Carbatrol Information
Carbatrol (Carbamazepine)
Carbatrol (Carbamazepine) Description
Carbatrol (Carbamazepine) 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:
Carbatrol (Carbamazepine) is a multi-component capsule formulation consisting of three different types of beads: immediate-release beads, extended-release beads, and enteric-release beads. The three bead types are combined in a specific ratio to provide twice daily dosing of Carbatrol (Carbamazepine) .
The 100 mg capsule shells contain gelatin-NF, FD&C Blue #2, Yellow Iron Oxide, and titanium dioxide and are imprinted with white ink; the 200 mg capsule shells contain gelatin-NF, FD&C Red #3, FD&C Yellow #6, Yellow Iron Oxide, FD&C Blue #2, and titanium dioxide, and are imprinted with white ink; and the 300 mg capsule shells contain gelatin-NF, FD&C Blue #2, FD&C Yellow #6, Red Iron Oxide, Yellow Iron Oxide, and titanium dioxide, and are imprinted with white ink.
Carbatrol (Carbamazepine) 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.
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 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.
Carbamazepine (CBZ):
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):
Food Effect:
Hepatic Dysfunction:
Renal Dysfunction:
Gender:
Age:
Race:
Carbatrol (Carbamazepine) 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.
Carbatrol (Carbamazepine) Warnings
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. Carbatrol (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
HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans).
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 Carbatrol (Carbamazepine) .
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or non-serious 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 anti-epileptic 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 carbamazepine 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 AED dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied.
Patients should be made aware that Carbatrol (Carbamazepine) contains carbamazepine and should not be used in combination with any other medications containing carbamazepine.
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.
Antiepileptic drugs (AEDs), including Carbatrol (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 (5-100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
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 Carbatrol (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 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.
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.
To provide information regarding the effects of in utero exposure to Carbatrol (Carbamazepine) , physicians are advised to recommend that pregnant patients taking Carbatrol (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/.
Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression.
In patients with seizure disorder, carbamazepine should not be discontinued abruptly because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
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.
Co-administration of carbamazepine and delavirdine may lead to loss of virologic response and possible resistance to PRESCRIPTOR or to the class of non-nucleoside reverse transcriptase inhibitors.
Carbatrol (Carbamazepine) Precautions
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 ).
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.
Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, such as fever, sore throat, rash, ulcers in the mouth, easy bruising, petechial or purpuric hemorrhage, and should be advised to report to the physician immediately if any such signs or symptoms appear.
Patients, their caregivers, and families should be counseled that AEDs, including Carbatrol (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.
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 )
If necessary, the Carbatrol (Carbamazepine) capsules can be opened and the contents sprinkled over food, such as a teaspoon of applesauce or other similar food products. Carbatrol (Carbamazepine) capsules or their contents should not be crushed or chewed.
Carbatrol (Carbamazepine) 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 Carbatrol (Carbamazepine) . See FDA approved Medication Guide.
For genetically at-risk patients [See ], high-resolution '' 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. 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 ) 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.
Hyponatremia has been reported in association with carbamazepine use, either alone or in combination with other drugs.
Interference with some pregnancy tests has been reported.
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 Carbatrol (Carbamazepine) ® 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 Carbatrol (Carbamazepine) ® are the following:
Acetazolamide, azole antifungals, cimetidine, clarithromycin(1), dalfopristin, danazol, delavirdine, diltiazem, erythromycin(1), fluoxetine, fluvoxamine, grapefruit juice, isoniazid, itraconazole, ketoconazole, loratadine, nefazodone, niacinamide, nicotinamide, protease inhibitors, propoxyphene, quinine, quinupristin, troleandomycin, valproate(1), verapamil, zileuton.
(1)also inhibits epoxide hydrolase resulting in increased levels of the active metabolite carbamazepine 10, 11- epoxide
Thus, if a patient has been titrated to a stable dosage of Carbatrol (Carbamazepine) ®, 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 Carbatrol (Carbamazepine) ® may be necessary.
