 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
CarbamazepineWARNING
Before prescribing carbamazepine, the physician should be thoroughly familiar with the details of this prescribing information, particularly regarding use with other drugs, especially those which accentuate toxicity potential. Carbamazepine USP is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and as a suspension of 100 mg/5 ml (teaspoon). Its chemical name is 5H-dibenz(b,f)azepine-5-carboxamide. Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. It molecular weight is 236.27. Inactive Ingredients Tablets: Colloidal silicon dioxide, FD&C Red No. 30 (chewable tablets only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets only). XR Tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum. 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. Mechanism of Action Carbamazepine has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic response 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 linguomandibular 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-10, 11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Through clinical activity for the epoxide has been postulated, the significance of its activity with respect to the safety and efficacy of carbamazepine has not been established. Pharmacokinetics In clinical studies suspension, conventional tablets and XR tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR 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, carbamazepine suspension affords steady-state plasma levels comparable to carbamazepine tablets given b.i.d. when administered at the same total mg daily dose. Carbamazepine chewable tablets may produce higher peak levels than the same dose given as regular tablets. Carbamazepine in blood is 76% bound to plasma proteins. Plasma levels of carbamazepine are variable and may range from 0.5-25 mcg/ml, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 mcg/ml. Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4 to 5 hours after administration of oral tablets. The CSF/serum ratio is 0.22, similar to the 22% unbound carbamazepine in serum. Because carbamazepine may induce its own metabolism, the half-life is also variable. Initial half-life values range from 25-65 hours, with 12-17 hours on repeated doses. Carbamazepine is metabolized in the liver. 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. Transplacental passage of carbamazepine is rapid (30 to 60 minutes), and the drug is accumulated in fetal tissues, with higher levels found in liver and kidney than in brain and lungs.
INDICATIONSEpilepsy: 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: Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement 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 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.
TABLE 1A - Dosage Information: Tablets and Suspension
TABLE 1B - Dosage Information: Tablets and Suspension
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 patient. A low initial daily dosage with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very gradually to the minimum effective level. Medication should be taken with meals. Since a given dose of carbamazepine suspension will produce higher peak levels than the same dose give as the tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon four times a day) and to increase slowly to avoid unwanted side effects. Conversion Of Patients From Oral Carbamazepine Tablets To Carbamazepine Suspension: Patients should be converted by administering the same number of mg per day in smaller, more frequent doses (i.e., twice a day tablets to three times a day suspension). Epilepsy (see Adults And Children Over 12 Years Of Age Initial: Either 200 mg twice a day for tablets and extended release tablets or 1 teaspoon four times a day for suspension (400 mg per day). Increase at weekly intervals by adding up to 200 mg per day using a twice a day regimen of extened release or three times a day or four times a day regimen until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12 to 15 years 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 rare instances. Maintenance: Adjust dosage to the minimum effective level, usually 800-1200 mg daily. Children 6 - 12 Years Of Age Initial: Either 100 mg twice a day for tablets or 1/2 teaspoon four times a day for suspension (200 mg per day). Increase at weekly intervals by adding up to 100 mg per day using a three times a day or four times a day regimen until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level, usually 400-800 mg daily. Combination Therapy: Carbamazepine 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 and DRUG INTERACTIONS). Trigeminal Neuralgia (see Initial: On the first day, either 100 mg twice a day for tablets or 1/2 teaspoon four times a day for suspension for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg a day using increments of 100 mg every 12 hours for tablets or 50 mg (1/2 teaspoon) four times a day for suspension, 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 mg 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. HOW SUPPLIED No information provided. Storage Do not store above 86°F (30°C). Dispense in tight, light-resistant container (USP).
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 (see DESCRIPTION: BOXED WARNING) , the skin 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 low dosage recommended. The following additional adverse reactions have been reported: Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria. Skin: Pruritic and erythematous rashes, urticaria, toxic epidermal necrolysis (Lyell's Syndrome) (see WARNINGS), Stevens-Johnson syndrome (see WARNINGS), 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, primary thrombophlebitis, recurrence of thrombophlebitis, 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. 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, elevated BUN and microscopic deposits in the urine have also been reported. 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 two 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: 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. 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: Aching joints and muscles, and leg cramps. Metabolism: Fever 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 (see PRECAUTIONS, Laboratory Tests). Other: Isolated cases of 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 Abuse and Dependence No evidence of abuse potential has been associated with carbamazepine, nor is there evidence of psychological or physical dependence in humans.
The simultaneous administration of phenobarbital, phenytoin, or primidone, or a combination of two, produces a marked lowering of serum levels, of carbamazepine. The effect of valproic acid on carbamazepine blood levels is not clearly established, although an increase in the ratio of active 10, 11-epoxide metabolite to parent compound is a consistent finding. The half-lives of phenytoin, warfarin, doxycycline, and theophylline were significantly shortened when administered concurrently with carbamazepine. Haloperidol and valproic acid serum levels may be reduced when these drugs are administered with carbamazepine. The doses of these drugs may therefore have to be increased when carbamazepine is added to the therapeutic regimen. Concomitant administration of carbamazepine with erythromycin, cimetidine, propoxyphene, isoniazid, fluoxetine or calcium channel blockers has been reported to result in elevated plasma levels of carbamazepine resulting in toxicity in some cases. Also concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects. Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications. Breakthrough bleeding
has been reported among patients receiving concomitant oral contraceptives
and their reliability
may be adversely affected.
(
Patients with a history of adverse hematologic reaction to any drug may be particularly at risk. Severe dermatologic reactions including toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome, have been reported with carbamazepine. These reactions have been extremely rare. However, a few fatalities have been reported. Carbamazepine has shown mild anticholinergic activity: 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.
General Before 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, since in these patients carbamazepine has been associated with increased frequency of generalized convulsions (see INDICATIONS AND USAGE). Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac, hepatic or renal damage, adverse hematologic reaction to other drugs, or interrupted courses of therapy with carbamazepine. Since a given dose of carbamazepine suspension will produce higher peak levels than the same dose given as the tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION). Information for the Patient Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, such as fever, sore throat, rash, ulcers in the mouth, easy bruising, petechial or purpuric hemorrhage, and should be advised to report to the physician immediately if any such signs or symptoms appear. Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks. Laboratory Tests 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 monitored closely. 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 during treatment with this drug since liver damage may occur. The drug should be discontinued immediately in cases of aggravated liver dysfunction or active liver disease. Baseline and periodic eye examinations, including slit-lamp, funduscopy and tonometry, are recommended since many phenothiazines 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 of observed renal dysfunction. Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the cause of toxicity when more than one medication is being used. 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. Carcinogenesis, Mutagenesis, and 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. Pregnancy Category C Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10-25 times the maximum human daily dosage of 1200 mg. In rat teratology studies, 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 unkempt appearance at a maternal dosage level of 200 mg/kg. There are no adequate and well-controlled studies in pregnant women. Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. Carbamazepine should be used during pregnancy only if the potential benefit justifies the potential risk 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, monotherapy is recommended for pregnant women. It is important to note that anticonvulsant drugs should not be discontinued 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. Labor and Delivery The effect of carbamazepine on human labor and delivery is unknown. Nursing Mothers During lactation, concentration of carbamazepine in milk is approximately 60% of the maternal plasma concentration. Because of the potential of 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 Safety and effectiveness in children below the age of 6 years have not been established.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||