CARBAMAZEPINE- carbamazepine_tablet, chewable

CLINICAL PHARMACOLOGY
In controlled clinical trials, carbamazepine has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia. Carbamazepine has demonstrated anticonvulsant properties in rats and mice with elec trically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Carbamazepine greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the lin guomandibular reflex in cats. Carbamazepine is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown. The principal metabolite of carbamazepine, carbamazepine-10,11-epoxide, has anticon vulsant activity as demonstrated in several in vivo In clinical studies, Tegretol suspension, conventional tablets, and extended-release tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the extended-release tablet slightly slower, than the conventional tablet. The bioavailability of the extended-release tablet was 89% compared to suspension. Following a twice a day dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand, following a three times a day dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to carbamazepine tablets given twice a day when administered at the same total mg daily dose. Following a twice a day dosage regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional carbamazepine tablets given four times a day, when administered at the same total mg daily dose. Carbamazepine in blood is 76% bound to plasma proteins. Plasma levels of carba-mazepine are variable and may range from 0. 5 to 25 mcg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 mcg/mL. In polytherapy, the concentration of carbamazepine and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension, plasma levels peak at approximately 1. 5 hours compared to 4 to 5 hours after administration of conventional carbamazepine tablets, and 3 to 12 hours after administration of Tegretol-XR tablets. The CSF/serum ratio is 0. 22, similar to the 24% unbound carbamazepine in serum. Because carbamazepine induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3 to 5 weeks of a fixed dosing regimen. Initial half-life values range from 25 to 65 hours, decreasing to 12 to 17 hours on repeated doses. Carbamazepine is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide from carbamazepine. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged carbamazepine. The pharmacokinetic parameters of carbamazepine disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of carbamazepine and carbamazepine dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ- E/CBZ ratio and increasing age (in one report from 0. 44 in children below the age of 1 year to 0. 18 in children between 10 to 15 years of age). The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.
Mechanism of Action
Carbamazepine has demonstrated anticonvulsant properties in rats and mice with elec trically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Carbamazepine greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the lin guomandibular reflex in cats. Carbamazepine is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown. The principal metabolite of carbamazepine, carbamazepine-10,11-epoxide, has anticon vulsant activity as demonstrated in several in vivo
Pharmacokinetics
In clinical studies, Tegretol suspension, conventional tablets, and extended-release tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the extended-release tablet slightly slower, than the conventional tablet. The bioavailability of the extended-release tablet was 89% compared to suspension. Following a twice a day dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand, following a three times a day dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to carbamazepine tablets given twice a day when administered at the same total mg daily dose. Following a twice a day dosage regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional carbamazepine tablets given four times a day, when administered at the same total mg daily dose. Carbamazepine in blood is 76% bound to plasma proteins. Plasma levels of carba-mazepine are variable and may range from 0.5 to 25 mcg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 mcg/mL. In polytherapy, the concentration of carbamazepine and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4 to 5 hours after administration of conventional carbamazepine tablets, and 3 to 12 hours after administration of Tegretol-XR tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound carbamazepine in serum. Because carbamazepine induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3 to 5 weeks of a fixed dosing regimen. Initial half-life values range from 25 to 65 hours, decreasing to 12 to 17 hours on repeated doses. Carbamazepine is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide from carbamazepine. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged carbamazepine. The pharmacokinetic parameters of carbamazepine disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of carbamazepine and carbamazepine dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ- E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10 to 15 years of age). The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.

INDICATIONS AND USAGE
Carbamazepine is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types: 1. General Carbamazepine is indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia. This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
Epilepsy
Carbamazepine is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types: 1. 2. 3. General
Trigeminal Neuralgia
Carbamazepine is indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia. This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.

Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with carbamazepine treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Carbamazepine should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.
Aplastic Anemia and Agranulocytosis
Aplastic anemia and agranulocytosis have been reported in association with the use of carbamazepine (see BOXED WARNING). Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with Carbamazepine. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Carbamazepine should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin, primidone, and phenobarbital. If such history is present, benefits and risks should be carefully considered and, if carbamazepine is initiated, the signs and symptoms of hypersensitivity should be carefully monitored. Patients should be informed that about a third of patients who have had hypersensitivity reactions to carbamazepine also experience hypersensitivity reactions with oxcarbazepine (Trileptal registered Anaphylaxis and Angioedema Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips, and eyelids have been reported in patients after taking the first or subsequent doses of carbamazepine. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with carbamazepine, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards. The most severe adverse reactions have been observed in the hemopoietic system and skin (see boxed WARNING), the liver, and the cardiovascular system. The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the lowest dosage recommended. The following additional adverse reactions have been reported: Hemopoietic System: Skin: Cardiovascular System: Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds. Liver: Pancreatic: Respiratory System: Genitourinary System: Testicular atrophy occurred in rats receiving carbamazepine orally from 4 to 52 weeks at dosage levels of 50 to 400 mg/kg/day. Additionally, rats receiving carbamazepine in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown. Nervous System: There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established. Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of psychotropic drugs. Digestive System: Eyes: Musculoskeletal System: Metabolism: Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants. A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
Signs and Symptoms
The first signs and symptoms appear after 1 to 3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (greater than 60 g) have been ingested. Respiration: Cardiovascular System: Nervous System and Muscles: Gastrointestinal Tract: Kidneys and Bladder: Laboratory Findings: Combined Poisoning:

