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Carbamazepine

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Overview

What is Carbamazepine?

Carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as tablets of 200 mg. Its chemical name is 5-dibenz[b,f]azepine-5-carboxamide, and its structural formula is:

Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27.

The following inactive ingredients are contained in these tablets: lactose (monohydrate), microcrystalline cellulose, hypromellose, ethylcellulose, croscarmellose sodium, magnesium stearate.

Product meets USP Dissolution Test 3.



What does Carbamazepine look like?



What are the available doses of Carbamazepine?

Sorry No records found.

What should I talk to my health care provider before I take Carbamazepine?

Sorry No records found

How should I use Carbamazepine?

Epilepsy:

1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement 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 (petit mal) do not appear to be controlled by carbamazepine (see ).

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.

(See table below)

Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see ). 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. Tablets should be taken with meals.

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., b.i.d. tablets to t.i.d. suspension).

Epilepsy

Adults And Children Over 12 Years Of Age200 mg b.i.d. Increase at weekly intervals by adding up to 200 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 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. Adjust dosage to the minimum effective level, usually 800 to 1200 mg daily.

Children 6 to 12 years of age100 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.  Adjust dosage to the minimum effective level, usually 400 to 800 mg daily.

Children Under 6 Years Of Age10 to 20 mg/kg/day b.i.d. or t.i.d. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d.  Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range. No recommendation regarding the safety of carbamazepine 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 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 ,and ).

Trigeminal Neuralgia

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 using increments of 100 mg every 12 hours for tablets, 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 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.


What interacts with Carbamazepine?

Carbamazepine should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of carbamazepine, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits.


Co-administration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect.  Co-administration of carbamazepine with nefazodone is contraindicated.



What are the warnings of Carbamazepine?

Amoxicillin and clavulanate potassium should be used with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of amoxicillin and clavulanate potassium is usually reversible. On rare occasions, deaths have been reported (less than 1 death reported per estimated 4 million prescriptions worldwide). These have generally been cases associated with serious underlying diseases or concomitant medications (see and , ).

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.

The used 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. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.

As with all antiepileptic drugs, carbamazepine should be withdrawn gradually to minimize the potential of increased seizure frequency.

Usage In Pregnancy:

Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and 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 childbearing potential, 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 effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.

In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, with higher 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 the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 15-4 times the MHDD on a mg/m basis. 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.

Antiepileptic drugs should not be discontinued abruptly 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.

Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine.

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal carbamazepine use. These symptoms may represent a neonatal withdrawal syndrome.


What are the precautions of Carbamazepine?

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 ).

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 (see and ). 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 (see and ).

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 should be used in prescribing carbamazepine.

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 purpuric hemorrhage, 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.

Carbamzepine 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.

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 (see and ). Carbamazepine should be discontinued, based on clinical judgement, 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 (see ) 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.

Interference with some pregnancy tests has been reported.

Drug Interactions

Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following:

Agents That May Affect Carbamazepine Plasma Levels

CYP 3A4 inhibitors inhibit carbamazepine metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected to increase plasma carbamazepine levels include:

cimetidine, 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, to decrease plasma carbamazepine levels include:

cisplatin, doxorubicin HCl, felbamate, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline.

When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.

______________________________________

*increased levels of the active 10,11-epoxide

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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:

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, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin,ziprasidone, zonisamide.

In concomitant use with carbamazepine, dosage adjustment of the above agents may be necessary.

Co-administration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Co-administration of carbamazepine with nefazodone is contraindicated. (See ).

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.

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.

Pregnancy

Usage in Pregnancy:

Labor and Delivery

The effect of carbamazepine on human labor and delivery is unknown.

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 04 for carbamazepine and about 05 for the epoxide. The estimated doses given to the newborn during breast feeding 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 to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Substantial evidence of carbamazepine’s effectiveness for use in the management of children with epilepsy (see for specific seizure types) is derived from clinical investigations performed in adults and from studies in several 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., 4-12 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.

Geriatric Use

No systematic studies in geriatric patients have been conducted.


What are the side effects of 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 (see boxed ), 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:

Skin:

Cardiovascular System:

Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds.

