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carbamazepine 200 mg tablet generic tegretol, epitol

Out of Stock Manufacturer TORRENT PHARMAC 13668026801
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Uses

Seizure Disorders

Carbamazepine is used in adults and children in the management of partial seizures with complex symptomatology (psychomotor or temporal lobe seizures), generalized tonic-clonic (grand mal) seizures, and mixed seizure patterns that include partial seizures with complex symptomatology, generalized tonic-clonic seizures, or other partial or generalized seizures. Patients with partial seizures with complex symptomatology appear to show greater improvement during carbamazepine therapy than patients with other types of seizures. Although the drug is useful in the management of mixed seizures, the response in patients with mixed seizures may be variable. Carbamazepine is ineffective in the management of absence (petit mal) seizures or myoclonic and akinetic seizures.

Carbamazepine may be used as monotherapy or adjunctive therapy (i.e., in combination with other anticonvulsants) for the management of seizure disorders. Carbamazepine has been used concomitantly with various other anticonvulsants such as phenytoin, phenobarbital, and primidone. When carbamazepine is used in combination with other anticonvulsants, the potential for drug interactions should be considered.(See Drug Interactions: Anticonvulsants.)

Neuropathic Pain

Carbamazepine is used in the symptomatic treatment of pain associated with true trigeminal neuralgia. Carbamazepine is not a simple analgesic and should not be administered casually for relief of trivial facial pain. Although some patients with glossopharyngeal neuralgia may respond to carbamazepine, the drug usually does not provide relief in facial pain from causes other than trigeminal neuralgia. Some patients with trigeminal neuralgia who did not respond to carbamazepine have been successfully treated with combined carbamazepine-phenytoin therapy.

Like certain other anticonvulsants, carbamazepine also has been used for the symptomatic treatment of chronic pain arising from other peripheral neuropathic syndromes, including pain of diabetic neuropathy.

Bipolar Disorder

Carbamazepine is used in the treatment of acute manic or mixed episodes in patients with bipolar I disorder. The American Psychiatric Association (APA) considers carbamazepine an alternative treatment option for patients who do not respond adequately to first-line drugs (e.g., lithium, valproate, antipsychotic agents [e.g., olanzapine]). For additional information on the management of bipolar disorder,

Efficacy of carbamazepine in the management of bipolar disorder has been established in 2 short-term (3-week) multicenter, double-blind, randomized placebo-controlled studies in over 400 adults who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. In both studies, patients received carbamazepine (200-800 mg twice daily as extended-release capsules) or placebo. Carbamazepine was substantially more effective than placebo in reducing manic symptoms as assessed by the Young Mania Rating Scale (YMRS); the onset of effect was observed as early as 1-2 weeks. Improvements in scores on the Clinical Global Impression-Severity (CGI-S) scale and Hamilton Rating Scale for Depression (HAM-D) also were noted with carbamazepine therapy.

Schizophrenia

Carbamazepine has been used in the symptomatic management of the acute phase of schizophrenia as an adjunct to therapy with an antipsychotic agent in patients who fail to respond to an adequate trial of the antipsychotic agent alone. For adjunctive therapy with an antipsychotic agent, carbamazepine generally is administered at the same range in dosage and therapeutic plasma concentrations as in the management of seizure disorders and bipolar disorder. APA states that, with the exception of schizophrenic patients whose illness has strong affective components, carbamazepine therapy alone (i.e., monotherapy rather than adjunctive therapy) has not been shown to be substantially effective in the long-term treatment of schizophrenia. For additional information on the management of schizophrenia, .

Other Uses

Carbamazepine has been used for the management of aggression (e.g., uncontrolled rage outbursts) and/or loss of control (dyscontrol) in patients with or without an underlying seizure disorder (e.g., as features of intermittent explosive disorder, conduct disorder, antisocial personality disorder, borderline personality disorder, dementia), alcohol withdrawal syndrome, relief of neurogenic pain and/or control of seizures in a variety of conditions including ''lightning'' pains of tabes dorsalis, pain and control of paroxysmal symptoms of multiple sclerosis, paroxysmal kinesigenic choreoathetosis, Kluver-Bucy syndrome, post-hypoxic action myoclonus, acute idiopathic polyneuritis (Landry-Guillain-Barre syndrome), pain of posttraumatic paresthesia, and, in children, hemifacial spasm and dystonia. The drug also has been used for its antidiuretic effects in the management of neurohypophyseal diabetes insipidus; however, other less toxic agents are available, and patients with primary polydipsia and polyuria have shown signs of water intoxication during carbamazepine therapy.

Dosage and Administration

Administration

Carbamazepine is usually administered orally; however, an IV preparation is available for temporary (i.e., no longer than 7 days) use in the management of seizure disorders in adults when oral administration is not feasible.

Patients who are currently receiving or beginning therapy with carbamazepine and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.(See Cautions: Nervous System Effects and see Cautions: Precautions and Contraindications.)

Pharmacogenetic Testing

Because of a strong association between the presence of the variant HLA-B*1502 allele and risk of developing carbamazepine-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), pharmacogenetic testing for HLA-B*1502 is recommended.(See Pharmacogenomics of Carbamazepine-induced Cutaneous Reactions under Cautions: Dermatologic and Sensitivity Reactions.) Prior to initiating carbamazepine therapy, patients with ancestry in high-risk populations (e.g., Han Chinese and other Asian populations) should be screened for the presence of HLA-B*1502. High-resolution HLA-B*1502 typing is recommended; the test is considered positive if 1 or 2 copies of HLA-B*1502 are detected and negative if no copies of the variant allele are detected. Patients who test positive for HLA-B*1502 should not be initiated on carbamazepine therapy unless the benefits clearly outweigh the risks. Genetic testing for the presence of HLA-A*3101, another variant allele associated with a wider range of carbamazepine hypersensitivity reactions, also may be considered.

Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502- and HLA-A*3101-positive patients who are treated with carbamazepine will never develop SJS, TEN, or other hypersensitivity reactions, and such reactions may develop infrequently in HLA-B*1502- and HLA-A*3101-negative patients of any ethnicity. For additional information and guidance on how to interpret and apply the results of HLA-B*1502 and HLA-A*3101 testing, the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for HLA genotype and use of carbamazepine and oxcarbazepine should be consulted.

Dispensing and Administration Precautions

Because of similarity in spelling between Tegretol or Tegretol-XR (trade names for carbamazepine) and Toprol-XL (a trade name for metoprolol succinate, a β-adrenergic blocking agent), the potential exists for dispensing errors involving these drugs. According to medication error reports, the overlapping tablet strengths (100 and 200 mg) between Tegretol or Tegretol-XR and Toprol-XL and the fact that these drugs were stored closely together in pharmacies also may have been contributing factors in causing these errors. Therefore, extra care should be exercised to ensure the accuracy of both oral and written prescriptions for these drugs. The manufacturer of Toprol-XL also recommends that pharmacists assess various measures of avoiding dispensing errors and implement them as appropriate (e.g., by verifying all orders for these drugs by citing both the trade and generic names to prescribers, attaching reminders to pharmacy shelves, separating the drugs on pharmacy shelves, counseling patients).(See Cautions: Precautions and Contraindications.)

Oral Administration

Carbamazepine is administered orally as conventional tablets, chewable tablets, extended-release tablets, extended-release capsules, or oral suspension.

Conventional or chewable tablets of carbamazepine are administered 2-4 times daily with meals.

Carbamazepine extended-release tablets are administered (usually twice daily) with meals. When administered at the same total daily dosage, steady-state plasma concentrations of carbamazepine from the extended-release tablet administered twice daily are comparable to concentrations from the conventional tablets given 4 times daily. Bioavailability of the extended-release tablet is 89% of that of the oral suspension. Carbamazepine extended-release tablets must be swallowed whole and not crushed, chewed, or broken. Prior to administration, the tablets should be inspected for chips or cracks; damaged tablets or tablets without a release portal should not be used. Because the coating of the extended-release tablet is not absorbed, it may be noticeable in the stool.

Carbamazepine extended-release capsules are administered (usually twice daily) without regard to meals. The extended-release capsules should be swallowed whole or administered by opening the capsule and sprinkling the contents over food (e.g., teaspoonful of applesauce). Carbamazepine extended-release capsules and their contents should not be chewed or crushed.

Carbamazepine oral suspension is administered 3 or 4 times daily with meals. The suspension should be shaken well before administration. Because coadministration of carbamazepine suspension with certain liquid preparations (e.g., chlorpromazine, thioridazine) has resulted in formation of a precipitate, the manufacturer states that the oral suspension should not be administered simultaneously with other liquid medications or diluents.

IV Administration

Carbamazepine is administered by IV infusion over 30 minutes. When patients are switched from oral to IV therapy, the corresponding total daily IV dosage (equivalent to 70% of the total daily oral dosage) should be administered in 4 equally divided 30-minute infusions every 6 hours. Bioequivalence has been demonstrated between oral carbamazepine and 30-minute IV infusions of the drug. IV carbamazepine is intended for temporary use only; patients should be switched back to oral therapy at the previously administered oral dose and frequency as soon as clinically appropriate. Use of IV carbamazepine for periods longer than 7 days has not been studied and is not recommended.