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 Carbatrol (Carbamazepine) ® are the following:
Cisplatin, doxorubicin HCL, felbamate, rifampin, phenobarbital, phenytoin(2), primidone, methsuximide, and theophylline
(2)Phenytoin plasma levels have also been reported to increase and decrease in the presence of carbamazepine, see below.
Thus, if a patient has been titrated to a stable dosage on Carbatrol (Carbamazepine) ®, and then begins a course of treatment with one of these CYP3A4 inducers, it is reasonable to expect that a dose increase for Carbatrol (Carbamazepine) ® may be necessary.
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 Carbatrol (Carbamazepine) ® 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, nortriptyline, olanzapine, oral contraceptives(3), oxcarbazepine, phenytoin(4), praziquantel, protease inhibitors, quetiapine, risperidone, theophylline, topiramate, tiagabine, tramadol, triazolam, trazodone(5), valproate, warfarin(6), nefazodone, ziprasidone, and zonisamide.
(3)Break through bleeding has been reported among patients receiving concomitant oral contraceptives and their reliability may be adversely affected.
(4)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.
(5)Following co-administration of carbamazepine 400mg/day with trazodone 100mg to 300mg daily, carbamazepine reduced trough plasma concentrations of trazodone (as well as meta-chlorophenylpiperazine [mCPP]) by 76 and 60% respectively, compared to precarbamazepine values.
(6)Warfarin's anticoagulant effect can be reduced in the presence of carbamazepine.
Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see ).
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 Carbatrol (Carbamazepine) ®, it is reasonable to expect that a dose increase for the concomitant agent may be necessary.
Agents with Increased Levels in the Presence of Carbamazepine:
Carbatrol (Carbamazepine) ® increases the plasma levels of the following agents:
Clomipramine HCl, phenytoin(7), and primidone
(7)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 Carbatrol (Carbamazepine) ®, it is reasonable to expect that a dose decrease for the concomitant agent may be necessary.
Pharmacological/Pharmacodynamic Interactions with Carbamazepine:
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.
Given the anticonvulsant properties of carbamazepine, Carbatrol (Carbamazepine) ® may reduce the thyroid function as has been reported with other anticonvulsants. Additionally, anti-malarial drugs, such as chloroquine and mefloquine, may antagonize the activity of carbamazepine.
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 Carbatrol (Carbamazepine) ®, it is reasonable to expect that a dose adjustment may be necessary.
Because of its primary CNS effect, caution should be used when Carbatrol (Carbamazepine) ® is taken with other centrally acting drugs and alcohol.
Administration of carbamazepine to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day (low dose approximately 0.2 times the maximum human daily dose of 1200 mg on a mg/m2 basis), resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.
Substantial evidence of carbamazepine effectiveness for use in the management of children with epilepsy (see for specific seizure types) is derived from clinical investigations performed in adults and from studies in several systems which support the conclusion that (1) the pathogenic mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.
Taken as a whole, this information supports a conclusion that the generally acceptable therapeutic range of total carbamazepine in plasma (i.e., 4-12 μg/mL) is the same in children and adults.
The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer term data from clinical trials is available.
Carbatrol (Carbamazepine) Adverse Reactions
The most severe adverse reactions previously observed with carbamazepine were reported in the hemopoietic system and skin (see ), and the cardiovascular system.
The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the lowest dosage recommended.
The following additional adverse reactions were previously reported with carbamazepine:
Testicular atrophy occurred in rats receiving carbamazepine orally from 4-52 weeks at dosage levels of 50-400 mg/kg/day. Additionally, rats receiving carbamazepine in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg/day and higher. Relevance of these findings to humans is unknown.
There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported with concomitant use of psychotropic drugs.
A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
Carbatrol (Carbamazepine) Drug Abuse And Dependence
No evidence of abuse potential has been associated with carbamazepine, nor is there evidence of psychological or physical dependence in humans.
