CARBAMAZEPINE tablet

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Active ingredient:
CARBAMAZEPINE (UNII: 33CM23913M) (CARBAMAZEPINE - UNII:33CM23913M)
Available from:
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Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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: 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 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. Carbamazepine should not be used in patients
Product summary:
Carbamazepine Tablets USP, 100 mg- Pink Colored, round flat beveled edge, uncoated single scored tablet debossed with ‘CAR’ on one side and ‘100’ on the scored side and other side plain, free from physical defects: Carbamazepine Tablets USP, 200 mg - Pink colored, capsule-shaped biconvex, uncoated tablet, debossed ‘CAR’ on one side and ‘200’ on the partially scored side, free from physical defects: Store at 20º to 25ºC (68º to 77ºF); excursions permitted between 15º to 30ºC (59º to 86ºF) [See USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight, light-resistant container. *The other brands listed are trademarks of their respective owners and are not trademarks of Umedica Laboratories Pvt. Ltd. The makers of these brands are not affiliated with and do not endorse Umedica Laboratories Pvt. Ltd. or its products. Revised: April 2020, V-05 MEDICATION GUIDE CARBAMAZEPINE (kar-bah-MAZ-eh-peen) TABLETS USP, 100 mg and 200 mg Read this Medication Guide before you start taking carbamazepine. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. What is the most important information I should know about carbamazepine? Do not stop taking carbamazepine without first talking to your healthcare provider. Stopping carbamazepine suddenly can cause serious problems. Carbamazepine can cause serious side effects, including: 1. Carbamazepine may cause rare but serious skin rashes that may lead to death. These serious skin reactions are more likely to happen when you begin taking carbamazepine within the first four months of treatment but may occur at later times. These reactions can happen in anyone, but are more likely in people of Asian descent. If you are of Asian descent, you may need a genetic blood test before you take carbamazepine to see if you are at a higher risk for serious skin reactions with this medicine. Symptoms may include: • skin rash • hives • sores in your mouth • blistering or peeling of the skin 2. Carbamazepine may cause rare but serious blood problems. Symptoms may include: • fever, sore throat, or other infections that come and go or do not go away • easy bruising • red or purple spots on your body • bleeding gums or nose bleeds • severe fatigue or weakness 3. Carbamazepine may cause allergic reactions or serious problems, which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Call your healthcare provider right away if you have any of the following: • swelling of your face, eyes, lips, or tongue • a skin rash • painful sores in the mouth or around your eyes • unusual bruising or bleeding • frequent infections or infections that do not go away • fever, swollen glands, or sore throat that do not go away or come and go • trouble swallowing or breathing • hives • yellowing of your skin or eyes • severe fatigue or weakness • an extreme increase in activity and talking (mania) • severe muscle pain 4. Like other antiepileptic drugs, carbamazepine may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Do not stop carbamazepine without first talking to a healthcare provider. Stopping carbamazepine suddenly can cause serious problems. You should talk to your healthcare provider before stopping. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. What is carbamazepine? Carbamazepine is a prescription medicine used to treat: • certain types of seizures (partial, tonic-clonic, mixed) • certain types of nerve pain (trigeminal and glossopharyngeal neuralgia) Carbamazepine is not a regular pain medicine and should not be used for aches or pains. Who should not take carbamazepine? Do not take carbamazepine if you: • have a history of bone marrow depression. • are allergic to carbamazepine or any of the ingredients in Carbamazepine Tablets. See the end of this Medication Guide for a complete list of ingredients in Carbamazepine Tablets. • take nefazodone. • are allergic to medicines called tricyclic antidepressants (TCAs). Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. • have taken a medicine called a Monoamine Oxidase Inhibitor (MAOI) in the last 14 days. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. What should I tell my healthcare provider before taking carbamazepine? Before you take carbamazepine, tell your healthcare provider if you: • have or have had suicidal thoughts or actions, depression, or mood problems • have or ever had heart problems • have or ever had blood problems • have or ever had liver problems • have or ever had kidney problems • have or ever had allergic reactions to medicines • have or ever had increased pressure in your eye • have any other medical conditions • drink grapefruit juice or eat grapefruit • use birth control. Carbamazepine may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you take birth control and carbamazepine. • are pregnant or plan to become pregnant. Carbamazepine may harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking carbamazepine. You and your healthcare provider should decide if you should take carbamazepine while you are pregnant. ▪ If you become pregnant while taking carbamazepine, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can enroll in this registry by calling 1-888-233-2334. • are breastfeeding or plan to breastfeed. Carbamazepine passes into breast milk. You and your healthcare provider should discuss whether you should take carbamazepine or breastfeed; you should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking carbamazepine with certain other medicines may cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take carbamazepine? • Do not stop taking carbamazepine without first talking to your healthcare provider. Stopping carbamazepine suddenly can cause serious problems. Stopping seizure medicine suddenly in a patient who has epilepsy may cause seizures that will not stop (status epilepticus). • Take carbamazepine exactly as prescribed. Your healthcare provider will tell you how much carbamazepine to take. • Your healthcare provider may change your dose. Do not change your dose of carbamazepine without talking to y
Authorization status:
Abbreviated New Drug Application
Authorization number:
72189-157-30

Read the complete document

CARBAMAZEPINE- carbamazepine tablet

direct rx

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CARBAMAZEPINE

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 WARNINGSAND 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.

Before prescribing carbamazepine, the physician should be thoroughly familiar with the details of this

prescribing information, particularly regarding use with other drugs, especially those which accentuate

toxicity potential.