Prior to administration, carbamazepine concentrate for injection must be diluted in a compatible diluent. The appropriate volume of the concentrate for injection (based on the prescribed dose) should be withdrawn from the vial(s) and diluted in 100 mL of 0.9% sodium chloride injection, lactated Ringer's injection, or 5% dextrose injection. Following dilution, the infusion solution may be stored for up to 4 hours at room temperature (20-25°C) or up to 24 hours in the refrigerator (2-8°C) if not used immediately.

IV solutions of carbamazepine should be inspected visually for particulate matter, cloudiness, and discoloration prior to administration whenever solution and container permit; the drug should not be used if the solution is discolored, cloudy, or contains any particulate matter. Vials are for single dose only; unused portions should be discarded.

Dosage

Dosage of carbamazepine must be carefully and slowly adjusted according to individual requirements and response. Therapy should be initiated with a low dosage and increased gradually. Once a therapeutic effect has been achieved, efforts should be made to reduce the dosage to the minimum effective dosage.

When transferring patients from conventional, immediate-release formulations to extended-release capsules or tablets, the same total daily dosage should be administered in 2 divided doses. Following the transition, patients should be closely monitored and dosage adjusted as necessary. Because a given dose of carbamazepine administered as the oral suspension will produce higher peak concentrations of the drug than when administered as tablets, therapy with the oral suspension should be initiated with low, frequent doses (e.g., 50 mg 4 times daily for children 6-12 years of age) and increased slowly to reduce the risk of adverse effects (e.g., sedation). When transferring patients from therapy with oral tablets to the oral suspension, the total daily dose administered as tablets should be divided into smaller, more frequent doses of the suspension (e.g., transfer from twice-daily divided dosing of tablets to thrice [3 times]-daily divided dosing of the suspension).

Seizure Disorders

When carbamazepine is added to an existing anticonvulsant regimen, the drug should be introduced gradually while dosage of the other anticonvulsant(s) is maintained or gradually decreased, except for certain enzyme-inducing anticonvulsants (e.g., phenytoin) that may require an increase in dosage.(See Drug Interactions.) Carbamazepine should be withdrawn slowly to avoid precipitating seizures or status epilepticus.

Monitoring of plasma concentrations has increased efficacy and safety of anticonvulsants and may be particularly useful for optimizing dosage selection, minimizing adverse effects and risk of drug toxicity, and for verification of drug compliance, particularly in patients who are more likely to experience alterations in plasma concentrations (e.g., those with hepatic impairment, those receiving concomitant enzyme-inducing or -inhibiting drugs).

Adult Dosage

The recommended initial oral dosage of carbamazepine for the management of seizure disorders in adults is 200 mg twice daily (as chewable, conventional, or extended-release tablets, or extended-release capsules) or 100 mg 4 times daily (as the oral suspension). Dosage should be increased by increments of up to 200 mg daily at weekly intervals using a twice-daily divided dosing regimen (if using extended-release dosage forms) or a 3- or 4-times-daily divided dosing regimen (if using conventional or chewable tablets or oral suspension) until the optimum response is obtained. Dosage generally should not exceed 1.2 g daily in adults; however, some patients have required dosages up to 1.6 g daily. Once adequate seizure control is achieved, dosage of carbamazepine should be adjusted to the minimum effective level, which is usually 800 mg to 1.2 g daily in adults.

When oral therapy is temporarily not feasible in adults, carbamazepine may be administered by IV infusion in a total daily dosage equivalent to 70% of the total daily oral dosage; the total daily IV dosage should be administered in 4 equally divided 30-minute infusions at 6-hour intervals (e.g., a patient receiving an oral dosage of 400 mg daily would be switched to a corresponding IV dosage of 280 mg daily, administered as 70 mg every 6 hours). Because of a reduction in first-pass metabolism, elevated plasma concentrations of carbamazepine may occur when switching from oral to IV therapy in patients with hepatic impairment; plasma carbamazepine concentrations should be monitored in such patients.

Pediatric Dosage

The recommended initial oral dosage of carbamazepine for the management of seizure disorders in children older than 12 years of age is 200 mg twice daily (as chewable, conventional, or extended-release tablets, or extended-release capsules) or 100 mg 4 times daily (as the oral suspension). Dosage should be increased by increments of up to 200 mg daily at weekly intervals using a twice-daily divided dosing regimen (if using extended-release dosage forms) or a 3- or 4-times-daily dosing regimen (if using conventional or chewable tablets or oral suspension) until the optimum response is obtained. Dosage generally should not exceed 1 g daily in children 12-15 years of age or 1.2 g daily in children older than 15 years of age. Once adequate seizure control is achieved, dosage of carbamazepine should be adjusted to the minimum effective level, which is usually 800 mg to 1.2 g daily in children older than 12 years of age.

Dosage recommendations for the management of seizure disorders in children younger than 12 years of age differ based on the specific preparation of carbamazepine used. When using tablets or the oral suspension, the recommended initial dosage of carbamazepine in children 6-12 years of age is 100 mg twice daily (as conventional, chewable, or extended-release tablets) or 50 mg 4 times daily (as the oral suspension). Dosage should be increased by increments of up to 100 mg daily at weekly intervals using a twice-daily divided dosing regimen (if using extended-release tablets) or a 3- or 4-times-daily divided dosing regimen (if using conventional or chewable tablets or oral suspension) until the optimum response is obtained. Dosage generally should not exceed 1 g daily in children 6-12 years of age; once adequate seizure control is achieved, dosage should be adjusted to the minimum effective level, which is usually 400-800 mg daily in this age group. In children younger than 6 years of age, the recommended initial oral dosage of carbamazepine is 10-20 mg/kg daily in 2 or 3 divided doses (as conventional or chewable tablets) or 4 divided doses (as the oral suspension). Dosage should be increased weekly (administered 3 or 4 times daily) until the optimum response is obtained. The manufacturers state that optimal clinical response in children younger than 6 years of age generally is achieved at daily maintenance dosages less than 35 mg/kg. If satisfactory clinical response has not been achieved, plasma carbamazepine concentrations should be obtained to determine whether they are in the therapeutic range; safety of carbamazepine dosages exceeding 35 mg/kg in 24 hours in children younger than 6 years of age has not been established.

When using extended-release carbamazepine capsules for the management of seizure disorders in children younger than 12 years of age, the manufacturers state that optimal clinical response generally is achieved at daily dosages of less than 35 mg/kg. If satisfactory response has not been achieved, plasma carbamazepine concentrations should be measured to determine whether they are in the therapeutic range; safety of carbamazepine dosages exceeding 35 mg/kg in 24 hours using the extended-release capsule formulation in children younger than 12 years of age has not been established.

Therapeutic carbamazepine concentrations have been achieved more rapidly (in about 2 hours) in pediatric patients with a loading-dose regimen using the oral suspension. In this regimen, an initial oral loading dose (as the oral suspension) of 8 mg/kg in children 12 years of age and older or 10 mg/kg in children younger than 12 years of age has been administered. Loading doses should preferably be administered in a clinic or hospital setting where plasma concentrations and the patient can be monitored closely.

Neuropathic Pain

For the symptomatic treatment of pain associated with trigeminal neuralgia in adults, the recommended initial oral dosage of carbamazepine on the first day of therapy is 100 mg twice daily as tablets (conventional, chewable, or extended-release), 200 mg once daily as extended-release capsules, or 50 mg 4 times daily as the oral suspension. Dosage may be increased gradually by up to 200 mg daily using 100-mg increments every 12 hours (if using tablets or capsules) or 50-mg increments 4 times daily (if using the oral suspension) until pain is relieved. Maintenance dosages of 400-800 mg daily usually are adequate; however, some patients may require as little as 200 mg daily while others may require as much as 1.2 g daily. The manufacturers state that a carbamazepine dosage of 1.2 g daily should not be exceeded for the treatment of pain associated with trigeminal neuralgia. At least once every 3 months, an attempt should be made to decrease dosage to the minimum effective level or to discontinue the drug.

Bipolar Disorder

For the management of acute manic and mixed episodes associated with bipolar I disorder, the recommended initial oral dosage of carbamazepine in adults is 200 mg twice daily (as extended-release capsules). Although the manufacturer states that efficacy and safety of carbamazepine for such use in pediatric patients have not been established, initial dosages of 200-600 mg daily, given in 3 or 4 divided doses, have been used in children older than 12 years of age. Dosage should be increased as tolerated by increments of 200 mg daily until optimal clinical response is achieved. In hospitalized patients with acute mania, some experts state that dosage may be increased as tolerated in 200-mg daily increments up to 800 mg to 1 g daily, with slower increases thereafter as indicated. In less acutely ill outpatients, dosage should be adjusted at a slower rate because rapid increases may cause patients to develop adverse GI (e.g., nausea, vomiting) or CNS (e.g., drowsiness, dizziness, ataxia, clumsiness, diplopia) effects. If such adverse effects occur, temporary dosage reduction should be considered. Dosage may be increased again more slowly once these adverse effects resolve. Maintenance dosages of carbamazepine in patients with bipolar disorder average about 1 g daily, but may range from 200 mg to 1.6 g daily in routine clinical practice.

