Generic Name: CARBAMAZEPINE
Brand Name: Carbamazepine
- Substance Name(s):
- CARBAMAZEPINE
WARNINGS
Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with carbamazepine treatment.
The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations.
However, the risk in some Asian countries is estimated to be about 10 times higher.
Carbamazepine should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related.
If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.
SJS/TEN and HLA-B*1502 Allele Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B*1502.
The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.
Across Asian populations, notable variation exists in the prevalence of HLA-B*1502.
Greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China.
South Asians, including Indians, appear to have intermediate prevalence of HLA-B*1502, averaging 2% to 4%, but higher in some groups.
HLA-B*1502 is present in less than 1% of the population in Japan and Korea.
HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans).
Prior to initiating carbamazepine therapy, testing for HLA-B*1502 should be performed in patients with ancestry in populations in which HLA-B*1502 may be present.
In deciding which patients to screen, the rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry.
Carbamazepine should not be used in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks.
Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see BOXED WARNING and PRECAUTIONS, Laboratory Tests ).
Over 90% of carbamazepine treated patients who will experience SJS/TEN have this reaction within the first few months of treatment.
This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on carbamazepine.
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine such as maculopapular eruption (MPE) or to predict Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin.
Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable.
Hypersensitivity Reactions and HLA-A*3101 Allele Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a moderate association between the risk of developing hypersensitivity reactions and the presence of HLA-A*3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine.
These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below).
HLA-A*3101 is expected to be carried by more than 15% of patients of Japanese, Native American, Southern Indian (for example, Tamil Nadu) and some Arabic ancestry; up to about 10% in patients of Han Chinese, Korean, European, Latin American, and other Indian ancestry; and up to about 5% in African-Americans and patients of Thai, Taiwanese, and Chinese (Hong Kong) ancestry.
The risks and benefits of carbamazepine therapy should be weighed before considering carbamazepine in patients known to be positive for HLA-A*3101.
Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management.
Many HLA-B*1502-positive and HLA-A*3101-positive patients treated with carbamazepine will not develop SJS/TEN or other hypersensitivity reactions, and these reactions can still occur infrequently in HLA-B*1502-negative and HLA-A*3101-negative patients of any ethnicity.
The role of other possible factors in the development of, and morbidity from, SJS/TEN and other hypersensitivity reactions, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring, have not been studied.
Aplastic Anemia and Agranulocytosis Aplastic anemia and agranulocytosis have been reported in association with the use of carbamazepine (see BOXED WARNING ).
Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, have occurred with carbamazepine.
Some of these events have been fatal or life-threatening.
DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection.
Eosinophilia is often present.
This disorder is variable in its expression, and other organ systems not noted here may be involved.
It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident.
If such signs or symptoms are present, the patient should be evaluated immediately.
Carbamazepine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Hypersensitivity Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin, primidone, and phenobarbital.
If such history is present, benefits and risks should be carefully considered and, if carbamazepine is initiated, the signs and symptoms of hypersensitivity should be carefully monitored.
Patients should be informed that about a third of patients who have had hypersensitivity reactions to carbamazepine also experience hypersensitivity reactions with oxcarbazepine (Trileptal ® ).
Anaphylaxis and Angioedema Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips, and eyelids have been reported in patients after taking the first or subsequent doses of carbamazepine.
Angioedema associated with laryngeal edema can be fatal.
If a patient develops any of these reactions after treatment with carbamazepine, the drug should be discontinued and an alternative treatment started.
These patients should not be rechallenged with the drug.
Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including carbamazepine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.
Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.
In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.
There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.
Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.
The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing carbamazepine or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.
Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
General Carbamazepine has shown mild anticholinergic activity that may be associated with increased intraocular pressure; 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 use of carbamazepine should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda).
Acute attacks have been reported in such patients receiving carbamazepine therapy.
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.
Hyponatremia can occur as a result of treatment with carbamazepine.
In many cases, the hyponatremia appears to be caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
The risk of developing SIADH with carbamazepine treatment appears to be dose-related.
Elderly patients and patients treated with diuretics are at greater risk of developing hyponatremia.
Signs and symptoms of hyponatremia include headache, new or increased seizure frequency, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls.
Consider discontinuing carbamazepine in patients with symptomatic hyponatremia.
Usage in Pregnancy Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and 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.
When 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 to 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 to 25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5 to 4 times the MHDD on a mg/m 2 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.
To provide information regarding the effects of in utero exposure to carbamazepine, physicians are advised to recommend that pregnant patients taking carbamazepine enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.
This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves.
Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
DRUG INTERACTIONS
Drug Interactions There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting carbamazepine suspension immediately followed by Thorazine ® * solution.
Subsequent testing has shown that mixing carbamazepine suspension and chlorpromazine solution (both generic and brand name) as well as carbamazepine 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 suspension should not be administered simultaneously with other liquid medicinal agents or diluents (See DOSAGE AND ADMINISTRATION ).
