Carbatrol Prescribing Information
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 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.
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).
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.
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 Carbatrol contains carbamazepine and should not be used in combination with any other medications containing carbamazepine.
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
HLA-A*3101 is expected to be carried by more than 15% of patients of Japanese, Native American, Southern Indian (e.g., Tamil Nadu) and some Arabic ancestry; up to about 10% in patients of Han Chinese, Korean, European, Latin American and other Indian ancestry; and up to about 5% in African-Americans and patients of Thai, Taiwanese, and Chinese (Hong Kong) ancestry.
The risks and benefits of carbamazepine therapy should be weighed before considering carbamazepine in patients known to be positive for HLA-A*3101.
Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive and HLA-A*3101-positive patients treated with carbamazepine will not develop SJS/TEN or other hypersensitivity reactions, and these reactions can still occur infrequently in HLA-B*1502-negative and HLA-A*3101-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN and other hypersensitivity reactions, such as AED dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied.
Aplastic anemia and agranulocytosis have been reported in association with the use of carbamazepine. (See
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 life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Carbatrol should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
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 (Trileptal®).
Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips, and eyelids have been reported in patients after taking the first or subsequent doses of carbamazepine. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with Carbatrol, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug.
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.
Antiepileptic drugs (AEDs), including Carbatrol, 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.
| 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 Carbatrol 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.
Hyponatremia can occur as a result of treatment with Carbatrol. 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 Carbatrol treatment may be dose-related. Elderly patients and patients treated with diuretics are at greater risk of developing hyponatremia. Signs and symptoms of hyponatremia include headache, new or increased seizure frequency, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Consider discontinuing Carbatrol in patients with symptomatic hyponatremia.
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects, cardiovascular malformations, and anomalies involving various body systems). Developmental delays have been reported. When treating or counseling women of childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30-60 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/m2basis. 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 Carbatrol, physicians are advised to recommend that pregnant patients taking Carbatrol 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
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 Carbatrol 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 Carbatrol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.
For genetically at-risk patients (see
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
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
Thyroid function tests have been reported to show decreased values with carbamazepine administered alone.
Interference with some pregnancy tests has been reported.
Carbatrol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types:
- Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvements than those with other types.
- Generalized tonic-clonic seizures (grand mal).
- 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 ).
GeneralBefore initiating therapy, a detailed history and physical examination should be made.
Carbatrol should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures, since in these patients carbamazepine has been associated with increased frequency of generalized convulsions (see
INDICATIONS AND USAGE).Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac conduction disturbance, including second- and third-degree atrioventricular (AV) block; cardiac, hepatic, or renal damage; adverse hematologic or hypersensitivity reaction to other drugs including reactions to other anticonvulsants; or interrupted courses of therapy with carbamazepine.
AV block, including second- and third-degree block, has been reported following carbamazepine treatment. This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure, have been reported (see ADVERSE REACTIONSand PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects may progress despite discontinuation of the drug. In addition, rare instances of vanishing bile duct syndrome have been reported. This syndrome consists of a cholestatic process with a variable clinical course ranging from fulminant to indolent, involving the destruction and disappearance of the intrahepatic bile ducts. Some, but not all, cases are associated with features that overlap with other immunoallergenic syndromes such as multiorgan hypersensitivity/ DRESS and serious dermatologic reactions. As an example, there has been a report of vanishing bile duct syndrome associated with Stevens-Johnson syndrome and in another case an association with fever and eosinophilia.
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see
For genetically at-risk patients (see
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
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
Thyroid function tests have been reported to show decreased values with carbamazepine administered alone.
Interference with some pregnancy tests has been reported.
Carbatrol is an extended-release formulation for twice a day administration. When converting patients from immediate release carbamazepine to Carbatrol extended-release capsules, the same total daily mg dose of carbamazepine should be administered. Following conversion to Carbatrol, patients should be closely monitored for seizure control. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions.
Carbatrol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types:
- Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvements than those with other types.
- Generalized tonic-clonic seizures (grand mal).
- 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 (seePRECAUTIONS, General).
Carbatrol 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.
Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to the following:
Carbamazepine is not highly bound to plasma proteins; therefore, administration of Carbatrol to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.
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 include, for example, the following:
Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. Coadministration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations. Accordingly, the dosage of Carbatrol should be adjusted and/or the plasma levels monitored when used concomitantly with loxapine, quetiapine, or valproic acid.
Thus, if a patient has been titrated to a stable dosage of Carbatrol, 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 may be necessary.
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 include, for example, the following:
(1)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, and then begins a course of treatment with one of these CYP3A4 inducers, it is reasonable to expect that a dose increase for Carbatrol may be necessary.
Carbamazepine is a potent inducer of hepatic CYP3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C9/19 and 3A4, through induction of their metabolism. When used concomitantly with Carbatrol, monitoring of concentrations or dosage adjustment of these agents may be necessary:
- When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole dose should be reduced.
- When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended.
- The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus. If patients must be coadministered carbamazepine with temsirolimus, an adjustment of temsirolimus dosage should be considered.
- The use of carbamazepine with lapatinib should generally be avoided. If carbamazepine is started in a patient already taking lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the lapatinib dose should be reduced.
- Concomitant use of carbamazepine with nefazodone results in plasma concentrations of nefazodone and its active metabolite insufficient to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see CONTRAINDICATIONS).
- Monitor concentrations of valproate when Carbatrol is introduced or withdrawn in patients using valproic acid.
In addition, