Carbamazepine (Suspension)

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(see table) Carbamazepine oral suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation, and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in the stool following coadministration of the two drugs . Because the extent to which this occurs with other liquid medications is not known, carbamazepine oral suspension should not be administered simultaneously with other liquid medications or diluents. Monitoring of blood levels has increased the efficacy and safety of anticonvulsants . 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 oral suspension will produce higher peak levels than the same dose given as the tablet, it is recommended to start with low doses (children 6���12 years: 1/2 teaspoonful q.i.d.) and to increase slowly to avoid unwanted side effects. Conversion of patients from oral carbamazepine tablets to carbamazepine oral suspension: Patients should be converted by administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d. suspension).<br/>Epilepsy: Adults and children over 12 years of age - Initial: 1 teaspoonful q.i.d. of the suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a t.i.d. or q.i.d. regimen of the suspension until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12���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 to 1200 mg daily. Children 6���12 years of age - Initial: 1/2 teaspoonful q.i.d. of the suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a t.i.d. or q.i.d. regimen of the suspension until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level, usually 400to 800 mg daily. Children under 6 years of age - Initial: 10 to 20 mg/kg/day q.i.d. of the suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: 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 carbamazepinefor use at doses above 35 mg/kg/24 hours can be made. Combination Therapy: Carbamazepine oral suspension 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 . Trigeminal Neuralgia

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.<br/>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 responses and blocking the post-tetanic potentiation. Carbamazepine greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the 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, carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Though 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.<br/>Pharmacokinetics: In clinical studies, carbamazepine 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 b.i.d. 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 t.i.d. dosage regimen, carbamazepine oral suspension affords steady-state plasma levels comparable to carbamazepine tablets given b.i.d. when administered atthe 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 to 25 mcg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 mcg/mL. In polytherapy, the concentration of carbamazepine and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered . Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4���5 hours after administration of conventional carbamazepine tablets, and 3���12 hours after administration of carbamazepine-XR tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound carbamazepine in serum. Because carbamazepine induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3���5 weeks of a fixed dosing regimen. Initial half-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 from carbamazepine. After oral administration ofC-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged carbamazepine. The pharmacokinetic parameters of carbamazepine disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of carbamazepine and carbamazepine oral suspension dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11- epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10���15 years of age). The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.

Carbamazepine Oral Suspension, USP 100 mg/5 mL (teaspoonful) is a yellow-orange, citrus-vanilla flavored suspension, supplied as follows: Shake well before using. Store at 20�����25��C (68�����77��F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP.

WARNING: 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.

dailymed-ingredient:FD&C_Yellow_No._6, dailymed-ingredient:alcohol_free_lemon_lime_flavor, dailymed-ingredient:citric_acid_anhydrous, dailymed-ingredient:citric_acid_solution, dailymed-ingredient:hydroxypropyl_methylcellulose_(polymer), dailymed-ingredient:orange_concentrate_flavor, dailymed-ingredient:potassium_sorbate, dailymed-ingredient:propylene_glycol, dailymed-ingredient:sodium_citrate_solution, dailymed-ingredient:sorbitol_solution, dailymed-ingredient:sucrose, dailymed-ingredient:vanillin, dailymed-ingredient:water, dailymed-ingredient:xanthan_gum

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 . 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 reaction to 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 occurred generally, 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 . In some cases, hepatic effects may progress despite discontinuation of the drug. Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases . 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 to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions should be obtained for a patient and the immediate family members. If positive, caution shouldbe used in prescribing carbamazepine. Since a given dose of carbamazepine oral 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 .<br/>Information for Patients: Patients 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 purpurichemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported 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 other prescription 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.<br/>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 . Carbamazepine should be discontinued, based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory evidence of liver 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 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 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 oral suspension use, either alone or in combination with other drugs. Interference with some pregnancy tests has been reported.<br/>Drug Interactions: There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting carbamazepine oral suspension immediately followed by Thorazine solution. Subsequent testing has shown that mixing carbamazepine oral suspension and chlorpromazine solution (both generic and brand name) as well as carbamazepine oral suspension and liquid Mellaril resulted in the occurrence of this precipitate. Because the extent to which this occurs with other liquid medications is not known, carbamazepine oral suspension should not be administered simultaneously with other liquid medicinalagents or diluents. . Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following:<br/>Agents That May Affect Carbamazepine Plasma Levels: CYP 3A4 inhibitors inhibit carbamazepine oral suspension metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include: CYP 3A4 inducers can increase the rate of carbamazepine metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include: When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, monitoring of carbamazepine levels is indicated and dosage adjustment may be required.<br/>Effect of Carbamazepine on Plasma Levels of Concomitant Agents: Increased levels: clomipramine HCl, phenytoin, primidone Carbamazepine induces hepatic CYP activity. Carbamazepine causes, or would be expected to cause, decreased levels of the following: In concomitant use with carbamazepine, dosage adjustment of the above agents may be necessary. Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated. 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. Concomitant use of carbamazepine 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. Alternative or back-up methods of contraception should be considered.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males. Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.<br/>Usage in Pregnancy: Pregnancy Category D .<br/>Labor and Delivery: The effect of carbamazepine on human labor and delivery is unknown.<br/>Nursing Mothers: Carbamazepine and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk to that in maternal plasma is about 0.4 for carbamazepine and about 0.5 for the epoxide. The estimated doses given to the newborn during breast feeding are in the range of 2 to 5 mg daily for carbamazepine and 1 to 2 mg daily for the epoxide. Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Substantial evidence of carbamazepine's effectiveness for use in the management of children with epilepsy (see Indications for specific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic mechanisms underlying seizure propagation are essentially identical in adults and children, 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 in plasma (i.e., 4 to 12 mcg/mL) is the same in children and adults. The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical trials is available.<br/>Geriatric Use: No systematic studies in geriatric patients have been conducted.

Carbamazepine

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 , the skin, liver, and the cardiovascular system. The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the 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) , Stevens-Johnson syndrome , 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; very rare cases of 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 to 400 mg/kg/day. Additionally, rats receiving carbamazepine in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings tohumans 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: 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 . Decreased levels of plasma calcium have been reported. Other: Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and abnormal liver function tests. These signs and symptoms may 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 . 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.

Epilepsy: Carbamazepine is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types:<br/>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.

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