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Uses

Seizure Disorders

Carbamazepine is used in adults and children in the prophylactic 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. The drug is ineffective in the management of absence (petit mal) seizures or myoclonic and akinetic seizures.

Carbamazepine may be administered concomitantly with other anticonvulsants such as phenytoin, phenobarbital, or primidone. However, the drug should be administered with caution in conjunction with those anticonvulsants that produce toxic effects similar to carbamazepine such as phenacemide (no longer commercially available in the US), mephenytoin, or trimethadione or paramethadione (both no longer commercially available in the US).

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.

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. The American Psychiatric Association (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, .

Bipolar Disorder

Carbamazepine has been used alone or in combination with other drugs (e.g., antipsychotic agents) for the treatment and prevention of acute manic or mixed episodes in patients with bipolar disorder. However, results of clinical studies of the drug in the management of bipolar disorder have been inconsistent, and the APA currently recommends that carbamazepine be reserved for patients unable to tolerate or who had an inadequate therapeutic response to lithium and valproate (e.g., valproic acid, divalproex). For further information on the management of bipolar disorder,

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 conventional tablets and suspension are administered orally with meals. The oral suspension should be shaken well before administration. To minimize loss of carbamazepine oral suspension during oral administration via a nasogastric tube (secondary to adherence to PVC tubing), the suspension can be diluted with an equal volume of diluent (e.g., sterile water, 5% dextrose, 0.9% sodium chloride) prior to administration, combined with flushing of the tube with 100 mL of the diluent after administration.

Because a rubbery, orange substance was noticed in the stool of a patient who ingested chlorpromazine oral solution immediately after ingesting carbamazepine oral suspension and subsequent testing has shown that mixing carbamazepine oral suspension with chlorpromazine or thioridazine oral solution results in a rubbery, orange precipitate, the manufacturer recommends that carbamazepine oral suspension not be administered with other liquid preparations. In addition, it is not known whether the development of this precipitate results in decreased bioavailability of carbamazepine or the other drugs.

Extended-release tablets of carbamazepine (Tegretol-XR) should be swallowed whole and not be broken or chewed. The manufacturer states that the extended-release tablets should be inspected visually for chips or cracks and that damaged tablets should not be used. Because the coating of the extended-release tablet is not absorbed, it may be noticeable in the stools. The extended-release tablet formulation of carbamazepine is administered twice daily. When patients are switched from conventional dosage forms to the extended-release tablets of carbamazepine, the same total daily dosage is then administered in 2 divided doses.

Extended-release capsules of carbamazepine (Carbatrol) may be opened and the beads sprinkled over food (e.g., a teaspoonful of applesauce). Extended-release capsules of carbamazepine and their contents should not be chewed or crushed. In addition, the extended-release capsules of carbamazepine may be taken without regard to meals. Patients receiving total daily carbamazepine dosages of 400 mg or greater in other preparations may be switched to the extended-release capsules; the same total daily dosage is then administered in 2 divided doses.

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.)

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.)

Dosage

Dosage of carbamazepine must be carefully and slowly adjusted according to individual requirements and response. It is important to begin therapy with a low dosage and to proceed slowly when increasing or decreasing the dosage of the drug. When carbamazepine is added to an anticonvulsant therapeutic regimen, the drug should usually be added gradually while the other anticonvulsant(s) is maintained or gradually decreased. Carbamazepine should be withdrawn slowly to avoid precipitating seizures or status epilepticus.

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). Alternatively, if rapid achievement of therapeutic plasma concentrations and control of seizures is necessary, an oral loading-dose regimen with carbamazepine oral suspension can be employed. 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

The usual initial dosage of carbamazepine for the management of seizure disorders in adults and children older than 12 years of age is 200 mg twice daily as tablets or 100 mg 4 times daily as the oral suspension. Dosage is increased by up to 200 mg daily at weekly intervals using a 3 or 4 times daily divided dosing regimen until the optimum response is obtained. Dosage generally should not exceed 1 g daily in children 12-15 years of age and 1.2 g daily in patients older than 15 years of age; however, some patients have required up to 1.6-2.4 g daily. When adequate seizure control is achieved, dosage should be adjusted to the minimum effective level, which is usually 800 mg to 1.2 g daily in adults and children older than 12 years of age.