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 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.
Agents That Increase Carbamazepine Levels CYP3A4 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 aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, trazodone, olanzapine, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene, azoles (e.g., ketoconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, and protease inhibitors.
Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide.
Coadministration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations.
Accordingly, the dosage of carbamazepine should be adjusted and/or the plasma levels monitored when used concomitantly with loxapine, quetiapine, or valproic acid.
Agents That Decrease Carbamazepine Levels CYP3A4 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, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline.
Effect of Carbamazepine on Plasma Levels of Concomitant Agents Decreased Levels of Concomitant Medications Carbamazepine is a potent inducer of hepatic 3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C9/19 and 3A4, through induction of their metabolism.
When used concomitantly with carbamazepine, monitoring of concentrations or dosage adjustment of these agents may be necessary: When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled.
Additional dose increases should be based on clinical evaluation.
If carbamazepine is later withdrawn, the aripiprazole dose should be reduced.
When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended.
The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus.
If patients must be coadministered carbamazepine with temsirolimus, an adjustment of temsirolimus dosage should be considered.
The use of carbamazepine with lapatinib should generally be avoided.
If carbamazepine is started in a patient already taking lapatinib, the dose of lapatinib should be gradually titrated up.
If carbamazepine is discontinued, the lapatinib dose should be reduced.
Concomitant use of carbamazepine with nefazodone results in plasma concentrations of nefazodone and its active metabolite insufficient to achieve a therapeutic effect.
Coadministration of carbamazepine with nefazodone is contraindicated (see CONTRAINDICATIONS ).
Monitor concentrations of valproate when carbamazepine is introduced or withdrawn in patients using valproic acid.
In addition, carbamazepine causes, or would be expected to cause, decreased levels of the following drugs, for which monitoring of concentrations or dosage adjustment may be necessary: acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, citalopram, clonazepam, clozapine, corticosteroids (e.g., prednisolone, dexamethasone), cyclosporine, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, eslicarbazepine, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, mianserin, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, sertraline, sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.
Other Drug Interactions Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A.
The rate of metabolism and the leukopenic activity of cyclophosphamide are reportedly increased by chronic coadministration of CYP3A4 inducers.
There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine.
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.
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.
Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered carbamazepine.
Whether or not carbamazepine has the same effect on other non-depolarizing agents is unknown.
Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
Concomitant use of carbamazepine with rivaroxaban, apixaban, dabigatran, and edoxaban (direct acting oral anticoagulants) is expected to result in decreased plasma concentrations of these anticoagulants that may be insufficient to achieve the intended therapeutic effect.
In general, coadministration of carbamazepine with rivaroxaban, apixaban, dabigatran, and edoxaban should be avoided.
OVERDOSAGE
Acute Toxicity Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia).
Oral LD 50 in animals (mg/kg): mice, 1100 to 3750; rats, 3850 to 4025; rabbits, 1500 to 2680; guinea pigs, 920.
Signs and Symptoms The first signs and symptoms appear after 1 to 3 hours.
Neuromuscular disturbances are the most prominent.
Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (greater than 60 g) have been ingested.
Respiration: Irregular breathing, respiratory depression.
Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma.
Convulsions, especially in 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 The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption.
If these measures cannot be implemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions are safeguarded.
There is no specific antidote.
Elimination of the Drug: Induction of vomiting.
Gastric lavage.
Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should be 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 not 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) 59 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 2 and F hemoglobin, and (7) serum folic acid and B 12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought.
DESCRIPTION
Carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as chewable tablets of 100 and 200 mg, tablets of 200 mg, extended-release tablets of 100 mg, 200 mg, and 400 mg, and as a suspension of 100 mg/5 mL (teaspoon).
Its chemical name is 5 H -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.
Inactive Ingredients: Carbamazepine Tablets USP, (Chewable), 100 mg and 200 mg – ammonio methacrylate copolymer, croscarmellose sodium, diethyl phthalate, FD&C red no.
40 lake, magnesium stearate, microcrystalline cellulose, natural cherry flavor, pregelatinized maize starch and sorbitol.
Carbamazepine Tablets USP, 200 mg – ammonio methacrylate copolymer, corn starch, croscarmellose sodium, diethyl phthalate, magnesium stearate and microcrystalline cellulose.
Carbamazepine Extended-Release Tablets USP, 100 mg, 200 mg, and 400 mg – ammonio methacrylate copolymer, corn starch, diethyl phthalate, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium starch glycolate.
Carbamazepine Oral Suspension USP, 100 mg/5 mL – citric acid monohydrate, FD&C yellow no.
6, orange flavor, poloxamer 188, potassium sorbate, propylene glycol, purified water, sorbitol solution, sucrose and xanthan gum.
Chemical Structure
HOW SUPPLIED
Carbamazepine Tablets USP, (Chewable), 100 mg: White, flat, round tablet with pink specks, and cherry fragrance.