Cautions

Hematologic Effects

Although transient or persistent, minor hematologic changes (e.g., decreased leukocyte counts) are not uncommon, the risk of serious carbamazepine-induced hematologic toxicity appears to be low. Deaths from aplastic anemia have occurred rarely following carbamazepine therapy. Other hematopoietic complications associated with the drug include leukopenia, agranulocytosis, eosinophilia, leukocytosis, thrombocytopenia, pancytopenia, bone marrow depression, and purpura. Although data from a population-based, case-control study indicate that the risk of developing aplastic anemia or agranulocytosis in patients receiving carbamazepine is 5-8 times greater than that in the general population, the overall risk of these reactions in the untreated general population is low (about 6 cases per million population per year for agranulocytosis and about 2 cases per million population per year for aplastic anemia). Transient or persistent decreases in platelet or leukocyte counts are not uncommonly associated with carbamazepine use, but currently available data do not permit accurate estimates of the incidence or outcome of these effects; however, the vast majority of cases of leukopenia reportedly have not progressed to aplastic anemia or agranulocytosis. In addition, because the apparent frequency of minor hematologic changes progressing to agranulocytosis and aplastic anemia is very low, the vast majority of such changes observed during routine, periodic hematologic monitoring of carbamazepine-treated patients are unlikely to be signaling the impending development of either abnormality. Nonetheless, determination of baseline hematologic function should be performed prior to initiation of carbamazepine therapy, and patients exhibiting abnormalities during therapy with the drug should be monitored closely.(See Cautions: Precautions and Contraindications.)

Dermatologic and Sensitivity Reactions

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported in patients receiving carbamazepine. These reactions are estimated to occur in 1-6 per 10,000 new users of the drug in countries with mainly Caucasian populations; however, the risk in some Asian countries is estimated to be approximately 10 times higher.(See Pharmacogenomics of Carbamazepine-induced Cutaneous Reactions under Cautions: Dermatologic and Sensitivity Reactions.)

Other adverse dermatologic effects of carbamazepine include pruritic, erythematous, and maculopapular rashes (e.g., maculopapular eruption); urticaria; photosensitivity reactions; alterations in skin pigmentation; and exfoliative dermatitis. In addition, erythema multiforme and nodosum and development of a lupus erythematosus-like syndrome or aggravation of systemic lupus erythematosus have been reported. Alopecia also may occur. Although a causal relationship has not been established, hirsutism has been reported rarely in patients receiving carbamazepine.

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening reaction, has been reported with carbamazepine. The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. However, signs and symptoms associated with other organ systems also may occur.

Anaphylaxis and angioedema involving the larynx, glottis, lips, and eyelids have been reported rarely following administration of the first or subsequent doses of carbamazepine; such reactions may be fatal. Other hypersensitivity reactions, including fever, rash, peripheral eosinophilia, and reversible aseptic meningitis (manifested by confusion, myoclonus, and CSF pleocytosis), also have been reported rarely.

Pharmacogenomics of Carbamazepine-induced Cutaneous Reactions

Retrospective, case-control studies in patients of Chinese ancestry have demonstrated a strong association between the risk of developing carbamazepine-induced SJS and TEN and the presence of human leukocyte antigen (HLA)-B*1502, an inherited allelic variant of the HLA-B gene. The allelic distribution pattern for HLA-B*1502 is distinct for specific geographic areas and ethnic groups. The allele is found almost exclusively in patients with ancestry across broad areas of Asia, although marked variation exists in its prevalence among specific Asian populations. Greater than 15% of the population is reportedly HLA-B*1502-positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines compared with about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have an intermediate prevalence of HLA-B*1502, which averages about 2-4% but may be higher in some groups. HLA-B*1502 is present in less than 1% of the population in Japan and Korea and is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, Native Americans). While these distribution frequencies may be helpful in predicting broad population risk, they should not be used in place of individual genotyping.

The manufacturers, FDA, and other experts recommend that patients with ancestry in genetically at-risk populations be screened for the presence of the HLA-B*1502 allele prior to initiating carbamazepine therapy.(See Pharmacogenetic Testing under Dosage and Administration: Administration.) In deciding which patients to screen, the rates provided above for the prevalence of the HLA-B*1502 allele may provide a rough guide; however, clinicians should keep in mind the limitations of these figures because of the wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Patients testing positive for HLA-B*1502 should not receive carbamazepine therapy unless the benefits clearly outweigh the risks. Patients who are found to be negative for the allele are thought to have a low risk of developing SJS and TEN. In addition, over 90% of carbamazepine-induced SJS and TEN cases will develop within the first few months of therapy and, thus, the risk of these serious dermatologic events in patients who have been taking carbamazepine for longer than 3 months without experiencing a cutaneous reaction is extremely low; this information may be considered in determining the need for screening genetically at-risk patients currently receiving the drug.

The HLA-B*1502 allele has not been found to predict risk of less severe adverse dermatologic reactions associated with carbamazepine (e.g., multi-organ hypersensitivity, non-serious rash such as maculopapular eruption). However, limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS and TEN in patients of Chinese ancestry who are receiving other anticonvulsants associated with these reactions (e.g., lamotrigine, fosphenytoin, phenytoin). Avoidance of such drugs should therefore be considered in HLA-B*1502-positive patients when alternative therapies are otherwise equally acceptable.

The HLA-A*3101 allele is a variant of the HLA-A gene that has been implicated in the development of a wider range of carbamazepine-induced hypersensitivity reactions. Retrospective, case-control studies in patients of European, Korean, and Japanese ancestry have demonstrated a moderate association between the risk of carbamazepine-induced hypersensitivity reactions (including multi-organ hypersensitivity, maculopapular exanthema, SJS, and TEN) and the presence of HLA-A*3101. Similar to HLA-B*1502, the allelic distribution of HLA-A*3101 varies considerably based on region and ethnic populations, with frequency ranging from more than 15% in patients with Japanese, Native American, South Indian, and some Arabic ancestry to no more than 5-10% of patients with Chinese, Korean, European, Latin American, African American, Thai, Taiwanese, and other Indian ancestry. In populations with low rates of the HLA-B*1502 allele (e.g., European, African, Japanese), the presence of HLA-A*3101 appears to be the primary determinant of carbamazepine-induced SJS and TEN and other hypersensitivity reactions. The risks versus benefits of carbamazepine therapy should be considered in patients who test positive for HLA-A*3101. Experts recommend that carbamazepine should not be used in treatment-naive, HLA-A*3101-positive patients if alternative therapies are available; however, cautious use of the drug may be considered in HLA-A*3101-positive patients who have previously received carbamazepine for longer than 3 months without experiencing a cutaneous reaction.

Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors, such as anticonvulsant dosage, compliance, concomitant medications and illnesses, in the development of, and morbidity from, these reactions and the level of dermatologic monitoring have not been adequately studied to date.

Cardiovascular Effects

Adverse cardiovascular effects (some of which may be fatal), including congestive heart failure, aggravation of hypertension, hypotension, syncope and collapse, edema, thrombophlebitis, thromboembolism, aggravation of coronary artery disease, arrhythmias, and AV block, have been reported with carbamazepine therapy. Such effects generally occurred in patients with underlying risk factors. Myocardial infarction has been associated with tricyclic compounds.

Hepatic Effects

Hepatic complications associated with carbamazepine include abnormalities in liver function test results, cholestatic and hepatocellular jaundice, hepatitis, and very rare cases of hepatic failure. Such hepatic effects have sometimes progressed despite discontinuance of the drug. Vanishing bile duct, a cholestatic condition with a variable clinical course, has been reported rarely and in some cases had overlapping manifestations with immune-mediated hypersensitivity reactions (e.g., multi-organ hypersensitivity).(See Cautions: Precautions and Contraindications.)

Genitourinary Effects

Genitourinary complications associated with carbamazepine include urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN concentrations, and microscopic deposits in the urine also have been reported.

Nervous System Effects

Adverse neurologic and sensory effects of carbamazepine include dizziness, vertigo, drowsiness, fatigue, ataxia, disturbances of coordination, confusion, headache, nystagmus, blurred vision, transient diplopia, visual hallucinations, hyperacusis, oculomotor disturbances, speech disturbances, and abnormal involuntary movements. Rarely, peripheral neuritis and paresthesia, depression with agitation, talkativeness, and tinnitus may occur. Reports of associated paralysis and other symptoms of cerebral arterial insufficiency have been described, but the exact relationship of these reactions to the administration of carbamazepine has not been established.