In children 6-12 years of age, the usual initial dosage of carbamazepine is 100 mg twice daily as tablets or 50 mg 4 times daily as the oral suspension. Dosage is increased by up to 100 mg daily at weekly intervals using a 3 or 4 times daily divided dosing regimen until the optimum response is obtained. Dosage generally should not exceed 1 g daily in children 6-12 years of age. When adequate seizure control is achieved, dosage should be adjusted to the minimum effective level, which is usually 400-800 mg daily in children 6-12 years of age.

In children younger than 6 years of age, the initial daily dosage of carbamazepine given as conventional tablets or oral suspension is 10-20 mg/kg in 2 or 3 divided doses (as tablets) or 4 divided doses (as the oral suspension). Optimal clinical response in children younger than 6 years of age generally is achieved at daily maintenance dosages of 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. The manufacturers state that safety of carbamazepine dosages exceeding 35 mg/kg in 24 hours in children younger than 6 years of age has not been established.

Therapeutic serum carbamazepine concentrations can be achieved more rapidly (in about 2 hours) by the use of an oral loading-dose regimen with the oral suspension, preferably in a clinic or hospital setting where plasma concentrations and the patient can be monitored closely. 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 is administered for the rapid control of seizures.

Neuropathic Pain

For the symptomatic treatment of pain associated with trigeminal neuralgia, the usual initial adult dosage of carbamazepine on the first day of therapy is 100 mg twice daily as tablets 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 for tablets or by using 50-mg increments 4 times daily for the oral suspension until pain is relieved. The dosage necessary to relieve pain may range from 200 mg to 1.2 g daily; daily dosage should not exceed 1.2 g. After control of pain is achieved, 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 1.2 g daily. At least once every 3 months throughout carbamazepine therapy for trigeminal neuralgia, an attempt should be made to decrease dosage to the minimum effective level or to discontinue the drug.

Bipolar Disorder

Although dosage of carbamazepine for the management of bipolar disorder has not been established, experts generally recommend administering the drug at the same range in dosage and therapeutic plasma concentrations as in the management of seizure disorders. In patients older than 12 years of age, the usual initial dosage of carbamazepine for the management of bipolar disorder is 200-600 mg daily, given in 3 or 4 divided doses. Dosage may be titrated upward according to patient response and tolerability. In hospitalized patients with acute mania, dosages may be increased as tolerated in 200-mg daily increments up to 800 mg to 1 g daily, with slower increases thereafter as indicated. However, dosages should not exceed 1.6 g daily. In less acutely ill outpatients, dosage adjustments should be slower because rapid increases may cause patients to develop adverse GI (e.g., nausea, vomiting) or nervous system (e.g., drowsiness, dizziness, ataxia, clumsiness, diplopia) effects. If such adverse effects occur, temporary dosage reductions should be considered. Dosage may be increased again more slowly once these adverse effects have been resolved. Maintenance dosages of carbamazepine 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 and Stevens-Johnson syndrome, have been reported in patients receiving carbamazepine therapy. 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. Retrospective, case-control studies in patients of Asian ancestry have demonstrated a strong association between the risk of developing Stevens-Johnson syndrome and toxic epidermal necrolysis with carbamazepine therapy and the presence of human leukocyte antigen (HLA)-B*1502, an inherited allelic variant of the HLA-B gene. The HLA-B*1502 allele is found almost exclusively in patients with ancestry across broad areas of Asia (including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais), although marked variation exists in its prevalence among various 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).

The US Food and Drug Administration (FDA) and the manufacturers of carbamazepine 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. 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. High-resolution HLA-B*1502 typing is recommended in genetically at-risk patients; the test is considered positive if 1 or 2 HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected. Patients testing positive for this allele should not receive carbamazepine therapy unless the benefit clearly outweighs the risk. Patients who are found to be negative for the allele are thought to have a low risk of developing Stevens-Johnson syndrome and toxic epidermal necrolysis. In addition, over 90% of carbamazepine-treated patients who will experience Stevens-Johnson syndrome and toxic epidermal necrolysis develop these reactions within the first few months of therapy; 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., multiple-organ hypersensitivity reactions, non-serious rash such as maculopapular eruption). However, limited evidence suggests that HLA-B*1502 may be a risk factor for the development of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients of Asian 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.