One side scored and engraved with “TARO” above the score and “16” under the score.
Other side plain.
Bottles of 100 NDC 51672-4041-1 Bottles of 500 NDC 51672-4041-2 Unit Dose of 50 NDC 51672-4041-9 Unit Dose of 100 NDC 51672-4041-0 Carbamazepine Tablets USP, (Chewable), 200 mg: White, flat, oval beveled tablet, with pink specks, and cherry fragrance.
One side scored and engraved with “T” above the score and “27” under the score.
Other side scored.
Bottles of 100 NDC 51672-4050-1 Bottles of 400 NDC 51672-4050-2 Store Carbamazepine Tablets USP, (Chewable) at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Protect from light and moisture.
Dispense in tight, light-resistant container (USP).
Meets USP Dissolution Test 1.
GERIATRIC USE
Geriatric Use No systematic studies in geriatric patients have been conducted.
MECHANISM OF ACTION
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.
INDICATIONS AND USAGE
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: 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.
PEDIATRIC USE
Pediatric Use Substantial evidence of carbamazepine’s effectiveness for use in the management of children with epilepsy (see INDICATIONS AND USAGE 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.
PREGNANCY
Usage in Pregnancy (see WARNINGS ).
NUSRING MOTHERS
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 breastfeeding 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.
BOXED WARNING
WARNINGS SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH CARBAMAZEPINE.
THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER.
STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE.
HLA-B*1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA.
PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH CARBAMAZEPINE.
PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH CARBAMAZEPINE UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS, LABORATORY TESTS ).
APLASTIC ANEMIA AND AGRANULOCYTOSIS APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF CARBAMAZEPINE.
DATA FROM A POPULATION-BASED CASE CONTROL STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5 TO 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.
INFORMATION FOR PATIENTS
Information for Patients Patients should be informed of the availability of a Medication Guide and they should be instructed to read the Medication Guide before taking carbamazepine.
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.
Patients should be advised that serious skin reactions have been reported in association with carbamazepine.
In the event a skin reaction should occur while taking carbamazepine, patients should consult with their physician immediately (see WARNINGS ).
Patients should be advised that anaphylactic reactions and angioedema may occur during treatment with carbamazepine (see WARNINGS ).
Advise patients to immediately report signs and symptoms suggesting angioedema (swelling of the face, eyes, lips, or tongue, or difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their healthcare provider.
Patients, their caregivers, and families should be counseled that AEDs, including carbamazepine, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
Carbamazepine may interact with some drugs.
Therefore, patients should be advised to report to their doctors the use of any other prescription or nonprescription 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.
Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant.
This registry is collecting information about the safety of antiepileptic drugs during pregnancy.
To enroll, patients can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection).
DOSAGE AND ADMINISTRATION
(SEE TABLE BELOW) Carbamazepine 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 (see PRECAUTIONS, Drug Interactions ).
Because the extent to which this occurs with other liquid medications is not known, carbamazepine suspension should not be administered simultaneously with other liquid medications or diluents.
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 given as the tablet, it is recommended to start with low doses (children 6 to 12 years: ½ 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).
Carbamazepine extended-release tablets is an extended-release formulation for twice-a-day administration.
When converting patients from carbamazepine conventional tablets to carbamazepine extended-release tablets, the same total daily mg dose of carbamazepine extended-release tablets should be administered.
Carbamazepine extended-release tablets must be swallowed whole and never crushed or chewed.
Carbamazepine extended-release tablets should be inspected for chips or cracks.
Damaged tablets should not be consumed.
Epilepsy (SEE INDICATIONS AND USAGE ) 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/day).
Increase at weekly intervals by adding up to 200 mg/day using a twice a day regimen of carbamazepine extended-release tablets or a three times a day or four times a day regimen of the other formulations 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 to 1200 mg daily.
Children 6 to 12 years of age-Initial Either 100 mg twice a day for tablets or extended-release tablets, or ½ teaspoon four times a day for suspension (200 mg/day).
Increase at weekly intervals by adding up to 100 mg/day using a twice a day regimen of carbamazepine extended-release tablets or a three times a day or four times a day regimen of the other formulations until the optimal response is obtained.
Dosage generally should not exceed 1000 mg daily.
Maintenance Adjust dosage to the minimum effective level, usually 400 to 800 mg daily.
Children under 6 years of age-Initial 10 mg/kg/day to 20 mg/kg/day twice a day or three times a day as tablets, or four times a day as suspension.
Increase weekly to achieve optimal clinical response administered three times a day or four times a day 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 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 PRECAUTIONS, Drug Interactions , and Pregnancy ).
Trigeminal Neuralgia (SEE INDICATIONS AND USAGE ) Initial On the first day, either 100 mg twice a day for tablets or extended-release tablets, or ½ 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/day using increments of 100 mg every 12 hours for tablets or extended-release tablets, or 50 mg (½ 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 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.