Tegretol, Page 1

Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia. Tegretol is indicated for use as an anticonvulsant drug. This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.

TEGRETOL- carbamazepine tablet, chewable
TEGRETOL- carbamazepine suspension
TEGRETOL- carbamazepine tablet
TEGRETOL XR- carbamazepine tablet, extended release
Novartis Pharmaceuticals Corporation

Tegretol ®

carbamazepine USP

Chewable Tablets of 100 mg – red -speckled, pink

Tablets of 200 mg – pink

Suspension of 100 mg/5 mL

Tegretol ® -XR

(carbamazepine extended -release tablets)

100 mg, 200 mg, 400 mg

Rx only

Prescribing Information

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 TEGRETOL. 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 TEGRETOL. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL 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 TEGRETOL. 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 TEGRETOL, 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 TEGRETOL 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 Tegretol , 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

Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f]azepine-5-carboxamide, and its structural formula is

Tegretol, carbamazepine structural formula

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 Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only).

CLINICAL PHARMACOLOGY

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

Mechanism of Action

Tegretol 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. Tegretol 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. Tegretol 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 Tegretol, 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 Tegretol has not been established.

Pharmacokinetics

In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand, following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In polytherapy, the concentration of Tegretol 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 4-5 hours after administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen. Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide from Tegretol. 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 Tegretol.

The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age).

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

Tegretol Indications and Usage

Epilepsy

Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol 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 Tegretol (see PRECAUTIONS, General).

Trigeminal Neuralgia

Tegretol 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.

CONTRAINDICATIONS

Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of Tegretol, 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 Tegretol 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. Tegretol 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 Tegretol 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. Tegretol 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 Tegretol 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 Tegretol.

The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from Tegretol, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption [MPE]).

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. 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.

Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian patients treated with Tegretol will not develop SJS/TEN, and these reactions can still occur infrequently in HLA-B*1502-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

Aplastic Anemia and Agranulocytosis

Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Tegretol, 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 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 Tegretol 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.

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.

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