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WARNINGSWARNINGSERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELESERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMALNECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENTWITH CARBAMAZEPINE. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERSIN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES ISESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND ASTRONG 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 INPATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLYAT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATINGTREATMENT WITH CARBAMAZEPINE. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BETREATED WITH CARBAMAZEPINE UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGSAND
LABORATORY TESTSLABORATORY TESTS).APLASTIC ANEMIA AND AGRANULOCYTOSISAPLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OFCARBAMAZEPINE. DATA FROM A POPULATION-BASED CASE CONTROL STUDY DEMONSTRATE THAT THERISK 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 ANDTWO PATIENTS PER ONE MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE BLOOD CELLCOUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF CARBAMAZEPINE, DATA ARE NOTAVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME. HOWEVER, THE VASTMAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONSOF APLASTIC ANEMIA OR AGRANULOCYTOSIS.BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA, THEVAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF PATIENTSON CARBAMAZEPINE ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER ABNORMALITY.NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS ABASELINE. IF A PATIENT IN THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOODCELL OR PLATELET COUNTS, THE PATIENT SHOULD BE MONITORED CLOSELY. DISCONTINUATION OFTHE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSIONDEVELOPS.Before prescribing carbamazepine, the physician should be thoroughly familiar with the details of this prescribinginformation, particularly regarding use with other drugs, especially those which accentuate toxicity potential.
DESCRIPTIONDESCRIPTIONCarbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as chewabletablets of 100 mg and tablets of 100 mg, 200 mg, 300 mg, 400 mg. Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, andits structural formula is Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecularweight is 236.27.Carbamazepine tablets, USP 100 mg, 200 mg, 300 mg and 400 mg contain the
INACTIVE INGREDIENTinactive ingredients: colloidal silicon dioxide, FD&CRed #40 aluminum lake, hypromellose, magnesium stearate, pregelatinized starch, corn starch, and sodium starch glycolate.Carbamazepine tablets, USP (chewable) contain the inactive ingredients: artificial flavors, colloidal silicon dioxide, compressiblesugar, corn starch, FD&C Red #40 aluminum lake, hydroxypropyl methyl cellulose, magnesium stearate, and sodium starch glycolate. page 2 of 11 Carbamazepine tablets, USP 100 mg, 200 mg, 300 mg, 400 mg meet USP Dissolution Test 2 and Carbamazepine Tablets USP(Chewable), 100 mg meet USP Dissolution Test 1.
CLINICAL PHARMACOLOGYCLINICAL PHARMACOLOGYIn controlled clinical trials, carbamazepine has been shown to be effective in the treatment of psychomotor and grand mal seizures, aswell as trigeminal neuralgia.
MECHANISM OF ACTIONMechanism of ActionCarbamazepine has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures.It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Carbamazepine greatly reducesor abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar andpolysynaptic reflexes, including the linguomandibular reflex in cats. Carbamazepine is chemically unrelated to other anticonvulsantsor 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 anticonvulsant activity as demonstrated in severalin vivo animal models of seizures. Though clinical activity for the epoxide has been postulated, the significance of its activity withrespect to the safety and efficacy of carbamazepine has not been established.
CLINICAL STUDIESclinical studies, carbamazepine suspension, conventional tablets, and extended-release tablets delivered equivalent amounts of drugto 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 b.i.d.dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tabletfor the same dosage regimen. On the other hand, following a t.i.d. dosage regimen, carbamazepine suspension affords steady-stateplasma levels comparable to carbamazepine tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d.dosage regimen, carbamazepine-extended-release tablets afford steady-state plasma levels comparable to conventional carbamazepinetablets given q.i.d., when administered at the same total mg daily dose. Carbamazepine in blood is 76% bound to plasma proteins.Plasma levels of carbamazepine are variable and may range from 0.5-25 265g/mL, with no apparent relationship to the daily intakeof the drug. Usual adult therapeutic levels are between 4 and 12 265g/mL. In polytherapy, the concentration of carbamazepine andconcomitant drugs may be increased or decreased during therapy, and drug effects may be altered (see PRECAUTIONS, DrugInteractions). Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5hours after administration of conventional carbamazepine tablets, and 3-12 hours after administration of carbamazepine-extended-release tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound carbamazepine in serum. Because carbamazepine inducesits own metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen. Initialhalf-life values range from 25-65 hours, decreasing to 12-17 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 fromcarbamazepine. After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% ofunchanged carbamazepine.The pharmacokinetic parameters of carbamazepine disposition are similar in children and in adults. However, there is a poorcorrelation between plasma concentrations of carbamazepine and carbamazepine dose in children. Carbamazepine is more rapidlymetabolized to carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animalscreens) 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 10-15 years ofage).The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.INDICATIONS AND USAGEEpilepsyCarbamazepine is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of carbamazepine as an anticonvulsantwas derived from active drug-controlled studies that enrolled patients with the following seizure types:1.Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greaterimprovement than those with other types.2.Generalized tonic-clonic seizures (grand mal).3.Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures (petitmal) do not appearto be controlled by carbamazepine (see PRECAUTIONS, General).Trigeminal NeuralgiaCarbamazepine is indicated in the treatment of the pain associated with true trigeminal neuralgia. page 3 of 11 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.