FDA and the manufacturers caution that application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian patients treated with carbamazepine will never develop Stevens-Johnson syndrome and toxic epidermal necrolysis, and such reactions may develop infrequently in HLA-B*1502-negative patients of any ethnicity. The role of other possible factors, such as anticonvulsant drug dosage, compliance, concomitant medications and illnesses, in the development of, and morbidity from, these reactions and the level of dermatologic monitoring has not been adequately studied to date.

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.

Multiple-organ hypersensitivity reactions occurring days to weeks or months after initiation of carbamazepine therapy have been reported rarely. Manifestations may include (but are not limited to) fever, rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, and abnormal liver function test results. These manifestations may initially be mild and may occur in various combinations and not necessarily concurrently. Various organs, including but not limited to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon, may be affected.

Other hypersensitivity reactions, including fever, rash, peripheral eosinophilia, and reversible aseptic meningitis (manifested by confusion, myoclonus, and CSF pleocytosis), have been reported rarely in patients receiving carbamazepine.

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. Myocardial infarction has been associated with tricyclic compounds.

Hepatic Effects

Hepatic complications associated with the long-term administration of carbamazepine include abnormalities in liver function test results, cholestatic and hepatocellular jaundice, hepatitis, and very rare cases of hepatic failure.

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 made, but the exact relationship of these reactions to the administration of carbamazepine has not been established.

The US Food and Drug Administration (FDA) has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants, including carbamazepine, and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%). FDA's analysis included 199 randomized, placebo-controlled studies of 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) involving over 43,000 patients 5 years of age or older; the studies evaluated the effectiveness of the anticonvulsants in epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain). 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. In addition, patients who were treated for epilepsy, psychiatric disorders, and other conditions were all found to be at increased risk for suicidality when compared with placebo; there did not appear to be a specific demographic subgroup of patients to which the increased risk could be attributed. However, the relative risk for suicidality was found to be higher in patients with epilepsy compared with patients who were given one of the drugs for psychiatric or 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. 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 dangerous and alarming 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 a responsive epileptic patient may precipitate seizures or status epilepticus. Carbamazepine therapy should be withdrawn gradually, whenever possible, 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.

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome, have been reported in patients receiving carbamazepine therapy. 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 about 10 times higher. Carbamazepine should be discontinued at the first sign of a skin rash, unless the rash is clearly not drug-related. If signs or symptoms suggest Stevens-Johnson syndrome or toxic epidermal necrolysis, carbamazepine therapy should not be resumed and alternative therapy should be considered. Retrospective case-control studies in patients of Asian ancestry have demonstrated a strong association between the risk of developing Stevens-Johnson syndrome and toxic epidermal necrolysis and the presence of human leukocyte antigen (HLA)-B*1502, an inherited allelic variant of the HLA-B gene; this allele is found almost exclusively in patients with ancestry across broad areas of Asia. Therefore, the US Food and Drug Administration (FDA) and the manufacturers of carbamazepine 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. Patients testing positive for this allele should not receive carbamazepine therapy unless the benefit clearly outweighs the risk.(See Cautions: Dermatologic and Sensitivity Reactions.)

Multiple-organ hypersensitivity reactions occurring days to weeks or months following initiation of carbamazepine have been reported rarely.(See Cautions: Dermatologic and Sensitivity Reactions.) Discontinuance of carbamazepine should be considered if any evidence of hypersensitivity develops. Because hypersensitivity reactions to carbamazepine have been reported in patients with a history of hypersensitivity reactions to other anticonvulsants (e.g., phenytoin, phenobarbital), a detailed drug history should be obtained from patients and their immediate family members. Carbamazepine should be used with caution in patients with a history of hypersensitivity reactions to other anticonvulsants. Approximately 25-30% of patients who demonstrated hypersensitivity reactions to carbamazepine also may experience hypersensitivity reactions to oxcarbazepine.

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 physician 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.

