Carbamazepine

INDICATIONS AND USAGE Epilepsy Carbamazepine extended-release capsules are indicated for use as an anticonvulsant drug. Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types: Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvements than those with other types. Generalized tonic-clonic seizures (grand mal). Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures (petit mal) do not appear to be controlled by carbamazepine (see PRECAUTIONS, General ). Trigeminal Neuralgia Carbamazepine extended-release capsules are indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia. This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.

DOSAGE AND ADMINISTRATION Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS, Laboratory Tests ). Dosage should be adjusted to the needs of the individual patients. A low initial daily dosage with gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very gradually to the minimum effective level. Carbamazepine extended-release capsules may be taken with or without food. Carbamazepine extended-release capsules may be swallowed whole or may be opened and all the beads sprinkled on a teaspoon of soft food such as applesauce. Make sure all of the food and medicine mixture is swallowed. Do not crush or chew carbamazepine extended-release capsules or the sprinkled beads. Carbamazepine extended-release capsule is an extended-release formulation for twice a day administration. When converting patients from immediate release carbamazepine to carbamazepine extended-release capsules, the same total daily mg dose of carbamazepine should be administered. Following conversion to carbamazepine, patients should be closely monitored for seizure control. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions. Epilepsy (see INDICATIONS AND USAGE ) Adults and children over 12 years of age. Initial: 200 mg twice daily. Increase at weekly intervals by adding up to 200 mg/day until the optimal response is obtained. Dosage generally should not exceed 1,000 mg per day in children 12 to 15 years of age, and 1,200 mg daily in patients above 15 years of age. Doses up to 1,600 mg daily have been used in adults. Maintenance: Adjust dosage to the minimum effective level, usually 800 to 1,200 mg daily. Children under 12 years of age: Children taking total daily dosages of immediate-release carbamazepine of 400 mg or greater may be converted to the same total daily dosage of carbamazepine extended-release capsules, using a twice daily regimen. Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range. No recommendation regarding the safety of carbamazepine extended-release capsules for use at doses above 35 mg/kg/24 hours can be made. Combination Therapy: Carbamazepine extended-release capsules may be used alone or with other anticonvulsants. When added to existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug Interactions ). Trigeminal Neuralgia (see INDICATIONS AND USAGE ) Initial: On the first day, start with one 200 mg capsule. This daily dose may be increased by up to 200 mg/day every 12 hours only as needed to achieve freedom from pain. Do not exceed 1,200 mg daily. Maintenance: Control of pain can be maintained in most patients with 400 to 800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug.

WARNINGS Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with carbamazepine treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Carbamazepine extended-release capsules should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. 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 present in <1% of the population in Japan and Korea. HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans). Prior to initiating carbamazepine extended-release capsules therapy, testing for HLA-B*1502 should be performed in patients with ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Carbamazepine extended-release capsules should not be used in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS/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 extended-release capsules. The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous 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 anti-epileptic 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. Patients should be made aware that carbamazepine extended-release capsules contain carbamazepine and should not be used in combination with any other medications containing carbamazepine. 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 …

CONTRAINDICATIONS Carbamazepine should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline and nortriptyline. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of carbamazepine, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits. Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated. Coadministration of carbamazepine is contraindicated with delavirdine due to the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

Drug Interactions Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to the following: Agents Highly Bound to Plasma Protein: Carbamazepine is not highly bound to plasma proteins; therefore, administration of carbamazepine extended-release capsules to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Agents that Inhibit Cytochrome P450 Isoenzymes and/or Epoxide Hydrolase: Carbamazepine is metabolized mainly by cytochrome P450 (CYP) 3A4 to the active carbamazepine 10, 11-epoxide, which is further metabolized to the trans-diol by epoxide hydrolase. Therefore, the potential exists for interaction between carbamazepine and any agent that inhibits CYP3A4 and/or epoxide hydrolase. Agents that are CYP3A4 inhibitors that have been found, or are expected, to increase plasma levels of carbamazepine extended-release capsules include, for example, the following: Acetazolamide, aprepitant, azole antifungals (e.g., ketoconazole, itraconazole, fluconazole, voriconazole), cimetidine, ciprofloxacin, clarithromycin, dalfopristin, danazol, dantrolene, delavirdine, diltiazem, erythromycin, fluoxetine, fluvoxamine, grapefruit juice, ibuprofen, isoniazid, loratadine, macrolides, nefazodone, niacinamide, nicotinamide, olanzapine, omeprazole, oxybutynin, protease inhibitors, propoxyphene, quinine, quinupristin, ticlopidine, troleandomycin, valproate, verapamil, zileuton. 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 extended-release capsules should be adjusted and/or the plasma levels monitored when used concomitantly with loxapine, quetiapine, or valproic acid. Thus, if a patient has been titrated to a stable dosage of carbamazepine extended-release capsules, and then begins a course of treatment with one of these CYP3A4 or epoxide hydrolase inhibitors, it is reasonable to expect that a dose reduction for carbamazepine extended-release capsules may be necessary. Agents that Induce Cytochrome P450 Isoenzymes : Carbamazepine is metabolized by CYP3A4. Therefore, the potential exists for interaction between carbamazepine and any agent that induces CYP3A4. Agents that are CYP inducers that have been found, or are expected, to decrease plasma levels of carbamazepine extended-release capsules include, for example, the following: Aminophylline, cisplatin, doxorubicin HCL, felbamate, fosphenytoin, methsuximide, phenobarbital, phenytoin( 1 ), primidone, rifampin and theophylline. (1) Phenytoin plasma levels have also been reported to increase and decrease in the presence of carbamazepine, see below. Thus, if a patient has been titrated to a stable dosage on carbamazepine extended-release capsules, and then begins a course of treatment with one of these CYP3A4 inducers, it is reasonable to expect that a dose increase for carbamazepine extended-release capsules may be necessary. Agents with Decreased Levels in the Presence of Carbamazepine due to Induction of Cytochrome P450 Enzymes: Carbamazepine is a potent inducer of hepatic CYP3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C9/19 and 3A4, through induction of their metabolism. When used concomitantly with carbamazepine extended-release capsules, monitoring of concentrations or dosage adjustment of these agents may be necessary: When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole dose should be reduced. Wh…

Usage in Pregnancy (See WARNINGS )

Nursing Mothers Carbamazepine and its epoxide metabolite are transferred to breast milk and during lactation. The concentrations of carbamazepine and its epoxide metabolite are approximately 50% of the maternal plasma concentration. Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

ADVERSE REACTIONS General : If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive patient with epilepsy may lead to seizures or even status epilepticus with its life-threatening hazards. The most severe adverse reactions previously observed with carbamazepine were reported in the hemopoietic system and skin (see BOXED WARNING ), 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 were previously reported with carbamazepine: Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria. Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING ), Acute Generalized Exanthematous Pustulosis (AGEP), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, diaphoresis, onychomadesis and hirsutism. In certain cases, discontinuation of therapy may be necessary. Cardiovascular System : Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism, and adenopathy or lymphadenopathy. Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds. Immune system disorders : Hypogammaglobulinemia. Liver : Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis, and hepatic failure. Pancreatic : Pancreatitis. Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia. Genitourinary System : Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported. There have been rare reports of impaired male fertility and/or abnormal spermatogenesis. 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/day and higher. Relevance of these findings to humans is unknown. Nervous System : Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, and hyperacusis. There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established. Isolated cases of neuroleptic malignant syndrome have been reported with concomitant use of psychotropic drugs. Digestive System : Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis. Eyes: Scattered punctate cortical lens opacities, as well as conjunctivitis, have been reported. Although a di…