An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of studies using various anticonvulsants, including carbamazepine, compared with placebo. The analysis of suicidality reports from 199 placebo-controlled studies involving 11 anticonvulsants (i.e., carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%). This increased suicidality risk was observed as early as one week after beginning therapy and continued through 24 weeks. The results were generally consistent among the 11 drugs studied. Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to be at increased risk for suicidality when compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.(See Cautions: Precautions and Contraindications.)

Initiation of carbamazepine for the management of complex partial seizures has been associated with exacerbation of seizures, principally atypical absence and/or generalized convulsive seizures, in some children with mixed seizure disorders. In one group of children, video-EEG monitoring revealed a generalized paroxysmal spike-and-wave discharge in all of the children in whom exacerbation of seizures occurred during carbamazepine therapy. Children who developed frequent generalized convulsive seizures had a pattern of spikes and slow waves with a frequency of 1-2 cycles/second, and those who developed more frequent and severe atypical absence seizures had a generalized spike-and-wave discharge of 2.5-3 cycles/second. Although the mechanism is not known, it was suggested that exacerbation of seizures in these children may result from carbamazepine-induced activation of epileptiform discharges. It has been suggested that carbamazepine be used with caution for the management of complex partial seizures in children with mixed seizure disorders, particularly those who have a generalized absence or atypical absence component, and that the drug be avoided when there is generalized, synchronous, spike-and-wave discharges of 2.5-3 cycles/second in association with clinical seizures regardless of their clinical manifestation. The possibility that a worsening of atypical absence and/or generalized convulsive seizures following initiation of carbamazepine therapy may be drug induced rather than the natural history of the child's epilepsy should be considered.

GI Effects

Adverse GI effects of carbamazepine include nausea, vomiting, gastric distress, abdominal pain, diarrhea, constipation, anorexia, dryness of the mouth and pharynx, glossitis, and stomatitis.

Other Adverse Effects

Other adverse effects reported during carbamazepine therapy include diaphoresis, fever and chills, adenopathy or lymphadenopathy, acute intermittent porphyria, aching joints and muscles, leg cramps, and conjunctivitis. Decreased plasma calcium concentrations and hyponatremia have been reported. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cases of frank water intoxication, with hyponatremia and confusion, have also been reported. Geriatric patients and patients receiving diuretics appear to be at greater risk of hyponatremia. Pulmonary hypersensitivity, characterized by fever, dyspnea, pneumonitis, or pneumonia, also has occurred. Isolated cases of neuroleptic malignant syndrome have been reported with concomitant use of carbamazepine and psychotropic drugs.

Although scattered, punctate lens opacities have occurred only rarely in patients receiving carbamazepine, other drugs such as the phenothiazines have caused various ocular changes.

Precautions and Contraindications

Carbamazepine may produce serious adverse effects, principally consisting of hematopoietic, dermatologic, cardiovascular, hepatic, and renal disturbances. The drug also shares the toxic potentials of the hydantoin-derivative anticonvulsants, and the usual precautions of anticonvulsant administration should be observed. When serious adverse effects occur requiring discontinuance of the drug, it is important to remember that abrupt withdrawal of any anticonvulsant drug in epileptic patients may precipitate seizures or status epilepticus. Carbamazepine therapy should be withdrawn gradually to minimize the potential for increased seizure frequency. Patients must be carefully examined prior to initiation of carbamazepine therapy and should remain under close medical supervision throughout therapy with the drug. Carbamazepine should be prescribed only after careful benefit-to-risk evaluation in patients with a history of cardiac conduction disturbances; cardiac, hepatic, or renal damage; or adverse hematologic or hypersensitivity reaction to other drugs (e.g., other anticonvulsants) or who have had interrupted therapy with carbamazepine.

Close attention by the patient and clinician to signs and symptoms of the possible development of adverse hematologic, dermatologic, or hypersensitivity reactions is important in patients receiving carbamazepine. Patients should be informed of the early signs and symptoms of these potential problems, such as fever, sore throat, infection, rash, mouth ulcers, easy bruising, lymphadenopathy, and petechial or purpuric hemorrhage, and should be instructed to report to their clinician immediately if any such sign or symptom occurs. In addition, patients should be advised that these manifestations should be reported even if they are mild in severity or if they occur after extended use.

Pharmacogenetic testing is recommended in patients who may have a genetic predisposition to carbamazepine-induced cutaneous reactions.(See Pharmacogenetic Testing under Dosage and Administration: Administration.) If manifestations of multi-organ hypersensitivity occur during carbamazepine therapy, patients should be evaluated immediately; if an alternative cause cannot be identified, the drug should be discontinued. Because anaphylactic reactions and angioedema have occurred during carbamazepine therapy, patients should be advised to stop taking the drug and immediately report any signs or symptoms of hypersensitivity to their clinician. If anaphylaxis or angioedema develops during carbamazepine therapy, the drug should be discontinued and alternative therapy initiated; patients who experience severe hypersensitivity reactions should not be rechallenged with the drug. Because cross-hypersensitivity between carbamazepine and other anticonvulsants (e.g., phenytoin, phenobarbital, primidone) has been reported, a detailed drug history should be obtained from patients and their immediate family members. The benefits versus risks of carbamazepine therapy should be carefully considered in patients with a history of previous hypersensitivity to other anticonvulsants. Approximately one-third of patients with a history of carbamazepine hypersensitivity will develop hypersensitivity to oxcarbazepine.

Complete blood counts, including platelet and possibly reticulocyte counts and serum iron determinations, should be performed prior to initiating carbamazepine therapy; subsequent monitoring should be individualized by the clinician. Guidelines for periodic monitoring of hematologic function have been suggested by some clinicians, and clinicians experienced in the use of carbamazepine and knowledgeable about the drug's potential toxicity can be consulted for more specific information. Patients exhibiting baseline abnormalities and those receiving other potentially myelotoxic drugs or with a history of adverse hematologic reactions to any drug should be considered at special risk, and carbamazepine therapy should be monitored closely or avoided in these patients. Patients with a history of bone marrow depression should not receive the drug. Patients who exhibit low or decreased leukocyte or platelet counts during the course of carbamazepine therapy should be monitored closely. Discontinuance of carbamazepine therapy should be considered if any evidence of significant bone marrow depression develops. In addition, if such evidence develops, particularly if it occurs as a result of overdosage, it has been suggested that complete blood counts, platelet counts, and reticulocyte counts be performed daily and bone marrow aspiration and trephine biopsy be done immediately and repeated as often as necessary to monitor recovery. Other special periodic hematologic studies may also be helpful in patients with evidence of significant bone marrow depression. Fully developed aplastic anemia requires appropriate, intensive monitoring and therapy for which specialized consultation should be sought. Some clinicians also advise hematologic consultation if neutropenia and depressed platelet and reticulocyte counts occur during therapy with the drug.

Adverse hepatic effects, ranging from slight elevations in hepatic enzymes to rare cases of hepatic failure, have been reported.(See Cautions: Hepatic Effects.) Liver function tests must be performed prior to carbamazepine therapy and periodically thereafter, particularly in patients with a history of liver disease. Discontinuance of the drug should be considered based on clinical judgment in patients with evidence of liver disease; some manufacturers recommend immediate discontinuance if worsening liver dysfunction or active liver disease is observed. In addition, patients should be advised of the early manifestations of adverse hepatic effects (e.g., anorexia, nausea/vomiting, jaundice) and instructed to report such symptoms to their clinician immediately, even if the symptoms are mild or occur after extended use.

Because acute attacks of porphyria have been reported, carbamazepine should not be used in patients with a history of hepatic porphyria.

Because impairment of renal function has been observed in patients receiving carbamazepine, renal function (e.g., complete urinalysis and BUN determinations) should be performed prior to and periodically during therapy. Because of potential accumulation of the cyclodextrin excipient present in the IV formulation of carbamazepine, the manufacturer states that the drug generally should not be used in patients with moderate or several renal impairment. Such patients may be at greater risk of adverse renal effects and should be closely monitored if IV carbamazepine therapy is necessary.

Patients who are currently receiving or beginning therapy with any anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior.(See Cautions: Nervous System Effects.) Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy and advise them to pay close attention to any day-to-day changes in mood, behavior, and actions; since changes can happen very quickly, it is important to be alert to any sudden differences. In addition, patients, family members, and caregivers should be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions). If these or any new and worrisome behaviors occur, the responsible clinician should be contacted immediately. Clinicians who prescribe carbamazepine or any other anticonvulsant should balance the risk of suicidality with the risk of untreated illness. Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.

Carbamazepine may exacerbate seizures in some children with mixed seizure disorders. Some clinicians recommend that prolonged video-EEG monitoring be performed prior to initiating carbamazepine therapy in children with mixed seizure disorders in an attempt to identify those children who may be at risk for carbamazepine-induced exacerbation of seizures.(See Cautions: Nervous System Effects.)

Persons who perform hazardous tasks requiring mental alertness or physical coordination should be warned about the possible adverse neurologic and sensory effects of carbamazepine. Patients receiving carbamazepine also should be advised that there is a potential for additive CNS effects if alcohol is used concomitantly with carbamazepine. Because of the relationship of carbamazepine to other tricyclic compounds, the possibility of activation of a latent psychosis or, in geriatric patients, confusion or agitation should be kept in mind.