Carbamazepine should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase (MAO) inhibitors is not recommended. Before administration of carbamazepine, MAO inhibitors should be dis continued for a minimum of 14 days, or longer if the clinical situation permits. Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated.

Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman. Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects, cardiovascular malformations, and anomalies involving various body systems). Developmental delays based on neurobehavioral assessments have been reported. When treating or counseling women of childbearing poten tial, the prescribing physician will wish to weigh the benefits of therapy against the risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women. In humans, transplacental passage of carbamazepine is rapid (30 to 60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung. Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10 to 25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5 to 4 times the MHDD on a mg/m 2 Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine. There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal carbamazepine use. These symptoms may represent a neonatal withdrawal syndrome. To provide information regarding the effects of in utero exposure to carbamazepine, physicians are advised to recommend that pregnant patients taking carbamazepine enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
Usage in Pregnancy
(see WARNINGS).
Nursing Mothers
Carbamazepine and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk to that in maternal plasma is about 0.4 for carba mazepine and about 0.5 for the epoxide. The estimated doses given to the newborn during breastfeeding are in the range of 2 to 5 mg daily for carbamazepine and 1 to 2 mg daily for the epoxide. Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Substantial evidence of carbamazepine''s effectiveness for use in the management of children with epilepsy (see INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total carbamazepine in plasma (i.e., 4 to 12 mcg/mL) is the same in children and adults. The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.

Drug Interactions
Clinically meaningful drug interactions have occurred with concomitant medications and include (but are not limited to) the following:
Agents That May Affect Carbamazepine Plasma Levels
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required. Agents That Increase Carbamazepine Levels CYP3A4 inhibitors inhibit carbamazepine metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, macrolides (e.g., erythromycin, clarithromycin), fluoxetine, fluvoxamine, trazodone, omeprazole, oxybutynin, isoniazid, niacinamide (nicotinamide), azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, and protease inhibitors. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. Coadministration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations. Accordingly, the dosage of carbamazepine should be adjusted and/or the plasma levels monitored when used concomitantly with loxapine, quetiapine, or valproic acid, or brivaracetam. Agents That Decrease Carbamazepine Levels CYP3A4 inducers can increase the rate of carbamazepine metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include cisplatin ,
Effect of Carbamazepine on Plasma Levels of Concomitant Agents
Decreased Levels of Concomitant Medications Carbamazepine is a potent inducer of hepatic 3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C8/9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C8/9/19 and 3A4, through induction of their metabolism. When used concomitantly with carbamazepine, monitoring of concentrations or dosage adjustment of these agents may be necessary: In addition, carbamazepine causes, or would be expected to cause, decreased levels of the following drugs, for which monitoring of concentrations or dosage adjustment may be necessary: acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, citalopram, clonazepam, clozapine, corticosteroids (e.g., prednisolone, dexamethasone), cyclosporine, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, eslicarbazepine, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, mianserin, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, sertraline, sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide. Other Drug Interactions