Although the manufacturers previously recommended initial frequent (possibly weekly during the first 3 months of therapy) and then less frequent, periodic (monthly for at least 2-3 years) testing of hematologic function in any patient receiving carbamazepine, they currently state that, because the frequency of minor hematologic changes progressing to aplastic anemia and agranulocytosis is very low, the vast majority of such changes observed during routine, periodic monitoring are unlikely to be signaling the impending development of either abnormality. Therefore, the manufacturers currently recommend that complete blood counts, including platelet and possibly reticulocyte counts and serum iron determinations, be performed prior to initiating carbamazepine therapy and that subsequent monitoring 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. The manufacturers recommend that patients with a history of bone marrow depression 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. Alternatively, one manufacturer suggests that the frequency of this monitoring in patients who develop evidence of significant bone marrow depression during the usual course of carbamazepine therapy (i.e., not resulting from overdosage) may be individualized by the clinician. 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. In some cases, hepatic effects may progress despite discontinuance of the drug. Liver function tests should be performed prior to carbamazepine therapy, particularly in patients with a history of liver disease, and periodically thereafter. Carbamazepine should be immediately discontinued if evidence of 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. Complete urinalysis and BUN determinations also should be performed prior to and periodically during carbamazepine therapy.

FDA has informed healthcare professionals about an increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants compared with placebo.(See Cautions: Nervous System Effects.) FDA recommends that all patients who are currently receiving or beginning therapy with any anticonvulsant for any indication be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior. Symptoms such as anxiety, agitation, hostility, mania, and hypomania may be precursors to emerging suicidality. Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality so that they are aware and able to notify their clinician of any unusual behavioral changes. Patients, family members, and caregivers also should be advised not to make any changes to the medication regimen without first consulting with the responsible clinician. They should 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. FDA also recommends that clinicians who prescribe carbamazepine or any other anticonvulsant 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 must consider whether the emergence of these symptoms in any given patient 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 increased intraocular pressure should be closely observed 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 previous bone marrow depression, acute intermittent porphyria, and/or hypersensitivity to the drug or in patients who have demonstrated sensitivity to 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 do 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.

To provide information regarding the effects of in utero exposure to carbamazepine, clinicians are advised to recommend that pregnant patients receiving carbamazepine enroll themselves in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 888-233-2334.

Lactation

Carbamazepine and its epoxide metabolite (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

Alcohol

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

Anticonvulsants

Because carbamazepine is an inducer of the cytochrome P-450 (CYP) 3A4 isoenzyme, concomitant use with certain other anticonvulsants (e.g., clonazepam, ethosuximide, lamotrigine, methsuximide, phensuximide [not commercially available in the US], phenytoin, tiagabine, topiramate, valproic acid, zonisamide) has been shown, or would be expected, to decrease plasma concentrations of the other anticonvulsant. It may be desirable to monitor serum concentrations of concomitantly administered anticonvulsants, making dosage adjustments as necessary.

Concomitant use of carbamazepine with other anticonvulsants that induce (e.g., methsuximide, phenobarbital, phenytoin, primidone) or inhibit (e.g., acetazolamide) CYP3A4 has been shown, or would be expected, to decrease or increase plasma carbamazepine concentrations, respectively. In addition, carbamazepine may decrease the half-life of phenytoin. Increased plasma concentrations of phenytoin and primidone have been reported following concomitant use with carbamazepine.

Felbamate and valproic acid apparently can affect both plasma carbamazepine and carbamazepine 10,11-epoxide (CBZ-E, an active metabolite) concentrations, but the interactions appear to be complex and resultant changes may be unpredictable. The effect of valproic acid on concentrations of the drug 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.

Recent evidence suggests that the human leukocyte antigen (HLA)-B*1502 allele, which is found almost exclusively in patients with ancestry across broad areas of Asia, may be a risk factor for the development of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients of Asian ancestry who are receiving carbamazepine and some 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 role of other possible factors, such as concomitant medications, anticonvulsant dosage, compliance, and illnesses, in the development of, and morbidity from, these reactions, and the level of dermatologic monitoring have not been adequately studied to date.(See Cautions: Dermatologic and Sensitivity Reactions and see Cautions: Precautions and Contraindications.)

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

Lithium

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

Calcium-channel Blocking Agents

Concomitant use of carbamazepine and diltiazem or verapamil may result in increased plasma carbamazepine concentrations and subsequent toxicity. In several patients receiving 1-2 g of carbamazepine daily, initiation of 360 mg of verapamil hydrochloride 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 carbamazepine 10,11-epoxide 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.