Baseline and periodic eye examinations including slit-lamp, funduscopy, and tonometry are recommended in patients receiving carbamazepine. Carbamazepine has shown mild anticholinergic activity; therefore, patients with a history of increased intraocular pressure should be assessed for such condition prior to and periodically during carbamazepine therapy.

Because of similarity in spelling between Tegretol or Tegretol-XR (trade names for carbamazepine) and Toprol-XL (metoprolol succinate, a β-adrenergic blocking agent), the potential exists for dispensing errors involving these drugs. These medication errors have been associated with serious adverse events sometimes requiring hospitalization as a result of either lack of the intended medication (e.g., seizure recurrence, return of hallucinations, suicide attempt, hypertension recurrence) or exposure to the wrong drug (e.g., bradycardia in a patient erroneously receiving metoprolol). Therefore, extra care should be exercised to ensure the accuracy of both oral and written prescriptions for these drugs.(See Dispensing and Administration Precautions under Dosage and Administration: Administration.) Dispensing errors involving Tegretol or Tegretol-XR (carbamazepine) and Toprol-XL (metoprolol succinate) should be reported to the manufacturers, the USP/ISMP (Institute for Safe Medication Practices) Medication Errors Reporting Program by phone (800-233-7767), or directly to the FDA MedWatch program by phone (800-FDA-1088), fax (800-FDA-0178), or internet (http://www.fda.gov/Safety/MedWatch).

Carbamazepine is contraindicated in patients with a history of bone marrow depression or hypersensitivity to the drug or any of the tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline, protriptyline). The drug also is contraindicated in patients currently receiving, or having recently received (i.e., within 2 weeks), monoamine oxidase (MAO) inhibitor therapy.(See Drug Interactions: Monoamine Oxidase Inhibitors.) Concomitant use of carbamazepine and nefazodone is contraindicated.(See Drug Interactions: Nefazodone.) In addition, the manufacturer of voriconazole states that concomitant use of carbamazepine and voriconazole is contraindicated. (See Drug Interactions: Azole Antifungal Agents.)

Pediatric Precautions

Efficacy of carbamazepine for management of seizures in children is based on extrapolation of the demonstrated efficacy of carbamazepine in adults and also on in vitro studies that confirmed that the pathogenetic mechanisms associated with seizure propagation in adults are essentially the same as those in children; in addition, mechanism of action of carbamazepine in the treatment of seizures is the same in adults and children. The therapeutic range for plasma carbamazepine concentrations (i.e., 4-12 mcg/mL) is the same in children and adults. Safety of carbamazepine in children is based on clinical studies in which the drug was administered for up to 6 months. Data from long-term clinical studies in children are not available.

Mutagenicity and Carcinogenicity

Bacterial and mammalian mutagenicity studies using carbamazepine have shown no evidence of mutagenicity. Carbamazepine has produced dose-related increases in the incidence of hepatocellular tumors in female rats and benign interstitial cell adenomas in male rats. The clinical importance of these findings is not known.

Pregnancy and Lactation

Pregnancy

Safe use of carbamazepine during pregnancy has not been established. Adverse fetal effects have been observed in reproduction studies in rats. Although several reports suggest an association between use of anticonvulsants in pregnant, epileptic women and an increased incidence of birth defects in children born to these women, a causal relationship to many of these drugs has not been established. However, epidemiologic data suggest that an association between carbamazepine use during pregnancy and certain congenital abnormalities such as spina bifida may exist. Other congenital anomalies and developmental disorders (e.g., craniofacial defects, cardiovascular malformations, anomalies involving various body systems) also have been reported in association with carbamazepine use.

Anticonvulsants should not be discontinued in pregnant women in whom the drugs are administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases, when the severity and frequency of the seizure disorder are such that discontinuance of therapy does not pose a serious threat to the patient, discontinuance of the drugs may be considered prior to and during pregnancy; however, it cannot be said with any certainty that even minor seizures do not pose some hazard to the fetus. Clinicians should carefully weigh these considerations in treating or counseling epileptic women of childbearing potential. Because carbamazepine can cause fetal harm when administered to pregnant women, the benefits of therapy must be weighed against the risks in women of childbearing potential. If carbamazepine is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus. Tests to detect fetal abnormalities using currently accepted procedures should be considered part of routine prenatal care in women of childbearing potential receiving carbamazepine.

There have been a few cases of seizures and/or respiratory depression in neonates born to women receiving carbamazepine concomitantly with other anticonvulsant agents. A few cases of vomiting, diarrhea, and/or decreased feeding also have been reported in neonates born to women receiving carbamazepine; these symptoms may represent a neonatal withdrawal syndrome.

Women who are pregnant while receiving carbamazepine should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 888-233-2334. Information on the registry also can be found on the website http://www.aedpregnancyregistry.org.

Lactation

Carbamazepine and its epoxide metabolite (carbamazepine 10,11-epoxide [CBZ-E]) are distributed into milk. Safe use of carbamazepine during lactation has not been established. Because of the potential for serious adverse reactions from carbamazepine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. Following daily oral administration of carbamazepine in nursing women, the milk-to-maternal plasma ratio of carbamazepine is about 0.4 and that of CBZ-E is about 0.5; it is estimated that neonates may receive about 2-5 and 1-2 mg of carbamazepine and CBZ-E, respectively, daily.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Carbamazepine is a substrate for and potent inducer of cytochrome P-450 (CYP) isoenzyme 3A4. The drug also induces CYP1A2, 2B6, and 2C9/19.

Concomitant use of carbamazepine with drugs that inhibit CYP3A4 may increase plasma concentrations of carbamazepine, resulting in possible increased risk of adverse effects. CYP3A4 inhibitors that have been shown, or would be expected, to increase plasma carbamazepine concentrations to a clinically important extent include (but are not limited to) acetazolamide, aprepitant, azole antifungals, cimetidine, ciprofloxacin, danazol, dantrolene, delavirdine, diltiazem, fluoxetine, fluvoxamine, grapefruit juice, ibuprofen, isoniazid, loratadine, macrolide antibiotics, nefazodone, niacinamide, olanzapine, omeprazole, oxybutynin, propoxyphene, protease inhibitors, quinine, quinupristin/dalfopristin, ticlopidine, trazodone, valproate, verapamil, and zileuton. When carbamazepine is used concomitantly with CYP3A4 inhibitors, close monitoring of plasma carbamazepine concentrations is recommended; dosage adjustment may be necessary.

Concomitant use of carbamazepine with drugs that induce CYP3A4 may decrease plasma concentrations of carbamazepine, resulting in possible reduced efficacy of the drug. CYP3A4 inducers that have been shown, or would be expected, to decrease plasma carbamazepine concentrations to a clinically important extent include (but are not limited to) cisplatin, doxorubicin, felbamate, fosphenytoin, methsuximide, phenobarbital, phenytoin, primidone, rifampin, and theophylline. When carbamazepine is used concomitantly with CYP3A4 inducers, close monitoring of plasma carbamazepine concentrations is recommended; dosage adjustment may be necessary.

Carbamazepine may reduce plasma concentrations of drugs metabolized by CYP3A4, 1A2, 2B6, or 2C9/19 through its enzyme-inducing effects. These drugs include (but are not limited to) acetaminophen, albendazole, alprazolam, aprepitant, aripiprazole, buprenorphine, bupropion, citalopram, clonazepam, clozapine, corticosteroids (e.g., dexamethasone, prednisolone), cyclosporine, dihydropyridine calcium-channel blocking agents, doxycycline, eslicarbazepine, ethosuximide, everolimus, haloperidol, hormonal contraceptives, imatinib, itraconazole, lamotrigine, lapatinib, levothyroxine, methadone, methsuximide, midazolam, mirtazapine, nefazodone, olanzapine, oxcarbazepine, paliperidone, phenytoin, praziquantel, protease inhibitors, risperidone, sertraline, simvastatin, sirolimus, tacrolimus, tadalafil, temsirolimus, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants, valproate, warfarin, ziprasidone, and zonisamide. When carbamazepine is used concomitantly with these drugs, monitoring of plasma concentrations or dosage adjustment of the concomitantly administered drug may be necessary.

Drugs Affected by P-glycoprotein Transport

Carbamazepine is an inducer of P-glycoprotein (P-gp) and can reduce plasma concentrations of drugs affected by this transport protein.

Drugs Metabolized by Uridine Diphosphate Glucuronosyltransferase

Carbamazepine is a potent inducer of uridine diphosphate glucuronosyltransferase (UGT) 1A1 and can reduce plasma concentrations of drugs metabolized by this enzyme.

Drugs Associated with Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Avoidance of other drugs associated with Stevens-Johnson syndrome and toxic epidermal necrolysis should be considered in HLA-B*1502-positive patients when alternative therapies are available.(See Cautions: Dermatologic and Sensitivity Reactions and see Cautions: Precautions and Contraindications.)

