Thus, if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of treatment with carbamazepine extended-release capsules, it is reasonable to expect that a dose increase for the concomitant agent may be necessary. Carbamazepine extended-release capsules increases the plasma levels of the following agents: Clomipramine HCl, phenytoin Phenytoin has also been reported to decrease in the presence of carbamazepine. Thus, if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of the treatment with carbamazepine extended-release capsules, it is reasonable to expect that a dose decrease for the concomitant agent may be necessary.
Agents Highly Bound to Plasma Protein
Carbamazepine is not highly bound to plasma proteins; therefore, administration of carbamazepine extended-release capsules to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.
Agents that Inhibits Cytochrome P450 Isoenzymes and/or Epoxide Hydrolase
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. Therefore, the potential exists for interaction between carbamazepine and any agent that inhibits CYP3A4 and/or epoxide hydrolase. Agents that are CYP3A4 inhibitors that have been found, or are expected, to increase plasma levels of carbamazepine extended-release capsules are the following: Acetazolamide, azole antifungals, cimetidine, clarithromycin also inhibits epoxide hydrolase resulting in increased levels of the active metabolite carbamazepine 10,11- epoxide Thus, if a patient has been titrated to a stable dosage of carbamazepine extended-release capsules, and then begins a course of treatment with one of these CYP3A4 or epoxide hydrolase inhibitors, it is reasonable to expect that a dose reduction for carbamazepine extended-release capsules may be necessary.
Agents that Induce Cytochrome P450 Isoenzymes
Carbamazepine is metabolized by CYP3A4. Therefore, the potential exists for interaction between carbamazepine and any agent that induces CYP3A4. Agents that are CYP inducers that have been found, or are expected, to decrease plasma levels of carbamazepine extended-release capsules are the following: Cisplatin, doxorubicin HCl, felbamate, rifampin, phenobarbital, phenytoin Phenytoin plasma levels have also been reported to increase and decrease in the presence of carbamazepine, see below. Thus, if a patient has been titrated to a stable dosage on carbamazepine extended-release capsules, and then begins a course of treatment with one of these CYP3A4 inducers, it is reasonable to expect that a dose increase for carbamazepine extended-release capsules may be necessary.
Agents with Decreased Levels in the Presence of Carbamazepine due to Induction of Cytochrome P450 Enzymes
Carbamazepine is known to induce CYP1A2 and CYP3A4. Therefore, the potential exists for interaction between carbamazepine and any agent metabolized by one (or more) of these enzymes. Agents that have been found, or are expected to have decreased plasma levels in the presence of carbamazepine extended-release capsules due to induction of CYP enzymes are the following: Acetaminophen, alprazolam, amitriptyline, bupropion, buspirone, citalopram, clobazam, clonazepam, clozapine, cyclosporin, delavirdine, desipramine, diazepam, dicumarol, doxycycline, ethosuximide, felbamate, felodipine, glucocorticoids, haloperidol, itraconazole, lamotrigine, levothyroxine, lorazepam, methadone, midazolam, mirtazapine, nefazodone 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 (see CONTRAINDICATIONS). Concomitant use of carbamazepine extended-release capsules with hormonal contraceptive products (e.g., oral and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported with carbamazepine. Alternative or back-up methods of contraception should be considered. Phenytoin has also been reported to increase in the presence of carbamazepine. Careful monitoring of phenytoin plasma levels following co-medication with carbamazepine is advised. Following co-administration of carbamazepine 400 mg/day with trazodone 100 mg to 300 mg daily, carbamazepine reduced trough plasma concentrations of trazodone (as well as metachlorophenylpiperazine [mCPP]) by 76 and 60% respectively, compared to precarbamazepine values. Warfarin''s anticoagulant effect can be reduced in the presence of carbamazepine. Thus, if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of treatment with carbamazepine extended-release capsules, it is reasonable to expect that a dose increase for the concomitant agent may be necessary.
Agents with Increased Levels in the Presence of Carbamazepine
Carbamazepine extended-release capsules increases the plasma levels of the following agents: Clomipramine HCl, phenytoin Phenytoin has also been reported to decrease in the presence of carbamazepine. Careful monitoring of phenytoin plasma levels following co-medication with carbamazepine is advised.
Pharmacological/Pharmacodynamic Interactions with Carbamazepine
Coadministration of carbamazepine extended-release capsules with delavirdine may lead to loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors (see CONTRAINDICATIONS Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects. Given the anticonvulsant properties of carbamazepine, carbamazepine extended-release capsules may reduce the thyroid function as has been reported with other anticonvulsants. Additionally, anti-malarial drugs, such as chloroquine and mefloquine, may antagonize the activity of carbamazepine. Thus if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of treatment with carbamazepine extended-release capsules, it is reasonable to expect that a dose adjustment may be necessary. Because of its primary CNS effect, caution should be used when carbamazepine extended-release capsules are taken with other centrally acting drugs and alcohol.
Combination Therapy
Carbamazepine extended-release capsules 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 (see PRECAUTIONS, Drug Interactions Pregnancy Category D

Carbamazepine (CBZ)
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 14
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 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 C max max

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