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

Because carbamazepine is an inducer of the CYP3A4 isoenzyme, concomitant use with dihydropyridine calcium-channel blocking agents (e.g., felodipine) has been shown, or would be expected, to decrease plasma concentrations of the dihydropyridine calcium-channel blocking agent.

Macrolides

Concomitant use of carbamazepine with certain macrolide antibiotics that inhibit CYP3A4 (e.g., clarithromycin, erythromycin, troleandomycin) has been shown, or would be expected, to increase plasma carbamazepine concentrations. 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. Patients receiving carbamazepine and erythromycin concomitantly should be monitored for evidence of carbamazepine toxicity; carbamazepine dosage should be reduced when necessary. Some clinicians suggest that use of an alternative anti-infective agent, instead of erythromycin, may be necessary in patients receiving carbamazepine.

Doxycycline

Preliminary studies indicate that carbamazepine may decrease the half-life of doxycycline, probably by inducing hepatic microsomal enzymes that metabolize the antibiotic. Concomitant administration of doxycycline and carbamazepine should be avoided if possible. If concomitant therapy is necessary, doxycycline probably should be administered at 12-hour intervals and/or serum doxycycline concentrations should be closely monitored.

Selective Serotonin-reuptake Inhibitors

Fluoxetine can increase plasma carbamazepine and carbamazepine 10,11-epoxide (CBZ-E, an active metabolite) 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, an inhibitor of CYP3A4, has been shown, or would be expected, to increase plasma carbamazepine concentrations.

Antipsychotic Agents

Because carbamazepine is an inducer of the CYP3A4 isoenzyme, concomitant use with some antipsychotic agents (e.g., aripiprazole, clozapine, haloperidol, risperidone, ziprasidone) has been shown, or would be expected, to decrease plasma concentrations of the antipsychotic agent. Reductions in antipsychotic efficacy with reemergence of symptoms has occurred in some, but not all, such patients. If carbamazepine therapy is added in patients receiving aripiprazole, the dosage of aripiprazole should be doubled and additional increases in aripiprazole dosage should be made based on clinical evaluation; if carbamazepine is withdrawn from combination therapy with aripiprazole, the dosage of aripiprazole should be reduced accordingly. Patients receiving carbamazepine and haloperidol concomitantly should be monitored carefully for loss of antipsychotic control and, if an interaction is suspected, haloperidol dosage adjusted accordingly. The possibility that haloperidol toxicity may occur following discontinuance of carbamazepine also should be considered.

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 manufacturers of clozapine and the American Psychiatric Association (APA) state 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.

Monoamine Oxidase Inhibitors

Combined therapy using carbamazepine and monoamine oxidase (MAO) inhibitors is contraindicated. A medication-free period of at least 14 days should be observed when transferring patients from MAO inhibitors to carbamazepine. Therapy with carbamazepine should then be initiated cautiously with gradual increases in dosage to obtain the desired response.

Anticoagulants

Because carbamazepine is an inducer of the CYP3A4 isoenzyme, concomitant use with dicumarol or warfarin has been shown, or would be expected, to decrease plasma concentrations of the anticoagulant. In one study when carbamazepine was administered to patients being treated with warfarin, the serum concentration of warfarin decreased after about 10 days of carbamazepine therapy. Carbamazepine also shortened the half-life of warfarin in some patients. If warfarin and carbamazepine must be used together, the patient should be closely monitored and the dosage of both drugs adjusted as required.

Theophylline

It has been suggested that concomitant administration 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, the patient and plasma concentrations of the drugs should be monitored and dosage adjusted accordingly.

Hormonal Contraceptives

Concomitant use of carbamazepine and hormonal contraceptives (e.g., oral contraceptives, levonorgesterol subdermal implant contraceptives [no longer commercially available]) may cause increased metabolism of the contraceptive resulting from induction of hepatic microsomal enzymes. Breakthrough bleeding and unintended pregnancies have been reported in patients receiving carbamazepine and hormonal contraceptives. Because the reliability of hormonal contraceptive therapy may be adversely affected during concomitant administration of carbamazepine, a nonhormonal method of birth control should be considered.