Drugs that Inhibit Epoxide Hydrolase

The active metabolite of carbamazepine (carbamazepine 10,11-epoxide [CBZ-E]) is metabolized by epoxide hydrolase. Drugs that inhibit this enzyme (e.g., clarithromycin, erythromycin, loxapine, quetiapine, valproic acid) can increase plasma concentrations of CBZ-E; if carbamazepine is used concomitantly with drugs that inhibit epoxide hydrolase, plasma concentrations of carbamazepine should be monitored and dosage of the drug adjusted as necessary.

Alcohol

Because of the risk of additive sedative effects, caution should be exercised if carbamazepine is used concomitantly with alcohol.

Alprazolam

In healthy individuals, concomitant administration of alprazolam and carbamazepine substantially increased oral clearance and decreased elimination half-life of alprazolam, but did not substantially alter peak plasma concentrations of the drug.

Anticoagulants

Warfarin

Carbamazepine may decrease plasma concentrations of warfarin through hepatic enzyme induction. The effects of warfarin should be monitored and dosage of the drug adjusted as necessary.

Direct Oral Anticoagulants

Carbamazepine may decrease plasma concentrations of apixaban, dabigatran, edoxaban, and rivaroxaban and reduce efficacy of these anticoagulants. Some manufacturers recommend that concomitant use of carbamazepine and these drugs generally should be avoided.

Anticonvulsants

Carbamazepine can induce the metabolism of and decrease plasma concentrations of certain anticonvulsants (e.g., clonazepam, eslicarbazepine, ethosuximide, lamotrigine, methsuximide, oxcarbazepine, phenytoin, tiagabine, topiramate, valproate, zonisamide). Plasma concentration monitoring or dosage adjustment of the concomitantly administered anticonvulsant may be necessary.

Concomitant use of carbamazepine with other anticonvulsants that induce CYP3A4 (e.g., felbamate, fosphenytoin, methsuximide, phenobarbital, phenytoin, primidone) may decrease plasma carbamazepine concentrations. Close monitoring of plasma carbamazepine concentrations is recommended and dosage should be adjusted as necessary.

Felbamate and valproic acid apparently can affect plasma concentrations of both carbamazepine and CBZ-E, but the interactions appear to be complex and resultant changes may be unpredictable. The effect of valproic acid on carbamazepine concentrations may depend principally on increases in plasma CBZ-E concentrations relative to parent drug (possibly secondary to inhibition of epoxide hydrolase activity), but other mechanisms (e.g., displacement of carbamazepine from protein binding sites) also have been suggested and may contribute to the overall effect. The importance of determining CBZ-E concentrations in patients exhibiting toxicity during concomitant carbamazepine and valproic acid therapy should be considered.

Carbamazepine can inhibit the metabolism of and increase plasma concentrations of primidone. Patients receiving stable dosages of primidone may require a dosage reduction when initiating concomitant therapy with carbamazepine.

Because the effect of carbamazepine on phenytoin pharmacokinetics is complex and can result in either increased or decreased concentrations of phenytoin, close monitoring of plasma phenytoin concentrations is recommended during concomitant therapy.

Results of a pharmacokinetic study in children with epilepsy showed no effect of levetiracetam on plasma carbamazepine concentrations.

No substantial pharmacokinetic interaction was observed in healthy individuals who received lacosamide and carbamazepine concomitantly.

In healthy individuals, concomitant administration of brivaracetam and carbamazepine decreased peak plasma concentrations and systemic exposure of brivaracetam by a modest degree (13 and 29%, respectively); systemic exposure to carbamazepine was not substantially altered, but exposure to CBZ-E was markedly increased by 2.6-fold.

Alterations of thyroid function have been reported with concomitant use of carbamazepine and other anticonvulsants.

Antimalarial Agents

Quinine (a CYP3A4 inhibitor) can increase plasma concentrations of carbamazepine; dosage adjustment of carbamazepine may be required.

The antimalarial agents chloroquine and mefloquine may antagonize the activity of carbamazepine.

Antimycobacterial Agents

Isoniazid

Isoniazid (a CYP3A4 inhibitor) can increase plasma concentrations of carbamazepine. Close monitoring of plasma carbamazepine concentrations is recommended during concomitant therapy; dosage adjustment of carbamazepine may be required.

Carbamazepine has been reported to increase isoniazid-induced hepatotoxicity.

Rifampin

Rifampin (a CYP3A4 inducer) can decrease plasma concentrations of carbamazepine. Close monitoring of plasma carbamazepine concentrations is recommended during concomitant therapy; dosage adjustment of carbamazepine may be required.

Antipsychotic Agents

Loxapine and quetiapine can inhibit epoxide hydrolase activity and increase plasma concentrations of CBZ-E. If carbamazepine is used concomitantly with loxapine or quetiapine, plasma concentrations of carbamazepine should be monitored closely; dosage adjustment of carbamazepine may be required.

Carbamazepine may induce the metabolism of and decrease plasma concentrations of certain antipsychotic agents (e.g., aripiprazole, clozapine, haloperidol, paliperidone, quetiapine, risperidone, ziprasidone). Reductions in antipsychotic efficacy with reemergence of symptoms has occurred in some, but not all, cases. Plasma concentration monitoring of the antipsychotic agent may be necessary during concomitant therapy and dosage should be adjusted accordingly.

Aripiprazole

In a study in patients with schizophrenia, concomitant administration of aripiprazole and carbamazepine substantially reduced plasma concentrations of aripiprazole and its metabolite by 64 and 68%, respectively. If carbamazepine therapy is initiated in a patient receiving aripiprazole, dosage of aripiprazole should be doubled and additional increases made based on clinical evaluation; if carbamazepine is withdrawn from therapy, dosage of aripiprazole should be reduced accordingly.

Clozapine

Concomitant use of carbamazepine and clozapine has been shown to decrease clozapine concentrations by about 40-50%. Both carbamazepine and clozapine also have the potential to cause adverse hematologic effects, including agranulocytosis. In addition, neuroleptic malignant syndrome (NMS) has been reported rarely during concomitant therapy with these drugs. Therefore, the American Psychiatric Association (APA) states that concomitant use of carbamazepine and clozapine generally is not recommended. However, if carbamazepine and clozapine are used concomitantly, it should be considered that discontinuance of carbamazepine may result in increased plasma concentrations of clozapine.

Haloperidol

Concomitant use of carbamazepine and haloperidol has resulted in substantially decreased plasma concentrations of haloperidol and reduced efficacy of the drug. Patients receiving carbamazepine and haloperidol concomitantly should be monitored carefully for loss of antipsychotic efficacy and, if an interaction is suspected, haloperidol dosage should be adjusted accordingly; the possibility that haloperidol toxicity may occur following discontinuance of carbamazepine also should be considered.

Olanzapine

Olanzapine (a CYP3A4 inhibitor) may increase plasma concentrations of carbamazepine. Close monitoring of plasma carbamazepine concentrations is recommended during concomitant therapy; dosage adjustment of carbamazepine may be required. In addition, carbamazepine may decrease plasma concentrations of olanzapine through hepatic enzyme induction.

Quetiapine

In a pharmacokinetic study in patients receiving quetiapine and carbamazepine concomitantly, peak plasma concentrations and systemic exposure of quetiapine were substantially decreased by 80 and 87%, respectively.

Risperidone

In a study in patients with schizophrenia, concomitant administration of risperidone and carbamazepine substantially reduced plasma concentrations of risperidone and its active 9-hydroxyrisperidone metabolite.

Ziprasidone

In healthy individuals, concomitant use of ziprasidone and carbamazepine resulted in modest reductions in peak plasma concentrations and systemic exposure of ziprasidone (by 27 and 36%, respectively); these changes were not considered to be clinically important.

Antiretroviral Agents

Dolutegravir

In healthy individuals, concomitant use of dolutegravir (a UGT1A1 and CYP3A4 substrate) and carbamazepine reduced peak plasma concentrations and systemic exposure of dolutegravir by 33 and 49%, respectively. An increase in dolutegravir dosage is recommended when the drug is administered concomitantly with carbamazepine.

HIV Nonnucleoside Reverse Transcriptase Inhibitors

Carbamazepine can induce the metabolism of and decrease plasma concentrations of concomitantly administered HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) that are metabolized by CYP3A4 (e.g., delavirdine, efavirenz); possible loss of virologic response and resistance to the NNRTI may occur. Carbamazepine has been shown to decrease delavirdine concentrations by 90%. Some manufacturers state that concomitant use of carbamazepine and delavirdine or other NNRTIs metabolized by CYP3A4 is contraindicated.

Delavirdine (a CYP3A4 inhibitor) may increase plasma concentrations of carbamazepine. Efavirenz may decrease plasma concentrations of carbamazepine, but exposure to its active metabolite does not appear to be substantially altered.