WARNINGS
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with carbamazepine treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Carbamazepine should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. SJS/TEN and HLA-B*1502 Allele Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity. Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate prevalence of HLA-B*1502, averaging 2% to 4%, but higher in some groups. HLA-B*1502 is pres ent in less than 1% of the population in Japan and Korea. HLA-B*1502 is largely absent in individuals not of Asian origin (e. , Caucasians, African-Americans, Hispanics, and Native Americans). Prior to initiating carbamazepine therapy, testing forHLA-B* 1502 should be performed in patients with ancestry in populations in which HLA-B*1502 may be present. BOXED WARNING Laboratory Tests Over 90% of carbamazepine treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on carbamazepine. The HLA-B*1502 allele has not been found to predict risk of less severe adverse cuta-neous reactions from carbamazepine, such as maculopapular eruption (MPE) or to predict Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable. Hypersensitivity Reactions and HLA-A*3101 Allele Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a moderate association between the risk of developing hypersensitivity reactions and the presence of HLA-A*3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine. These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below). HLA-A*3101 is expected to be carried by more than 15% of patients of Japanese, Native American, Southern Indian (for example, Tamil Nadu), and some Arabic ancestry; up to about 10% in patients of Han Chinese, Korean, European, Latin American, and other Indian ancestry; and up to about 5% in African-Americans and patients of Thai, Taiwanese, and Chinese (Hong Kong) ancestry. The risks and benefits of carbamazepine therapy should be weighed before considering carbamazepine in patients known to be positive for HLA-A*3101. 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-positive and HLA-A*3101-positive patients treated with carbamazepine will not develop SJS/TEN or other hypersensitivity reactions, and these reactions can still occur infrequently in HLA-B*1502-negative and HLA-A*3101-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN and other hypersensitivity reactions, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring, have not been studied. Aplastic anemia and agranulocytosis have been reported in association with the use of carbamazepine (see BOXED WARNING). Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with Carbamazepine. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e. , fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Carbamazepine should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Hypersensitivity Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin, primidone, and phenobarbital. If such history is present, benefits and risks should be carefully considered and, if carbamazepine is initiated, the signs and symptoms of hypersensitivity should be carefully monitored. Patients should be informed that about a third of patients who have had hypersensitivity reactions to carbamazepine also experience hypersensitivity reactions with oxcarbazepine (Trileptal registered Anaphylaxis and Angioedema Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips, and eyelids have been reported in patients after taking the first or subsequent doses of carbamazepine. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with carbamazepine, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug. Antiepileptic drugs (AEDs), including carbamazepine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1. 8, 95% CI:1. 7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0. 43%, compared to 0. 24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Placebo Patients Drug Patients Relative Risk: Risk Difference: Epilepsy 1. 4 Psychiatric 5. 9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing carbamazepine or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Carbamazepine has shown mild anticholinergic activity that may be associated with increased intraocular pressure; therefore, patients with increased intraocular pressure should be closely observed during therapy. Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind. The use of carbamazepine should be avoided in patients with a history of hepatic por phyria (e. , acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving carbamazepine therapy. Carbamazepine administration has also been demonstrated to increase porphyrin precur sors in rodents, a presumed mechanism for the induction of acute attacks of porphyria. As with all antiepileptic drugs, carbamazepine should be withdrawn gradually to mini mize the potential of increased seizure frequency. Hyponatremia can occur as a result of treatment with carbamazepine. In many cases, the hyponatremia appears to be caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The risk of developing SIADH with carbamazepine treatment appears to be dose-related. Elderly patients and patients treated with diuretics are at greater risk of developing hyponatremia. Signs and symptoms of hyponatremia include headache, new or increased seizure frequency, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Consider discontinuing carbamazepine in patients with symptomatic hyponatremia. Carbamazepine can cause fetal harm when administered to a pregnant woman. Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and congenital anomalies (e. , craniofacial defects, cardiovascular malformations, and anomalies involving various body systems). Developmental delays based on neurobehavioral assessments have been reported. When treating or counseling women of childbearing poten tial, the prescribing physician will wish to weigh the benefits of therapy against the risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women. In humans, transplacental passage of carbamazepine is rapid (30 to 60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung. Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10 to 25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1. 5 to 4 times the MHDD on a mg/m 2 Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine. There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal carbamazepine use. These symptoms may represent a neonatal withdrawal syndrome. To provide information regarding the effects of in utero exposure to carbamazepine, physicians are advised to recommend that pregnant patients taking carbamazepine enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www. aedpregnancyregistry.
Carcinogenesis,Mutagenesis, Impairment of Fertility
Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males. Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.
Labor and Delivery
The effect of carbamazepine on human labor and delivery is unknown.
OVERDOSAGE
Lowest known lethal dose: adults, 3. 2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1. 6 g (a 3-year-old girl died of aspiration pneumonia). Oral LD 50 The first signs and symptoms appear after 1 to 3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (greater than 60 g) have been ingested. Respiration: Cardiovascular System: Nervous System and Muscles: Gastrointestinal Tract: Kidneys and Bladder: Laboratory Findings: Combined Poisoning: The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote. Elimination of the Drug: Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol. Measures to Reduce Absorption: Measures to Accelerate Elimination: Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated in severe poisoning in small children. Respiratory Depression: Hypotension, Shock: Convulsions: Warning: Surveillance: Treatment of Blood Count Abnormalities: Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59 2 12 A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought.
Treatment
The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote. Elimination of the Drug: Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol. Measures to Reduce Absorption: Measures to Accelerate Elimination: Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated in severe poisoning in small children. Respiratory Depression: Hypotension, Shock: Convulsions: Warning: Surveillance: Treatment of Blood Count Abnormalities: Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59 2 12 A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought.

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