Liver:

Pancreatic:

Respiratory System:

Genitourinary System:

Testicular atrophy occurred in rats receiving carbamazepine orally from 4-52 weeks at dosage levels of 50-400 mg/kg/day. Additionally, rats receiving carbamazepine in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown.

Nervous System:

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:

Eyes:

Musculoskeletal System:

Metabolism:

Other:

Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.

A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.


What should I look out for while using Carbamazepine?

Carbamazepine should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of carbamazepine, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits.

Co-administration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect.  Co-administration of carbamazepine with nefazodone is contraindicated.

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.

The used 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. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.

As with all antiepileptic drugs, carbamazepine should be withdrawn gradually to minimize the potential of increased seizure frequency.

Usage In Pregnancy:

Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and 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 childbearing potential, 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 effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.

In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, with higher 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 the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 15-4 times the MHDD on a mg/m basis. 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.

Antiepileptic drugs should not be discontinued abruptly 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.

Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine.

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal carbamazepine use. These symptoms may represent a neonatal withdrawal syndrome.




What might happen if I take too much Carbamazepine?

Acute Toxicity:

Oral LD in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.

Signs And Symptoms:

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 small children. 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, and acetonuria. EEG may show dysrhythmias.

Combined Poisoning:When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with carbamazepine may be aggravated or modified.

Treatment:

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 repeatedly irrigated, 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 in small children.

Respiratory Depression:Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, and administration of oxygen.

Hypotension, Shock:Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to rise despite measures taken 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 be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week).

Surveillance:Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary reflexes, and kidney and bladder function should be monitored for several days.

Treatment Of Blood Count Abnormalities:If evidence of significant bone marrow depression develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte counts, (3) do a bone marrow aspiration 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) Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A and F hemoglobin, and (7) serum folic acid and B levels.

A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought.


How should I store and handle Carbamazepine?

Store at 20°-25°C (68°-77°F). [See USP controlled room temperature.] Protect from excessive light and humidity.Dispense in a tight, light-resistant container according to USP/NF.*AN69 is a registered trademark of Hospal Ltd.WockhardtThis Product was Repackaged By:State of Florida DOH Central PharmacyStore at 20°-25°C (68°-77°F). [See USP controlled room temperature.] Protect from excessive light and humidity.Dispense in a tight, light-resistant container according to USP/NF.*AN69 is a registered trademark of Hospal Ltd.WockhardtThis Product was Repackaged By:State of Florida DOH Central PharmacyStore at 20°-25°C (68°-77°F). [See USP controlled room temperature.] Protect from excessive light and humidity.Dispense in a tight, light-resistant container according to USP/NF.*AN69 is a registered trademark of Hospal Ltd.WockhardtThis Product was Repackaged By:State of Florida DOH Central PharmacyStore at 20°-25°C (68°-77°F). [See USP controlled room temperature.] Protect from excessive light and humidity.Dispense in a tight, light-resistant container according to USP/NF.*AN69 is a registered trademark of Hospal Ltd.WockhardtThis Product was Repackaged By:State of Florida DOH Central PharmacyStore at 20°-25°C (68°-77°F). [See USP controlled room temperature.] Protect from excessive light and humidity.Dispense in a tight, light-resistant container according to USP/NF.*AN69 is a registered trademark of Hospal Ltd.WockhardtThis Product was Repackaged By:State of Florida DOH Central PharmacyStore at 20°-25°C (68°-77°F). [See USP controlled room temperature.] Protect from excessive light and humidity.Dispense in a tight, light-resistant container according to USP/NF.*AN69 is a registered trademark of Hospal Ltd.WockhardtThis Product was Repackaged By:State of Florida DOH Central PharmacyCarbamazepine Tablets, USP are supplied by as follows:Store at controlled room temperature 15°-30°C (59°-86°F) (see USP).Store in a dry place. Protect from moisture.Rx onlyManufactured by:Taro HAWTHORNE, NY or Apotex Indianapolis, INThis Product was Repackaged By:State of Florida DOH Central PharmacyCarbamazepine Tablets, USP are supplied by as follows:Store at controlled room temperature 15°-30°C (59°-86°F) (see USP).Store in a dry place. Protect from moisture.Rx onlyManufactured by:Taro HAWTHORNE, NY or Apotex Indianapolis, INThis Product was Repackaged By:State of Florida DOH Central PharmacyCarbamazepine Tablets, USP are supplied by as follows:Store at controlled room temperature 15°-30°C (59°-86°F) (see USP).Store in a dry place. Protect from moisture.Rx onlyManufactured by:Taro HAWTHORNE, NY or Apotex Indianapolis, INThis Product was Repackaged By:State of Florida DOH Central PharmacyCarbamazepine Tablets, USP are supplied by as follows:Store at controlled room temperature 15°-30°C (59°-86°F) (see USP).Store in a dry place. Protect from moisture.Rx onlyManufactured by:Taro HAWTHORNE, NY or Apotex Indianapolis, INThis Product was Repackaged By:State of Florida DOH Central PharmacyCarbamazepine Tablets, USP are supplied by as follows:Store at controlled room temperature 15°-30°C (59°-86°F) (see USP).Store in a dry place. Protect from moisture.Rx onlyManufactured by:Taro HAWTHORNE, NY or Apotex Indianapolis, INThis Product was Repackaged By:State of Florida DOH Central PharmacyCarbamazepine Tablets, USP are supplied by as follows:Store at controlled room temperature 15°-30°C (59°-86°F) (see USP).Store in a dry place. Protect from moisture.Rx onlyManufactured by:Taro HAWTHORNE, NY or Apotex Indianapolis, INThis Product was Repackaged By:State of Florida DOH Central PharmacyCarbamazepine Tablets, USP are supplied by as follows:Store at controlled room temperature 15°-30°C (59°-86°F) (see USP).Store in a dry place. Protect from moisture.Rx onlyManufactured by:Taro HAWTHORNE, NY or Apotex Indianapolis, INThis Product was Repackaged By:State of Florida DOH Central PharmacyCarbamazepine Tablets, USP are supplied by as follows:Store at controlled room temperature 15°-30°C (59°-86°F) (see USP).Store in a dry place. Protect from moisture.Rx onlyManufactured by:Taro HAWTHORNE, NY or Apotex Indianapolis, INThis Product was Repackaged By:State of Florida DOH Central Pharmacy