HIV Protease Inhibitors

Concomitant use of carbamazepine with HIV protease inhibitors (PIs) that inhibit CYP3A4 may result in increased plasma concentrations of carbamazepine. If used concomitantly, plasma concentrations of carbamazepine should be monitored closely and dosage of the drug adjusted as necessary.

Carbamazepine can induce the metabolism of and decrease plasma concentrations of PIs. Monitoring of plasma concentrations or dosage adjustment of the PI may be necessary.

Aprepitant

Aprepitant (a CYP3A4 inhibitor) may increase plasma concentrations of carbamazepine. Close monitoring of plasma carbamazepine concentrations is recommended during concomitant therapy; dosage adjustment of carbamazepine may be required.

Carbamazepine may induce metabolism of and decrease plasma concentrations of aprepitant; plasma concentration monitoring or dosage adjustment of aprepitant may be necessary.

Azole Antifungal Agents

Azole antifungal agents that inhibit CYP3A4 (e.g., fluconazole, itraconazole, ketoconazole, voriconazole) may increase plasma concentrations of carbamazepine. Close monitoring of plasma carbamazepine concentrations is recommended during concomitant therapy; dosage adjustment of carbamazepine may be required.

Carbamazepine can induce the metabolism of and decrease plasma concentrations of itraconazole and voriconazole, resulting in possible loss of antifungal efficacy. Increased dosage of itraconazole may be necessary when used concomitantly with carbamazepine. The manufacturer of voriconazole states that concomitant use of carbamazepine and voriconazole is contraindicated.

Bupropion

Carbamazepine can induce the metabolism of bupropion and has been shown to decrease peak plasma concentrations and systemic exposure of the drug by 87 and 90%, respectively. Monitoring of plasma concentrations or dosage adjustment of bupropion may be necessary.

Calcium-channel Blocking Agents

Concomitant use of carbamazepine and calcium-channel blocking agents that inhibit CYP3A4 may increase plasma concentrations and subsequent toxicity of carbamazepine. In several patients receiving carbamazepine (1-2 g daily), initiation of verapamil hydrochloride (360 mg daily) resulted in development of neurologic manifestations (e.g., dizziness, ataxia, nystagmus) of carbamazepine toxicity within 36-96 hours. Plasma total and unbound carbamazepine concentrations increased by a mean of 46 and 33%, respectively, but returned to baseline values within 1 week after discontinuance of verapamil; manifestations of toxicity also resolved during this period. The ratio of plasma CBZ-E to unchanged drug decreased during verapamil therapy but returned toward pretreatment levels following discontinuance of verapamil. Limited experience suggests that a similar interaction also may occur when diltiazem, but not nifedipine, is administered concomitantly with carbamazepine. It appears that verapamil and diltiazem inhibit hepatic metabolism of carbamazepine via the CYP3A4 isoenzyme.

Patients should be monitored closely for manifestations of carbamazepine toxicity and for alterations in the pharmacokinetics of carbamazepine during concomitant therapy, and carbamazepine dosage should be adjusted accordingly. If verapamil is initiated in patients receiving carbamazepine, a 40-50% reduction in carbamazepine dosage may be necessary. If verapamil is discontinued, dosage of carbamazepine should be increased to avoid loss of seizure control.

Carbamazepine can induce the metabolism of and decrease plasma concentrations of dihydropyridine calcium-channel blocking agents (e.g., felodipine). Monitoring of plasma concentrations or dosage adjustment of the calcium-channel blocking agent may be necessary.

Cyclophosphamide

Carbamazepine may increase the rate of metabolism of cyclophosphamide prodrug to its active metabolite, resulting in possible increased toxicity.

Diuretics

Concomitant use of diuretics (e.g., hydrochlorothiazide, furosemide) may increase the risk of carbamazepine-induced symptomatic hyponatremia.

Fexofenadine

In healthy individuals, concomitant administration of fexofenadine and carbamazepine substantially decreased peak plasma concentrations and systemic exposure of fexofenadine.

Grapefruit Juice

Grapefruit juice (a CYP3A4 inhibitor) has been shown to substantially increase peak plasma concentrations, trough concentrations, and systemic exposure of carbamazepine. Plasma concentrations of carbamazepine should be monitored and dosage adjusted as necessary.

Hormonal Contraceptives

Carbamazepine can induce the metabolism of and reduce plasma concentrations of hormonal contraceptives. Breakthrough bleeding and unintended pregnancies have been reported in patients receiving carbamazepine and hormonal contraceptives concomitantly. In a study in healthy women, concomitant use of carbamazepine and an oral contraceptive containing ethinyl estradiol and levonorgestrel decreased systemic exposure of both components of the contraceptive and increased the incidence of breakthrough bleeding.

Because the reliability of hormonal contraceptive therapy may be adversely affected by carbamazepine, alternative or additional methods of contraception should be considered in patients receiving carbamazepine.

Immunosuppressive Agents

Carbamazepine may induce the metabolism of and decrease plasma concentrations of cyclosporine, sirolimus, and tacrolimus. Plasma concentration monitoring or dosage adjustment of the immunosuppressive agent may be necessary.

Lapatinib

Carbamazepine may induce the metabolism of and decrease plasma concentrations of lapatinib. In healthy individuals, carbamazepine decreased peak plasma concentrations and systemic exposure of lapatinib by 59 and 72%, respectively.

The manufacturer of carbamazepine recommends that concomitant use of carbamazepine and lapatinib generally should be avoided. If carbamazepine is initiated in a patient receiving lapatinib, dosage of lapatinib should be gradually increased; if carbamazepine is withdrawn from therapy, dosage of lapatinib should be decreased.

Lithium

Concomitant use of carbamazepine with lithium may increase the risk of adverse neurologic effects.

Macrolides

Concomitant use of carbamazepine with certain macrolide antibiotics that inhibit CYP3A4 (e.g., clarithromycin, erythromycin) may increase plasma carbamazepine concentrations. Clarithromycin and erythromycin also may increase concentrations of CBZ-E secondary to inhibition of epoxide hydrolase activity. Increased plasma concentrations of carbamazepine and subsequent signs of carbamazepine toxicity (e.g., ataxia, dizziness, drowsiness, vomiting) have occurred in adults or children following concomitant use of carbamazepine and erythromycin. Studies in adults indicate that erythromycin can substantially decrease serum clearance of carbamazepine, presumably by inhibiting hepatic metabolism of the drug.

Close monitoring of plasma carbamazepine concentrations is recommended when carbamazepine is used concomitantly with macrolide antibiotics that inhibit CYP3A4; dosage adjustment of carbamazepine may be required. In addition, patients receiving carbamazepine and erythromycin concomitantly should be monitored for evidence of carbamazepine toxicity. Some clinicians suggest that use of an alternative anti-infective agent, instead of erythromycin, may be necessary in patients receiving carbamazepine.

Monoamine Oxidase Inhibitors

Concomitant use of carbamazepine and monoamine oxidase (MAO) inhibitors is contraindicated based on a theoretical concern of serotonin syndrome. At least 14 days should elapse between discontinuance of an MAO inhibitor and initiation of carbamazepine.

Nefazodone

Concomitant use of carbamazepine and nefazodone is contraindicated; plasma concentrations of nefazodone and its active metabolite may decrease substantially, reducing the drug's therapeutic effect.

Neuromuscular Blocking Agents

Resistance to the nondepolarizing neuromuscular blocking agents cisatracurium, pancuronium, rocuronium, and vecuronium has been reported in patients receiving long-term carbamazepine therapy. It is not known whether the same effect occurs with other neuromuscular blocking agents. Carbamazepine-treated patients who are receiving these nondepolarizing neuromuscular blocking agents should be monitored closely for more rapid than normal recovery from neuromuscular blockade; higher dosages of the neuromuscular blocking agent may be required.

Omeprazole

In healthy individuals, concomitant use of omeprazole and carbamazepine resulted in increased peak plasma concentrations and systemic exposure of carbamazepine. Close monitoring of plasma carbamazepine concentrations is recommended during concomitant therapy; dosage adjustment of carbamazepine may be required.

Selective Serotonin-reuptake Inhibitors

Fluoxetine can increase plasma carbamazepine and CBZ-E concentrations, and carbamazepine toxicity (e.g., ocular changes, vertigo, tremor) has been reported in some patients maintained on carbamazepine following initiation of fluoxetine. It has been suggested that fluoxetine-induced inhibition of hepatic metabolism (e.g., inhibition of epoxide hydrolase) of carbamazepine and/or CBZ-E may be principally responsible for such increases; alteration in protein binding does not appear to be principally responsible for this interaction. The patient and plasma concentrations of carbamazepine and its metabolite should be monitored closely whenever fluoxetine therapy is initiated or discontinued; carbamazepine dosage should be adjusted accordingly.

Concomitant use of carbamazepine with fluvoxamine (a CYP3A4 inhibitor) may result in increased plasma carbamazepine concentrations. Close monitoring of plasma carbamazepine concentrations is recommended during concomitant therapy; dosage adjustment of carbamazepine may be required.

