CARBAMAZEPINE capsule, extended release

Carbamazepine by

Drug Labeling and Warnings

Carbamazepine by is a Prescription medication manufactured, distributed, or labeled by Taro Pharmaceuticals U.S.A., Inc., Taro Pharmaceutical Industries, Ltd.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

SPL UNCLASSIFIED SECTION

Rx only

BOXED WARNING

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WARNING

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 EXTENDED-RELEASE CAPSULES. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH CARBAMAZEPINE EXTENDED-RELEASE CAPSULES 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 5-8 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.

SPL UNCLASSIFIED SECTION

Before prescribing carbamazepine extended-release capsules, 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.

DESCRIPTION

Carbamazepine extended-release capsules is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as 100 mg, 200 mg and 300 mg extended-release capsules of Carbamazepine, USP. Carbamazepine is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27. Its chemical name is 5H-dibenz[b,f]azepine-5-carboxamide, and its structural formula is:

Carbamazepine

Carbamazepine extended-release capsules are composed of an extended-release matrix granulation.

Inactive ingredients: ammonio methacrylate copolymer, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and triethyl citrate.

The 100 mg and 200 mg capsule shells contain FD&C Blue 1, gelatin, iron oxide yellow, sodium lauryl sulfate and titanium dioxide, and are imprinted with black ink. The 300 mg capsule shells contain gelatin, sodium lauryl sulfate and titanium dioxide, and are imprinted with black ink.

CLINICAL PHARMACOLOGY

In controlled clinical trials, carbamazepine has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia.

Mechanism of Action

Carbamazepine has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic 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

Carbamazepine (CBZ)

Taken every 12 hours, carbamazepine extended-release capsules provide steady state plasma levels comparable to immediate-release carbamazepine tablets given every 6 hours, when administered at the same total mg daily dose.

Following a single 200 mg oral extended-release dose of carbamazepine, peak plasma concentration was 1.9 ± 0.3 µg/mL and the time to reach the peak was 19 ± 7 hours. Following chronic administration (800 mg every 12 hours), the peak levels were 11.0 ± 2.5 µg/mL and the time to reach the peak was 5.9 ± 1.8 hours. The pharmacokinetics of extended-release carbamazepine is linear over the single dose range of 200-800 mg.

Carbamazepine is 76% bound to plasma proteins. Carbamazepine is primarily metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide. Since carbamazepine induces its own metabolism, the half-life is also variable. Following a single extended-release dose of carbamazepine, the average half-life range from 35-40 hours and 12-17 hours on repeated dosing. The apparent oral clearance following a single dose was 25 ± 5 mL/min and following multiple dosing was 80 ± 30 mL/min.

After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged carbamazepine.

Carbamazepine-10,11-epoxide (CBZ-E)

Carbamazepine-10,11-epoxide is considered to be an active metabolite of carbamazepine. Following a single 200 mg oral extended-release dose of carbamazepine, the peak plasma concentration of carbamazepine-10,11-epoxide was 0.11 ± 0.012 µg/mL and the time to reach the peak was 36 ± 6 hours. Following chronic administration of a extended-release dose of carbamazepine (800 mg every 12 hours), the peak levels of carbamazepine-10,11-epoxide were 2.2 ± 0.9 µg/mL and the time to reach the peak was 14 ± 8 hours. The plasma half-life of carbamazepine-10,11-epoxide following administration of carbamazepine is 34 ± 9 hours. Following a single oral dose of extended-release carbamazepine (200-800 mg) the AUC and Cmax of carbamazepine-10,11-epoxide were less than 10% of carbamazepine. Following multiple dosing of extended-release carbamazepine (800-1600 mg daily for 14 days), the AUC and Cmax of carbamazepine-10,11-epoxide were dose related, ranging from 15.7 µg.hr/mL and 1.5 µg/mL at 800 mg/day to 32.6 µg.hr/mL and 3.2 µg/mL at 1600 mg/day, respectively, and were less than 30% of carbamazepine. Carbamazepine-10,11-epoxide is 50% bound to plasma proteins.

Food Effect

A high fat meal diet increased the rate of absorption of a single 300 mg dose (mean Tmax was reduced from 26.7 hours, in the fasting state, to 16.7 hours and Cmax increased from 1.9 to 2.6 µg/mL) and the extent (AUC) of absorption (increased from 208.9 to 251.4 µg/mL). The elimination half-life slightly decreased in the fed state. The multiple dose study conducted in the fed state showed that the steady-state Cmax values were within the therapeutic concentration range. The pharmacokinetic profile of extended-release carbamazepine was similar when given by sprinkling over applesauce compared to the intact capsule administered in the fasted state.

