WARNING SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH CARBAMAZEPINE. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH CARBATROL®. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH CARBATROL® UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS/LABORATORY TESTS ). APLASTIC ANEMIA AND AGRANULOCYTOSIS APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF CARBAMAZEPINE. DATA FROM A POPULATION-BASED CASE-CONTROL STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA. ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF CARBAMAZEPINE, DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS. BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF PATIENTS ON CARBAMAZEPINE ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.
INDICATIONS AND USAGE Epilepsy Carbatrol® 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: 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 Carbatrol® 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.
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 Carbatrol® 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.
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 ), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear. 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. 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. Testicular atrophy occurred in rats receiving carbamazepine orally from 4-52 weeks at dosage levels of 50-400 mg/kg/day. Additionally, rats receiving carbamazepine in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg/day and higher. Relevance of these findings to humans is unknown. Nervous System: 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 direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes. Musculoskeletal System: Bone loss, aching joints and muscles, and leg cramps. Metabolism: Fever and chills. Decreased levels of plasma calcium leading to osteoporosis have been reported. Other: 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.
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 Carbatrol® to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Agents that Inhibits Cytochrome P450 Isoenzymes and/or Epoxide Hydrolase: Carbamazepine is metabolized mainly by cytochrome P450 (CYP) 3A4 to the active carbamazepine 10,11-epoxide, which is further metabolized to the trans-diol by epoxide hydrolase. Therefore, the potential exists for interaction between carbamazepine and any agent that inhibits CYP3A4 and/or epoxide hydrolase. Agents that are CYP3A4 inhibitors that have been found, or are expected, to increase plasma levels of Carbatrol® are the following: Acetazolamide, azole antifungals, cimetidine, clarithromycin(1), dalfopristin, danazol, delavirdine, diltiazem, erythromycin(1), fluoxetine, fluvoxamine, grapefruit juice, isoniazid, itraconazole, ketoconazole, loratadine, nefazodone, niacinamide, nicotinamide, protease inhibitors, propoxyphene, quinine, quinupristin, troleandomycin, valproate(1), verapamil, zileuton. (1)also inhibits epoxide hydrolase resulting in increased levels of the active metabolite carbamazepine 10, 11- epoxide Thus, if a patient has been titrated to a stable dosage of Carbatrol®, 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 Carbatrol® 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 Carbatrol® are the following: Cisplatin, doxorubicin HCL, felbamate, rifampin, phenobarbital, phenytoin(2), primidone, methsuximide, and theophylline (2)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 Carbatrol®, and then begins a course of treatment with one of these CYP3A4 inducers, it is reasonable to expect that a dose increase for Carbatrol® may be necessary. Agents with Decreased Levels in the Presence of Carbamazepine due to Induction of Cytochrome P450 Enzymes: Carbamazepine is known to induce CYP1A2 and CYP3A4. Therefore, the potential exists for interaction between carbamazepine and any agent metabolized by one (or more) of these enzymes. Agents that have been found, or are expected to have decreased plasma levels in the presence of Carbatrol® due to induction of CYP enzymes are the following: Acetaminophen, alprazolam, amitriptyline, bupropion, buspirone, citalopram, clobazam, clonazepam, clozapine, cyclosporin, delavirdine, desipramine, diazepam, dicumarol, doxycycline, ethosuximide, felbamate, felodipine, glucocorticoids, haloperidol, itraconazole, lamotrigine, levothyroxine, lorazepam, methadone, midazolam, mirtazapine, nefazodone(7), nortriptyline, olanzapine, oral and other hormonal contraceptives(3), oxcarbazepine, phenytoin(4), praziquantel, protease inhibitors, quetiapine, risperidone, theophylline, topiramate, tiagabine, tramadol, triazolam, trazodone(5), valproate, warfarin(6), ziprasidone, and zonisamide. (3)Concomitant use of Carbatrol® with hormonal contraceptive products (e.g., oral and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported with carbamazepine. Alternative or back-up methods of contraception should be considered. (4)Phenytoin has also been reported to increase in the presence of carbamazepine. Careful monitoring of phenytoin plasma levels following co-medication with carbamazepine is advised. (5)Following co-administration of carbamazepine 400mg/day with trazodone 100mg to 300mg daily, carbamazepine reduced trough plasma concentrations of trazodone (as well as meta-chlorophenylpiperazine [mCPP]) by 76 and 60% respectively, compared to precarbamazepine values. (6)Warfarin's anticoagulant effect can be reduced in the presence of carbamazepine. (7) Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see CONTRAINDICATIONS ). Thus, if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of treatment with Carbatrol®, it is reasonable to expect that a dose increase for the concomitant agent may be necessary. Agents with Increased Levels in the Presence of Carbamazepine: Carbatrol® increases the plasma levels of the following agents: Clomipramine HCl, phenytoin(8), and primidone (8)Phenytoin has also been reported to decrease in the presence of carbamazepine. Careful monitoring of phenytoin plasma levels following co-medication with carbamazepine is advised. Thus, if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of the treatment with Carbatrol®, it is reasonable to expect that a dose decrease for the concomitant agent may be necessary. Pharmacological/Pharmacodynamic Interactions with Carbamazepine: Coadministration of Carbatrol® with delavirdine may lead to loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors (see CONTRAINDICATIONS ). Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects. Given the anticonvulsant properties of carbamazepine, Carbatrol® may reduce the thyroid function as has been reported with other anticonvulsants. Additionally, anti-malarial drugs, such as chloroquine and mefloquine, may antagonize the activity of carbamazepine. Thus if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of treatment with Carbatrol®, it is reasonable to expect that a dose adjustment may be necessary. Because of its primary CNS effect, caution should be used when Carbatrol® is taken with other centrally acting drugs and alcohol.