CONTRAINDICATIONSCONTRAINDICATIONSCarbamazepine should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, orknown sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline,etc. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration ofcarbamazepine, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits.Co-administration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its activemetabolite to achieve a therapeutic effect. Co-administration of carbamazepine with nefazodone is contraindicated.WARNINGSSerious Dermatologic ReactionsSerious 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 usersin 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 symptomssuggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.SJS/TEN and HLA-B*1502 AlleleRetrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk ofdeveloping SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B*1502. Theoccurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increasedin 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 reportedpositive 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 somegroups. 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 NativeAmericans).Prior to initiating carbamazepine therapy, testing for HLA-B*1502 should be performed in patients with ancestry inpopulations in which HLA-B*1502 may be present. In deciding which patients to screen, the rates provided above for theprevalence of HLA-B*1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rateseven within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Carbamazepine shouldnot be used in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to benegative for the allele are thought to have a low risk of SJS/TEN (see
WARNINGS AND PRECAUTIONSWARNINGS 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 oncarbamazepine.The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such asanticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption [MPE]).Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestrytaking other anti-epileptic drugs associated with SJS/TEN. Consideration should be given to avoiding use of other drugs associatedwith SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable.Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute for appropriateclinical vigilance and patient management. Many HLA-B*1502-positive Asian patients treated with carbamazepine will notdevelop SJS/TEN, and these reactions can still occur infrequently in HLA-B*1502-negative patients of any ethnicity. The role ofother possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance,concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied.Aplastic Anemia and AgranulocytosisPatients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression.GeneralCarbamazepine has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should be closelyobserved during therapy.Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderlypatients, of confusion or agitation should be borne in mind.The use of carbamazepine should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria,variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving carbamazepine therapy. page 4 of 11 Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for theinduction of acute attacks of porphyria.As with all antiepileptic drugs, carbamazepine should be withdrawn gradually to minimize the potential of increased seizurefrequency.Usage in
PREGNANCYPregnancyCarbamazepine 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 congenitalmalformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disordersand congenital anomalies (e.g., craniofacial defects, cardiovascular malformations and anomalies involving various body systems).Developmental delays based on neurobehavioral assessments have been reported. In treating or counseling women of childbearingpotential, 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 EFFECTSteratogenic effectsassociated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may bepreferable for pregnant women.In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, withhigher 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 10-25 times themaximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times the MHDD on a mg/m2 basis. In rat teratologystudies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate,1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkemptappearance at a maternal dosage level of 200 mg/kg.Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizuresbecause of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases wherethe 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 evenminor 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 womenreceiving carbamazepine.There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine and otherconcomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported inassociation with maternal carbamazepine use. These symptoms may represent a neonatal withdrawal syndrome.PRECAUTIONSGeneralBefore initiating therapy, a detailed history and physical examination should be made.Carbamazepine should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures, sincein these patients carbamazepine has been associated with increased frequency of generalized convulsions (see INDICATIONS ANDUSAGE).Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac conduction disturbance,including second and third degree AV heart block; cardiac, hepatic, or renal damage; adverse hematologic or hypersensitivity reactionto other drugs, including reactions to other anticonvulsants; or interrupted courses of therapy with carbamazepine.AV heart block, including second and third degree block, have been reported following, carbamazepine treatment. This occurredgenerally, but not solely, in patients with underling EKG abnormalities or risk factors for conduction disturbances.Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported (see ADVERSEREACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects may progress despite discontinuation of thedrug.Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases(see