Special Populations

Hepatic Dysfunction

The effect of hepatic impairment on the pharmacokinetics of carbamazepine is not known. However, given that carbamazepine is primarily metabolized in the liver, it is prudent to proceed with caution in patients with hepatic dysfunction.

Renal Dysfunction

The effect of renal impairment on the pharmacokinetics of carbamazepine is not known.

Gender

No difference in the mean AUC and Cmax of carbamazepine and carbamazepine-10,11-epoxide was found between males and females.

Age

Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide in young children than adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age.

Race

No information is available on the effect of race on the pharmacokinetics of carbamazepine.

INDICATIONS AND USAGE

Epilepsy

Carbamazepine extended-release capsules are 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 improvements 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 extended-release capsules are 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.

CONTRAINDICATIONS

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 and nortriptyline. 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.

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.

Coadministration of carbamazepine is contraindicated with delavirdine due to the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

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 extended-release capsules 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 <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 extended-release capsule 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 extended-release capsules 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 WARNINGS 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 extended-release capsules. 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 anti-epileptic 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.

Patients should be made aware that carbamazepine extended-release capsules contains carbamazepine and should not be used in combination with any other medications containing carbamazepine.

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 present in the following approximate frequencies: greater than 15% in patients of Japanese and Native American ancestry; up to about 10% in patients of Han Chinese, Korean, European, and Latin American ancestry; and up to about 5% in African-Americans and patients of Indian, 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.

General Information on HLA Genotyping and Hypersensitivity

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 AED dose, compliance, concomitant medications, co-morbidities, 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 lifethreatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, 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 extended-release capsules 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. A history of hypersensitivity reactions should be obtained for patients and their immediate family members. 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.

In patients who have exhibited hypersensitivity reactions to carbamazepine, approximately 25 to 30% may experience hypersensitivity reactions with oxcarbazepine.

Withdrawal Precipitated Seizure, Status Epilepticus

Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including carbamazepine extended-release capsules, 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 (5-100 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 1000 Patients	Drug Patients with Events Per 1000 Patients	Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events Per 1000 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 extended-release capsules 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 or 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.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and 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.

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. The prescribing physician will wish to weigh the benefits of therapy against the risks in treating or counseling women of childbearing potential. 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. 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 1.5-4 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 current 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 reported in association 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 extended-release capsules, physicians are advised to recommend that pregnant patients taking carbamazepine extended-release capsules 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/.

General

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 considered.

The use of carbamazepine extended-release capsules 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 extended-release capsules therapy. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.

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, hepatic, or renal damage; adverse hematologic reaction to other drugs; or interrupted courses of therapy with carbamazepine.

Hyponatremia, Syndrome of Inappropriate Antidiuretic Hormone Secretion, and Water Intoxication

Hyponatremia can occur as a result of treatment with carbamazepine extended-release capsules. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The risk of developing SIADH with carbamazepine extended-release capsules treatment may be dose-related. Elderly patients may be at greater risk of developing hyponatremia. Patients treated with diuretics can be at greater risk. Consider discontinuing carbamazepine extended-release capsules in patients with symptomatic hyponatremia. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls.

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 extended-release capsules.

Patients should be made aware of the early toxic signs and symptoms of potential hematologic, 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. Patients should be advised that, because these signs and symptoms may signal a serious reaction, they must report any occurrence immediately to their physicians. 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, their caregivers, and families should be counseled that AEDs, including carbamazepine extended-release capsules, 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.

Caution should be exercised if alcohol is taken in combination with carbamazepine extended-release capsules 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).

If necessary, the carbamazepine extended-release capsules can be opened and the contents sprinkled over food, such as a teaspoon of applesauce or other similar food products. Carbamazepine extended-release capsules or their contents should not be crushed or chewed.

Carbamazepine extended-release capsules may interact with some drugs. Therefore, patients should be advised to report to their doctors the use of any other prescription or non-prescription medication or herbal products.

Patients, their caregivers, and families should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking carbamazepine extended-release capsules. See FDA approved Medication Guide.

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. In addition, rare cases of hepatic failure have been reported (see ADVERSE REACTIONS, Liver). The drug should be discontinued immediately in cases of aggravated liver dysfunction or active liver disease.

Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended since many phenothiazines and related drugs have been shown to cause eye changes.

Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because of observed renal dysfunction.

Increases in total cholesterol, LDL and HDL have been observed in some patients taking anticonvulsants. Therefore, periodic evaluation of these parameters is also recommended.

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.

Drug Interactions

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

Agents Highly Bound to Plasma Protein

Carbamazepine is not highly bound to plasma proteins; therefore, administration of carbamazepine extended-release capsules to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.

