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.
`
`ARGENTUM Exhibit 1144
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`Page 00001
`
`

`
`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
`
`
`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
`
`Page 00002
`
`

`
`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.
`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.
`
`
`
`Page 00003
`
`

`
`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.
`
`Page 00004
`
`

`
` 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
`
`
`Relative Risk:
`Drug Patients
`Indication
`Placebo Patients
`with Events Per
`with Events Per
`Incidence of
`
`1,000 Patients
`1,000 Patients
`Events in Drug
`
`Patients/Incidence
`
`in Placebo
`Patients
`
`
`3.5
`
`Risk Difference:
`Additional Drug
`Patients with
`Events Per 1,000
`Patients
`
`
`
`2.4
`
`3.4
`
`
`
`
`
`
`Epilepsy
`
`1.0
`
`
`
`Page 00005
`
`

`
`
`
`
`
`
`1.5
`8.5
`5.7
`2.9
`Psychiatric
`
`
`
`
`
`1.9
`1.8
`1.0
`0.9
`Other
`
`
`
`
`
`1.8
`4.3
`2.4
`1.9
`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 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.
`General
`Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should
`be closely observed during therapy.
`Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent
`psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
`The use of Tegretol 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 Tegretol 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, Tegretol should be withdrawn gradually to minimize the potential of
`increased seizure frequency.
`
` 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, hypospadias and anomalies involving various body systems). Developmental
`delays based on neurobehavioral assessments have been reported. In treating or counseling women of
`childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If
`this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should
`be apprised of the potential hazard to the fetus.
`Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of
`teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to
`be continued, monotherapy may be preferable for pregnant women.
`In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated
`in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
`
`Page 00006
`
`

`
`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 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
`Tegretol 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 Tegretol use. These symptoms may
`represent a neonatal withdrawal syndrome.
`To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to
`recommend that pregnant patients taking Tegretol 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.
`Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical
`absence seizures, since in these patients Tegretol 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 Tegretol.
`AV heart block, including second and third degree block, have been reported following Tegretol 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.
`Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have
`been reported in rare cases (see ADVERSE REACTIONS, Other and PRECAUTIONS, Information for
`Patients).
`Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops.
`
`Page 00007
`
`

`
`Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this
`reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions
`should be obtained for a patient and the immediate family members. If positive, caution should be used in
`prescribing carbamazepine.
`Since a given dose of Tegretol 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).
`Information for Patients
`Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as
`well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to,
`fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric
`hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be
`advised that, because these signs and symptoms may signal a serious reaction, that they must report any
`
`occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms
`should be reported even if mild or when occurring after extended use.
`Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, 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
`Tegretol 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 Tegretol 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.
`
`Page 00008
`
`

`
`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 Tegretol administered alone.
`Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other
`drugs.
`Interference with some pregnancy tests has been reported.
`Drug Interactions
`There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting
`Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing
`Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol 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, Tegretol 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 Tegretol Plasma Levels
`CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that
`have been shown, or would be expected, to increase plasma carbamazepine levels include:
`cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine,
`fluvoxamine, nefazodone, loratadine, terfenadine, isoniazid, niacinamide, nicotinamide, propoxyphene,
`azoles (e.g., ketaconazole, itraconazole, fluconazole), acetazolamide, verapamil, grapefruit juice,
`protease inhibitors, valproate.*
`CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would
`be expected, to decrease plasma carbamazepine levels include:
`cisplatin, doxorubicin HCl, felbamate,† rifampin, phenobarbital, phenytoin, primidone, methsuximide,
`theophylline.
`When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close
`monitoring of carbamazepine levels is indicated and dosage adjustment may be required.
`*increased levels of the active 10,11-epoxide
`†decreased levels of carbamazepine and increased levels of the 10,11-epoxide
`Effect of Tegretol on Plasma Levels of Concomitant Agents
`Increased levels: clomipramine HCl, phenytoin, primidone
`Tegretol induces hepatic CYP activity. Tegretol causes, or would be expected to cause, decreased levels of the
`following:
`acetaminophen, alprazolam, dihydropyridine calcium channel blockers (e.g., felodipine), cyclosporine,
`corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine, dicumarol, doxycycline,
`ethosuximide,haloperidol, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide,
`midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, phensuximide,
`phenytoin, praziquantel, protease inhibitors, risperidone, theophylline, tiagabine, topiramate, tramadol,
`
`Page 00009
`
`

`
`tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone,
`
` zonisamide.
`In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.
`Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of
`nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with
`nefazodone is contraindicated (see CONTRAINDICATIONS).
`
`Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.
`Alterations of thyroid function have been reported in combination therapy with other anticonvulsant
`medications.
`Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal
`implant contrac