INFORMATION FOR PATIENTSInformation for Patients).Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops.Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction toanticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions should be obtained for a patient and theimmediate family members. If positive, caution should be used in prescribing carbamazepine.Information for patientsPatients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as well as dermatologic,hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth,easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, page 5 of 11 or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they mustreport any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should bereported even if mild or when occurring after extended use.Carbamazepine may interact with some drugs. Therefore, patients should be advised to report to their doctors the use of any otherprescription or non-prescription medications or herbal products.Caution should be exercised if alcohol is taken in combination with carbamazepine therapy, due to a possible additive sedative effect.Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating machinery or automobiles orengaging in other potentially dangerous tasks.Laboratory testsFor genetically at-risk patients (See WARNINGS), high-resolution 221HLA-B*1502 typing222 is recommended. The test is positive ifeither one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected.Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, 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 monitoredclosely. Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops.Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed duringtreatment with this drug since liver damage may occur (see PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepineshould be discontinued, based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory evidence ofliver dysfunction or hepatic damage, or in the case of active liver disease.Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended since manyphenothiazines and related drugs have been shown to cause eye changes.Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because ofobserved renal dysfunction.Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of anticonvulsants. Thismonitoring may be particularly useful in cases of dramatic increase in seizure frequency and for verification of compliance. Inaddition, measurement of drug serum levels may aid in determining the cause of toxicity when more than one medication is beingused.Thyroid function tests have been reported to show decreased values with carbamazepine administered alone.Hyponatremia has been reported in association with carbamazepine use, either alone or in combination with other drugs.Interference with some pregnancy tests has been reported.
DRUG INTERACTIONSDrug InteractionsClinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following:Agents That May Affect Carbamazepine Plasma LevelsCYP 3A4 inhibitors inhibit carbamazepine metabolism and can thus increase plasma carbamazepine levels. Drugs that have beenshown, or would be expected, to increase plasma carbamazepine levels includecimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, nefazodone,loratadine, terfenadine, isoniazid, niacinamide, nicotinamide, propoxyphene, azoles (e.g., ketaconazole, itraconazole, fluconazole),acetazolamide, verapamil, grapefruit juice, protease inhibitors, valproate.*CYP 3A4 inducers can increase the rate of carbamazepine metabolism. Drugs that have been shown, or that would be expected, todecrease plasma carbamazepine levels includecisplatin, doxorubicin HCl, felbamate,206 rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline.When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepinelevels is indicated and dosage adjustment may be required. *increased levels of the active 10,11-epoxide206 decreased levels of carbamazepine and increased levels of the 10,11-epoxideEffect of Carbamazepine on Plasma Levels of Concomitant AgentsIncreased levels: clomipramine HCl, phenytoin, primidoneCarbamazepine induces hepatic CYP activity. Carbamazepine causes, or would be expected to cause, decreased levels of thefollowing:acetaminophen, alprazolam, dihydropyridine calcium channel blockers (e.g., felodipine), cyclosporine, corticosteroids (e.g.,prednisolone, dexamethasone), clonazepam, clozapine, dicumarol, doxycycline, ethosuximide, haloperidol, itraconazole, lamotrigine,levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine,phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, theophylline, tiagabine, topiramate, tramadol, tricyclicantidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.In concomitant use with carbamazepine, dosage adjustment of the above agents may be necessary.Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects. page 6 of 11 Co-administration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone and itsactive metabolite to achieve a therapeutic effect. Co-administration of carbamazepine with nefazodone is contraindicated. (SeeCONTRAINDICATIONS).Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications.Concomitant use of carbamazepine with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal implantcontraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased.Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should beconsidered.Carcinogenesis, mutagenesis, impairment of fertilityCarbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day, resultedin a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes ofmales.Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicitystudies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine inhumans is, at present, unknown.Usage in PregnancyPregnancy Category D (see WARNINGS).Labor and deliveryThe effect of carbamazepine on human labor and delivery is unknown.