Agents that Inhibits Cytochrome P450 Isoenzymes and/or Epoxide Hydrolase

Carbamazepine is metabolized mainly by cytochrome P450 (CYP) 3A4 to the active carbamazepine 10,11-epoxide, which is further metabolized to the trans-diol by epoxide hydrolase. Therefore, the potential exists for interaction between carbamazepine and any agent that inhibits CYP3A4 and/or epoxide hydrolase. Agents that are CYP3A4 inhibitors that have been found, or are expected, to increase plasma levels of carbamazepine extended-release capsules are the following:

Acetazolamide, azole antifungals, cimetidine, clarithromycin1, dalfopristin, danazol, delavirdine, diltiazem, erythromycin1, fluoxetine, fluvoxamine, grapefruit juice, isoniazid, itraconazole, ketoconazole, loratadine, nefazodone, niacinamide, nicotinamide, protease inhibitors, propoxyphene, quinine, quinupristin, troleandomycin, valproate1, verapamil, zileuton.

Thus, if a patient has been titrated to a stable dosage of carbamazepine extended-release capsules, and then begins a course of treatment with one of these CYP3A4 or epoxide hydrolase inhibitors, it is reasonable to expect that a dose reduction for carbamazepine extended-release capsules may be necessary.

1 also inhibits epoxide hydrolase resulting in increased levels of the active metabolite carbamazepine 10,11- epoxide

Agents that Induce Cytochrome P450 Isoenzymes

Carbamazepine is metabolized by CYP3A4. Therefore, the potential exists for interaction between carbamazepine and any agent that induces CYP3A4. Agents that are CYP inducers that have been found, or are expected, to decrease plasma levels of carbamazepine extended-release capsules are the following:

Cisplatin, doxorubicin HCl, felbamate, rifampin, phenobarbital, phenytoin2, primidone, methsuximide, and theophylline

Thus, if a patient has been titrated to a stable dosage on carbamazepine extended-release capsules, and then begins a course of treatment with one of these CYP3A4 inducers, it is reasonable to expect that a dose increase for carbamazepine extended-release capsules may be necessary.

2 Phenytoin plasma levels have also been reported to increase and decrease in the presence of carbamazepine, see below.

Agents with Decreased Levels in the Presence of Carbamazepine due to Induction of Cytochrome P450 Enzymes

Carbamazepine is known to induce CYP1A2 and CYP3A4. Therefore, the potential exists for interaction between carbamazepine and any agent metabolized by one (or more) of these enzymes. Agents that have been found, or are expected to have decreased plasma levels in the presence of carbamazepine extended-release capsules due to induction of CYP enzymes are the following:

Acetaminophen, alprazolam, amitriptyline, bupropion, buspirone, citalopram, clobazam, clonazepam, clozapine, cyclosporin, delavirdine, desipramine, diazepam, dicumarol, doxycycline, ethosuximide, felbamate, felodipine, glucocorticoids, haloperidol, itraconazole, lamotrigine, levothyroxine, lorazepam, methadone, midazolam, mirtazapine, nefazodone3, nortriptyline, olanzapine, oral and other hormonal contraceptives4, oxcarbazepine, phenytoin5, praziquantel, protease inhibitors, quetiapine, risperidone, theophylline, topiramate, tiagabine, tramadol, triazolam, trazodone6, valproate, warfarin7, ziprasidone, and zonisamide.

Thus, if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of treatment with carbamazepine extended-release capsules, it is reasonable to expect that a dose increase for the concomitant agent may be necessary.

3 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 (see CONTRAINDICATIONS).

4 Concomitant use of carbamazepine extended-release capsules 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 with carbamazepine. Alternative or back-up methods of contraception should be considered.

5 Phenytoin has also been reported to increase in the presence of carbamazepine. Careful monitoring of phenytoin plasma levels following co-medication with carbamazepine is advised.

6 Following co-administration of carbamazepine 400 mg/day with trazodone 100 mg to 300 mg daily, carbamazepine reduced trough plasma concentrations of trazodone (as well as metachlorophenylpiperazine [mCPP]) by 76 and 60% respectively, compared to precarbamazepine values.

7 Warfarin's anticoagulant effect can be reduced in the presence of carbamazepine.

Agents with Increased Levels in the Presence of Carbamazepine

Carbamazepine extended-release capsules increases the plasma levels of the following agents:

Clomipramine HCl, phenytoin8, and primidone

8 Phenytoin has also been reported to decrease in the presence of carbamazepine. Careful monitoring of phenytoin plasma levels following co-medication with carbamazepine is advised.

Thus, if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of the treatment with carbamazepine extended-release capsules, it is reasonable to expect that a dose decrease for the concomitant agent may be necessary.