Carbamazepine may induce the metabolism of and decrease plasma concentrations of citalopram and sertraline; plasma concentration monitoring or dosage adjustment of the selective serotonin-reuptake inhibitor (SSRI) may be necessary. Citalopram does not appear to alter plasma concentrations of carbamazepine.

Simvastatin

In healthy individuals, systemic exposure of simvastatin and simvastatin acid were reduced by 75 and 82%, respectively, with carbamazepine; peak plasma concentrations of both simvastatin and its metabolite were reduced by 68%. Some experts recommend that concomitant use of carbamazepine and simvastatin be avoided; if concomitant use is necessary, dosage of simvastatin should be increased.

Temsirolimus

Carbamazepine can induce the metabolism of and decrease plasma concentrations of temsirolimus. Such concomitant therapy generally should be avoided. If carbamazepine and temsirolimus must be used concomitantly, dosage adjustment of temsirolimus should be considered.

Theophylline

Concomitant use of carbamazepine and theophylline may induce each other's metabolism, with resultant changes in elimination half-life and plasma concentrations. If carbamazepine and theophylline are used concomitantly, plasma concentrations of the drugs should be monitored and dosages adjusted accordingly.

Trazodone

Carbamazepine can induce the metabolism of and decrease plasma concentrations of trazodone. Concomitant use of carbamazepine (400 mg daily) with trazodone (100-300 mg daily) decreased plasma concentrations of trazodone and an active metabolite, m-chlorophenylpiperazine, by 76 and 60%, respectively. Patients receiving carbamazepine and trazodone concomitantly should be closely monitored and dosage of trazodone increased if necessary.

Trazodone also is a CYP3A4 inhibitor and can increase plasma concentrations of carbamazepine. Close monitoring of plasma carbamazepine concentrations is recommended during concomitant therapy; dosage adjustment of carbamazepine may be required.

Tricyclic Antidepressants

Carbamazepine may induce the metabolism of and decrease plasma concentrations of certain tricyclic antidepressants (e.g., amitriptyline, imipramine, nortriptyline). Monitoring of plasma concentrations or dosage adjustment of the tricyclic antidepressant may be necessary.

Carbamazepine can inhibit the metabolism of and increase plasma concentrations of clomipramine. In patients receiving stable dosages of clomipramine, dosage reduction may be required when initiating carbamazepine therapy.

Zolpidem

In healthy individuals, concomitant administration of zolpidem and carbamazepine reduced bioavailability of zolpidem by 57%; the clinical importance of this interaction is not known.

Pharmacokinetics

The pharmacokinetic parameters of carbamazepine disposition are similar in children and in adults; however, there is a poor correlation between dosage and plasma concentrations of carbamazepine in children. The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated. However, retrospective, case-control studies in patients of Chinese ancestry have demonstrated a strong pharmacogenomic association between the risk of developing Stevens-Johnson syndrome and toxic epidermal necrolysis and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene.(See Cautions: Dermatologic and Sensitivity Reactions.)

Absorption

Carbamazepine is slowly absorbed from the GI tract. Following chronic oral administration of carbamazepine tablets, suspension, extended-release tablets, or extended-release capsules, peak plasma concentrations are reached in 4-5, 1.5, 3-12, or 4.1-7.7 hours, respectively. The oral bioavailabilities of carbamazepine conventional (immediate-release) tablets and suspension reportedly are equivalent, although the rate of absorption is faster for the suspension. The bioavailability of the extended-release tablets is reportedly 89% of that of the suspension, and the absorption of the extended-release tablets is slightly slower than that of the conventional tablets. Peak plasma concentrations of the drug are higher and trough concentrations are lower for the suspension compared with tablets when the drug is administered once or twice daily, but steady-state concentrations reportedly are comparable when the suspension is administered in 3 divided doses daily and the tablets are administered in 2 divided doses daily. Following oral administration of carbamazepine extended-release capsules or tablets every 12 hours, steady-state plasma carbamazepine concentrations were comparable to those achieved with corresponding dosages of the conventional tablets every 6 hours. Although one manufacturer states that peak plasma concentrations may be higher with chewable tablets than with conventional tablets, a crossover study employing this manufacturer's tablets in adults with seizure disorders showed no such difference. In this study, the oral pharmacokinetics, including bioavailability, and peak and trough plasma concentrations, were comparable for conventional and chewable tablets of the drug, although individual patients may have achieved somewhat higher concentrations for one or the other tablet formulation.

Following IV administration of carbamazepine at a dosage adjusted by the 70% oral-to-IV conversion factor, systemic exposure was comparable to that observed following oral administration. The pharmacokinetics of the principal metabolite of carbamazepine (carbamazepine-10,11-epoxide [CBZ-E]) were similar following oral and IV dosing.

Following oral administration, a period of 2-4 days of therapy may be required to achieve steady-state plasma concentrations. Although optimal therapeutic plasma concentrations suitable for all patients have not yet been determined, therapeutic plasma concentrations of carbamazepine (for both anticonvulsant effects and relief of pain of trigeminal neuralgia) are usually 3-14 mcg/mL. Some investigators have noted that nystagmus frequently occurs when plasma concentrations are greater than 4 mcg/mL and that ataxia, dizziness, and anorexia often occur when plasma concentrations are 10 mcg/mL or greater. There appears to be wide variation in steady-state plasma concentrations produced by specific daily dosages of carbamazepine (e.g., daily dosages of 800 mg, 1.2 g, or 1.6 g may produce plasma concentrations of 2-10 mcg/mL).

In one study, when carbamazepine extended-release capsules were administered as a single 400-mg dose with a high-fat meal, the rate, but not the extent, of carbamazepine absorption was increased when compared with administration of the capsules in the fasting state. Results of a multiple-dose study of the extended-release capsules indicate that when these capsules are administered in the fed state, peak steady-state plasma concentrations are within the therapeutic range. When the extended-release capsules of carbamazepine are broken and the beads sprinkled over applesauce prior to administration, the pharmacokinetic profile of the drug is similar to that following oral administration of the intact capsule to fasting individuals. The manufacturer of carbamazepine extended-release capsules states that the elimination half-life of the drug does not differ substantially between fasted and nonfasted conditions of administration.

Distribution

Carbamazepine is widely distributed in the body; the drug has been detected in CSF (approximately 15-22% of serum concentrations), the brain (at autopsy), duodenal fluids, bile, and saliva. CBZ-E has also been detected in CSF. Carbamazepine rapidly crosses the placenta (i.e., 30-60 minutes) and accumulates in fetal tissues, with higher concentrations in the liver and kidney than in brain and lungs. Carbamazepine and its epoxide metabolite are distributed into breast milk. The ratio of the concentration in breast milk to that in plasma is approximately 0.4 for the drug and 0.5 for the epoxide metabolite.

In vitro studies indicate that at plasma concentrations of 1-50 mcg/mL, 75-90% of the drug is bound to plasma proteins.

Elimination

Carbamazepine has a relatively long plasma half-life, variously reported to be 8-72 hours. The variability results in part because carbamazepine can induce its own metabolism; autoinduction of metabolism usually is completed after 3-5 weeks of a fixed dosing regimen. The plasma half-life generally ranges from 25-65 hours initially and from 12-17 hours with multiple dosing.

The metabolic fate of carbamazepine has not been completely elucidated. A major metabolic pathway appears to be oxidation by microsomal enzymes in the liver (principally cytochrome P-450 isoform 3A4) to form CBZ-E, which is almost completely metabolized to trans-10,11-dihydroxy-10,11-dihydrocarbamazepine (trans-CBZ-diol) and excreted in urine mainly unconjugated. CBZ-E has anticonvulsant activity in animals and potent analgesic activity in patients with trigeminal neuralgia. CBZ-E also has been implicated as contributing to adverse neurologic effects of the drug. Carbamazepine is more rapidly metabolized to CBZ-E in children than in adults. In children younger than 15 years of age, there is an inverse relationship between the CBZ-E/CBZ ratio and increasing age; this ratio was reported to be 0.44 in children younger than 1 year old and 0.18 in children 10-15 years of age. Carbamazepine also undergoes aromatic hydroxylation to form 2-hydroxycarbamazepine and 3-hydroxycarbamazepine. The pathway is not clearly determined, but the drug also undergoes metabolism to form 9-hydroxymethyl-10-carbamoyl-acridan. Carbamazepine and its metabolites are excreted in urine. Only about 1-3% of the drug is excreted in urine unchanged. Carbamazepine induces liver microsomal enzymes and thus may accelerate its own metabolism and that of other concomitantly administered drugs that are metabolized by these enzymes. (See Drug Interactions.)

Clearance of carbamazepine is unchanged in patients with mild renal impairment (creatinine clearance 60-89 mL/minute); the effects of moderate or severe renal impairment (creatinine clearance 15-59 mL/minute) on the pharmacokinetics of carbamazepine are not known. The effects of hepatic impairment on carbamazepine pharmacokinetics are not known; however, patients with hepatic impairment may exhibit increased plasma concentrations of the drug when switching from oral to IV therapy because of a reduction in first-pass metabolism.

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