Carbamazepine Tablets, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal

neuralgia, available for oral administration as tablets of 100 mg and 200 mg. Its chemical name is 5H-

dibenz[b,f ]azepine-5-carboxamide, and its structural formula is:

[carbamazepine-strecture]

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 IngredientsTablets: pregelatinized maize starch, FD & C red 40, croscarmellose sodium,

colloidal silicon dioxide and magnesium stearate.

"Meets USP Dissolution Test 2"

In controlled clinical trials, carbamazepine has been shown to be effective in the treatment of

psychomotor and grand mal seizures, as well as trigeminal neuralgia.

Mechanism of Action

Carbamazepine has demonstrated anticonvulsant properties in rats and mice with electrically and

chemically induced seizures. It appears to act by reducing polysynaptic 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.

Pharmacokinetics

In clinical studies, Carbamazepine suspension, conventional tablets, and XR tablets delivered equivalent

amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster,

and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was

89% compared to suspension. Following a twice a day dosage regimen, the suspension provides higher

peak levels and lower trough levels than those obtained from the conventional tablet for the same

dosage regimen. On the other hand, following a three times a day dosage regimen, Carbamazepine

suspension affords steady-state plasma levels comparable to Carbamazepine tablets given twice a day

when administered at the same total mg daily dose. Following a twice a day dosage regimen,

Carbamazepine-XR tablets afford steady-state plasma levels comparable to conventional Carbamazepine

tablets given four times a day, when administered at the same total mg daily dose.Carbamazepine in

blood is 76% bound to plasma proteins. Plasma levels of Carbamazepine are variable and may range

from 0.5 to 25 mcg/mL, with no apparent relationship to the daily intake of the drug. Usual adult

therapeutic levels are between 4 and 12 mcg/mL. In polytherapy, the concentration of Carbamazepine

and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered

(see PRECAUTIONS, DRUG INTERACTIONS). Following chronic oral administration of suspension,

plasma levels peak at approximately 1.5 hours compared to 4 to 5 hours after administration of

conventional Carbamazepine tablets, and 3 to 12 hours after administration of Carbamazepine-XR tablets.

The CSF/serum ratio is 0.22, similar to the 24% unbound Carbamazepine in serum. Because

Carbamazepine induces its own metabolism, the half-life is also variable. Autoinduction is completed

after 3 to 5 weeks of a fixed dosing regimen. Initial half-life values range from 25 to 65 hours,

decreasing to 12 to 17 hours on repeated doses. Carbamazepine is metabolized in the liver.

Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of

carbamazepine-10,11-epoxide from Carbamazepine. Human microsomal epoxide hydrolase has been

identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from

carbamazepine10,11 epoxide. After oral administration of 14 C-carbamazepine, 72% of the administered

radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed

largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Carbamazepine.

The pharmacokinetic parameters of carbamazepine disposition are similar in children and in adults.

However, there is a poor correlation between plasma concentrations of carbamazepine and

Carbamazepine Tablets dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-

10, 11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal

screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse

relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below

the age of 1 year to 0.18 in children between 10 to 15 years of age).

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

evaluated.

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:

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 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.

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 (MAO) 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.

Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of

nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine

with nefazodone is contraindicated.

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, has occurred with carbamazepine. Some of these events have been fatal or life-

threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or

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 eyelid 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 with Carbamazepine, the

drug should be discontinued and an alternative treatment started. These patients should not be

rechallenged with the drugs.

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

Psychiatric

Other

Total

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/m2 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/.

PRECAUTIONS

General

Before initiating therapy, a detailed history and physical examination should be made.

Carbamazepine should be used with caution in patients with a mixed seizure disorder that includes

atypical absence seizures, since in these patients carbamazepine has been associated with increased

frequency of generalized convulsions (see INDICATIONS AND USAGE).

Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of

cardiac 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 underlying 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 ADVERSE REACTIONS and PRECAUTIONS, LABORATORY TESTS). In some

cases, hepatic effects may progress despite discontinuation of the drug. In addition rare instances of

vanishing bile duct syndrome have been reported. This syndrome consists of a cholestatic process with

a variable clinical course ranging from fulminant to indolent, involving the destruction and

disappearance of the intrahepatic bile ducts. Some, but not all, cases are associated with features that

overlap with other immunoallergenic syndromes such as multiorgan hypersensitivity (DRESS

syndrome) and serious dermatologic reactions. As an example there has been a report of vanishing bile

duct syndrome associated with Stevens-Johnson syndrome and in another case an association with fever

and eosinophilia.

Since a given dose of carbamazepine suspension will produce higher peak levels than the same dose

given as the tablet, it is recommended that patients given the suspension be started on lower doses and

increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).

Carbamazepine suspension contains sorbitol and, therefore, should not be administered to patients with

rare hereditary problems of fructose intolerance.

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 and angioedema may occur during treatment with

Carbamazepine (see WARNINGS). Advise patients to immediately report signs and symptoms

suggesting angioedema (swelling of 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).

Laboratory Tests

For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B*1502 typing’ is

recommended. The test is positive if either one or two HLA-B*1502 alleles are detected and negative

if no HLA-B*1502 alleles are detected.

Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron,

should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white

blood cell or platelet counts, the patient should be 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

PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued,

based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory

evidence of liver dysfunction or hepatic damage, or in the case of active liver disease.

Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are

recommended since many phenothiazines and related drugs have been shown to cause eye changes.

Baseline and periodic complete urinalysis and BUN determinations are recommended for patients

treated with this agent because of observed renal dysfunction.

Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety

of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure

frequency and for verification of compliance. In addition, measurement of drug serum levels may aid in

determining the cause of toxicity when more than one medication is being used.

Thyroid function tests have been reported to show decreased values with carbamazepine administered

alone.

Interference with some pregnancy tests has been reported.

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., ketaconazole, 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

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