NURSING MOTHERSNursing mothersCarbamazepine and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk to that inmaternal plasma is about 0.4 for carbamazepine and about 0.5 for the epoxide. The estimated doses given to the newborn during breastfeeding are in the range of 2-5 mg daily for carbamazepine and 1-2 mg daily for the epoxide.Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether todiscontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
PEDIATRIC USEPediatric useSubstantial evidence of carbamazepine's effectiveness for use in the management of children with epilepsy (see Indications forspecific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro systems whichsupport the conclusion that (1) the pathogenetic mechanisms underlying seizure propagation are essentially identical in adults andchildren, and (2) the mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total carbamazepine inplasma (i.e., 4-12 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 hasbeen systematically studied up to 6 months. No longer-term data from clinical trials is available.
GERIATRIC USEGeriatric useNo systematic studies in geriatric patients have been conducted.ADVERSE REACTIONSIf adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuationof any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threateninghazards.The most severe adverse reactions have been observed in the hemopoietic system (see
BOXED WARNINGboxed WARNING), the liver and thecardiovascular 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 low dosagerecommended.The following additional adverse reactions have been reported:Hemopoietic SystemAplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia,acute intermittent porphyria.SkinToxic 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, page 7 of 11 purpura, aggravation of disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy maybe necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear.Cardiovascular SystemCongestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary arterydisease, 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 tricycliccompounds.LiverAbnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of hepatic failure.PancreaticPancreatitis.Respiratory SystemPulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.Genitourinary SystemUrinary 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-relatedincidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in theurinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown.Nervous SystemDizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transientdiplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis andparesthesias, 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 ofthese reactions to the drug has not been established.Isolated cases of neuroleptic malignant syndrome have been reported with concomitant use of psychotropic drugs.Digestive SystemNausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx,including glossitis and stomatitis.EyesScattered punctate cortical lens opacities, as well as conjunctivitis, have been reported. Although a direct causal relationship has notbeen established, many phenothiazines and related drugs have been shown to cause eye changes.Musculoskeletal SystemAching joints and muscles, and leg cramps.MetabolismFever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported. Cases of frank water intoxication,with decreased serum sodium (hyponatremia) and confusion, have been reported in association with carbamazepine use (seePRECAUTIONS, Laboratory Tests). Decreased levels of plasma calcium have been reported.OtherMulti-organ hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rarecases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis, lymphadenopathy, disorders mimickinglymphoma, arthralgia, leukopenia, eosinophilia, hepato-splenomegaly and abnormal liver function tests. These signs and symptomsmay occur in various combinations and not necessarily concurrently. Signs and symptoms may initially be mild. Various organs,including but not limited to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (seePRECAUTIONS, General and PRECAUTIONS, Information for Patients).Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels ofcholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants. page 8 of 11 A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient takingcarbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared uponrechallenge with carbamazepine.
DEPENDENCEDEPENDENCENo evidence of abuse potential has been associated with carbamazepine, nor is there evidence of psychological or physicaldependence in humans.
OVERDOSAGEOVERDOSAGEAcute ToxicityLowest 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 pneumoniaand hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g (a 3-yearold girl died of aspirationpneumonia).Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.Signs and SymptomsThe first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disordersare generally milder, and severe cardiac complications occur only when very high doses (> 60 g) have been ingested.Respiration: Irregular breathing, respiratory depression.Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in smallchildren. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis,nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia.Gastrointestinal Tract: Nausea, vomiting.Kidneys and Bladder: Anuria or oliguria, urinary retention.Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, andacetonuria. EEG may show dysrhythmias.Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs andsymptoms of acute poisoning with carbamazepine may be aggravated or modified.TreatmentThe prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achievedby inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption. If these measures cannot beimplemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions aresafeguarded. There is no specific antidote.Elimination of the Drug: Induction of vomiting.Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should be repeatedlyirrigated, especially if the patient has also consumed alcohol.Measures to Reduce Absorption: Activated charcoal, laxatives.Measures to Accelerate Elimination: Forced diuresis.Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated in severe poisoning insmall children.Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, andadministration of oxygen.Hypotension, Shock: Keep the patient's legs raised and administer a plasma expander. If blood pressure fails to rise despite measurestaken to increase plasma volume, use of vasoactive substances should be considered.Convulsions: Diazepam or barbiturates.Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension, and coma. However,barbiturates should not be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage or inrecent therapy (within 1 week).Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary reflexes, and kidney andbladder function should be monitored for several days.Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the followingrecommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte counts, (3) do a bone marrowaspiration and trephine biopsy immediately and repeat with sufficient frequency to monitor recovery.Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic studies, (3) peripheralblood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow culture studies for colony-forming units,(6) hemoglobin electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels. page 9 of 11 A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultationshould be sought.DOSAGE AND ADMINISTRATION(see table below)Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS, Laboratory Tests). Dosageshould be adjusted to the needs of the individual patient. A low initial daily dosage with a gradual increase is advised. As soon asadequate control is achieved, the dosage may be reduced very gradually to the minimum effective level. Medication should be takenwith meals.Conversion of patients from oral carbamazepine tablets to carbamazepine suspension: Patients should be converted by administeringthe same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d. suspension).Epilepsy(see INDICATIONS AND USAGE)Adults and children over 12 years of age - Initial: 200 mg b.i.d. Increase at weekly intervals by adding up to 200 mg/day using at.i.d. or q.i.d. regimen until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12-15years of age, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rareinstances. Maintenance: Adjust dosage to the minimum effective level, usually 800-1200 mg daily.Children 6-12 years of age - Initial: 100 mg b.i.d. Increase at weekly intervals by adding up to 100 mg/day using a t.i.d. or q.i.d.regimen until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance: Adjust dosage tothe minimum effective level, usually 400-800 mg daily.Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. Increase weekly to achieve optimal clinical responseadministered t.i.d. or q.i.d. Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. Ifsatisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in thetherapeutic range. No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be made.Combination Therapy: Carbamazepine may be used alone or with other anticonvulsants. When added to existing anticonvulsanttherapy, 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, and Pregnancy Category D).Trigeminal Neuralgia(see INDICATIONS AND USAGE)Initial: On the first day, 100 mg b.i.d. for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day usingincrements of 100 mg every 12 hours only as needed to achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance:Control of pain can be maintained in most patients with 400-800 mg daily. However, some patients may be maintained on as littleas 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.Dosage Information Initial Dose Subsequent Dose Maximum Daily Dose Indication Tablet* Tablet* Tablet* Epilepsy under 6 yr 10-20 mg/kg/dayb.i.d. or t.i.d. increase weekly to achieveoptimal clinical response,t.i.d. or q.i.d. 35 mg/kg/24 hr.(See Dosage and Administrationsection above) 6-12 yr 100 mg b.i.d (200 mg/day) Add up to 100 mg/day atweekly intervals, t.i.d. orq.i.d. 1000 mg/24 hr. Over 12 yr 200 mg b.i.d. (400 mg/day) Add up to 200 mg/day atweekly intervals, t.i.d. orq.i.d. 1000 mg/24 hr (12-15 yr)1200 mg/ 24 hr (>15 yr)1600 mg/24 hr (adults, in rare instances) Trigeminal Neuralgia 100 mg b.i.d. (200 mg/day) Add up to 200 mg/day inincrements of 100 mg every12 hr. 1200 mg/24 hr. *Tablet = Chewable or conventional tablets
HOW SUPPLIEDHOW SUPPLIEDCarbamazepine Tablets USP (Chewable), 100 mg are available in the following form: pink colored, circular, strawberry/vanillaflavored, flat beveled, uncoated tablets with 223342224 debossed on one side and scoreline on the other. page 10 of 11 Unit Dose Packages of 100 (10x10)...................................NDC 62584-639-01Store at 20260-25260C (68260-77260F) [see USP Controlled Room Temperature].Protect from light and moisture.Manufactured by:Caraco Pharmaceutical Laboratories, Ltd.1150 Elijah McCoy DriveDetroit, MI 48202Packaged by:American Health PackagingColumbus, Ohio 432178008735/0108PRINCIPAL DISPLAY PANEL Label TextCarbamazepineTablets, USP (Chewable)100 mg100 Tablets (10x10)Each Tablet Cotains:carbamazepine, USP.......................100 mgUSUAL DOSAGE: See Package insert for completeproduct information.Store at controlled room temperature 20260-25260C(68260 -77260 F). Store in a dry place. Protect from moisture. page 11 of 11 [See USP].Keep out of the reach of childrenMeets USP Dissolution Test 1Rx only
PACKAGE LABEL.PRINCIPAL DISPLAY PANELDRUG: carbamazepine
SCORE: No score
SIZE: 2 mm
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 CARBAMAZEPINE. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE
TREATED WITH CARBAMAZEPINE 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
Revised: 07/2010 REMEDYREPACK INC.
Reproduced with permission of U.S. National Library of Medicine
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