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Clinical Information

Chemical Structure

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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:

The principal metabolite of carbamazepine, carbamazepine-10, 11-epoxide, has anticonvulsant activity as demonstrated in several 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.

Pharmacokinetics:

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.

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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 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 044 in children below the age of 1 year to 018 in children between 10-15 years of age).

The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.

Non-Clinical Toxicology
Carbamazepine should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of carbamazepine, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits.

Co-administration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect.  Co-administration of carbamazepine with nefazodone is contraindicated.

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.

The used 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. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.

As with all antiepileptic drugs, carbamazepine should be withdrawn gradually to minimize the potential of increased seizure frequency.

Usage In Pregnancy:

Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and 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 childbearing potential, 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 effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.

In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, with higher 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 the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 15-4 times the MHDD on a mg/m basis. 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.

Antiepileptic drugs should not be discontinued abruptly 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.

Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine.

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal carbamazepine use. These symptoms may represent a neonatal withdrawal syndrome.

Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following:

Agents That May Affect Carbamazepine Plasma Levels

CYP 3A4 inhibitors inhibit carbamazepine metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected to increase plasma carbamazepine levels include:

cimetidine, 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, to decrease plasma carbamazepine levels include:

cisplatin, doxorubicin HCl, felbamate, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline.

When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.

______________________________________

*increased levels of the active 10,11-epoxide

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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:

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, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin,ziprasidone, zonisamide.

In concomitant use with carbamazepine, dosage adjustment of the above agents may be necessary.

Co-administration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Co-administration of carbamazepine with nefazodone is contraindicated. (See ).

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.

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 ).

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 (see and ). 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 (see and ).

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 should be used in prescribing 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 (see boxed ), 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:

Skin:

Cardiovascular System:

Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds.

Liver:

Pancreatic:

Respiratory System:

Genitourinary System:

Testicular atrophy occurred in rats receiving carbamazepine orally from 4-52 weeks at dosage levels of 50-400 mg/kg/day. Additionally, rats receiving carbamazepine in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown.

Nervous System:

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:

Eyes:

Musculoskeletal System:

Metabolism:

Other:

Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.

A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Professional

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72
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Interactions

Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).