Carbatrol (Carbamazepine) Overdosage
Lowest known lethal dose: adults, >60 g (39-year-old man). Highest known doses survived: adults, 30 g (31-year-old woman); children, 10 g (6-year-old boy); small children, 5 g (3-year-old girl).
Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.
The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (>60 g) have been ingested.
Respiration:
Cardiovascular System:
Nervous System and Muscles:
Gastrointestinal Tract:
Kidneys and Bladder:
Laboratory Findings:
Combined Poisoning:
For the most up to date information on management of carbamazepine overdose, please contact the poison center for your area by calling 1-800-222-1222. The prognosis in cases of carbamazepine poisoning is generally favorable. Of 5,645 cases of carbamazepine exposures reported to US poison centers in 2002, a total of 8 deaths (0.14% mortality rate) occurred. Over 39% of the cases reported to these poison centers were managed safely at home with conservative care. Successful management of large or intentional carbamazepine exposures requires implementation of supportive care, frequent monitoring of serum drug concentrations, as well as aggressive but appropriate gastric decontamination.
Elimination of the Drug:
Measures to Accelerate Elimination:
Respiratory Depression:
Hypotension, Shock:
Convulsions:
Surveillance:
Treatment of Blood Count Abnormalities:
Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought.
Carbatrol (Carbamazepine) Dosage And Administration
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see ). Dosage should be adjusted to the needs of the individual patients. A low initial daily dosage with gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very gradually to the minimum effective level. The Carbatrol (Carbamazepine) capsules may be opened and the beads sprinkled over food, such as a teaspoon of applesauce or other similar food products if this method of administration is preferred. Carbatrol (Carbamazepine) capsules or their contents should not be crushed or chewed. Carbatrol (Carbamazepine) can be taken with or without meals.
Carbatrol (Carbamazepine) is an extended-release formulation for twice a day administration. When converting patients from immediate release carbamazepine to Carbatrol (Carbamazepine) extended-release capsules, the same total daily mg dose of carbamazepine should be administered.
Carbatrol (Carbamazepine) How Supplied
Supplied in bottles of 120........................... NDC 54092-171-12
Supplied in bottles of 120 ............................NDC 54092-172-12
Supplied in bottles of 120 ............................NDC 54092-173-12
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP controlled room temperature]. PROTECT FROM LIGHT AND MOISTURE.
Manufactured for:
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Carbatrol (Carbamazepine) Medication Guidecarbatrol (car-ba-trol)(carbamazepine)extended-release Capsules
Read this Medication Guide before you start taking Carbatrol (Carbamazepine) and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
Stopping Carbatrol (Carbamazepine) suddenly can cause serious problems.
Stopping Carbatrol (Carbamazepine) suddenly can cause serious problems.
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.
Carbatrol (Carbamazepine) is a medicine used to treat:
Carbatrol (Carbamazepine) is not a regular pain medicine and should not be used for aches or pains.
Do not take Carbatrol (Carbamazepine) if you:
Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.
- If you become pregnant while taking Carbatrol (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.
Taking Carbatrol (Carbamazepine) with certain other medicines can 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.
See
Irregular heartbeat - symptoms include:
Liver problems - symptoms include:
Get medical help right away if you have any of the symptoms listed above or listed in
These are not all the side effects of Carbatrol (Carbamazepine) . For more information, ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you. or that does not go away.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Carbatrol (Carbamazepine) for a condition for which it was not prescribed. Do not give Carbatrol (Carbamazepine) to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Carbatrol (Carbamazepine) . If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Carbatrol (Carbamazepine) that is written for health professionals.
For more information go to or call 1-800-828-2088.
Active ingredient: carbamazepine
Inactive ingredients: citric acid, colloidal silicon dioxide, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, povidone, sodium lauryl sulfate, talc, triethyl citrate and Eudragit.
In addition:
This Medication Guide has been approved by the US Food and Drug Administration.
Shire US Inc.
Wayne, PA 19087
Issued [01/2011]