Antihistamines

Concomitant use of carbamazepine with antihistamines that inhibit CYP3A4 (e.g., loratadine, terfenadine [no longer commercially available]) has been shown, or would be expected, to increase plasma carbamazepine concentrations.

Antituberculosis Agents

Concomitant use of carbamazepine with antituberculosis agents that inhibit CYP3A4 (e.g., isoniazid) has been shown, or would be expected, to increase plasma carbamazepine concentrations. Conversely, concomitant use of carbamazepine with antituberculosis agents that induce CYP3A4 (e.g., rifampin) has been shown, or would be expected, to decrease plasma carbamazepine concentrations.

Antineoplastic Agents

Concomitant use of carbamazepine with antineoplastic agents that induce CYP3A4 (e.g., cisplatin, doxorubicin) has been shown, or would be expected, to decrease plasma carbamazepine concentrations.

Azole Antifungal Agents

Concomitant use of carbamazepine with azole antifungal agents that inhibit CYP3A4 (e.g., fluconazole, itraconazole, ketoconazole, voriconazole) has been shown, or would be expected, to increase plasma carbamazepine concentrations.

Concomitant use of carbamazepine and fluconazole has resulted in increased carbamazepine concentrations and associated toxicity, presumably as the result of fluconazole inhibiting CYP isoenzymes involved in metabolism of the anticonvulsant. It has been suggested that carbamazepine concentrations be monitored in patients receiving fluconazole concomitantly.

Because carbamazepine also is an inducer of the CYP3A4 isoenzyme, concomitant use with itraconazole has been shown, or would be expected, to decrease plasma concentrations of itraconazole.

Although the interaction has not been specifically studied to date, carbamazepine would be expected to substantially decrease plasma voriconazole concentrations due to potent induction of CYP enzymes; therefore, the manufacturer of voriconazole states that concomitant use of carbamazepine and voriconazole is contraindicated.

Corticosteroids

Because carbamazepine is an inducer of the CYP3A4 isoenzyme, concomitant use with corticosteroids metabolized by CYP3A4 (e.g., dexamethasone, prednisolone) has been shown, or would be expected, to decrease plasma concentrations of the corticosteroid.

HIV Protease Inhibitors

Concomitant use of carbamazepine with HIV protease inhibitors that inhibit CYP3A4 has been shown, or would be expected, to increase plasma carbamazepine concentrations. Because carbamazepine is an inducer of CYP3A4, concomitant use with HIV protease inhibitors that are metabolized by CYP3A4 has been shown, or would be expected, to decrease plasma concentrations of the HIV protease inhibitor.

Tricyclic Antidepressants

Because carbamazepine is an inducer of the CYP3A4 isoenzyme, concomitant use with tricyclic antidepressants metabolized by CYP3A4 (e.g., amitriptyline, imipramine, nortriptyline) has been shown, or would be expected, to decrease plasma concentrations of the tricyclic antidepressant.

Nefazodone

Concomitant use of carbamazepine and nefazodone is contraindicated since this may reduce plasma concentrations of nefazodone and its active metabolite, hydroxynefazodone, by 95% resulting in levels insufficient to achieve an antidepressant effect.

Trazodone

Because carbamazepine is an inducer of the CYP3A4 isoenzyme, concomitant use with trazodone has been shown to 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.

Other Drugs

Concomitant use of carbamazepine with drugs or foods that inhibit CYP3A4 (e.g., cimetidine, danazol, grapefruit juice, niacinamide, propoxyphene) has been shown, or would be expected, to increase plasma carbamazepine concentrations. In addition, because carbamazepine is an inducer of the CYP3A4 isoenzyme, concomitant use with drugs metabolized by CYP3A4 (e.g., acetaminophen, alprazolam, cyclosporine, levothyroxine, methadone, midazolam, praziquantel, tramadol) has been shown, or would be expected, to decrease plasma concentrations of the other drug.

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 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 (immediate-release) 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.

Two to 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 a 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 (Carbatrol) 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 after a meal, peak steady-state plasma concentrations are within the therapeutic range. When the extended-release capsules of carbamazepine (Carbatrol) 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. A major metabolite, carbamazepine 10,11-epoxide, 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 in 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 carbamazepine 10,11-epoxide (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.)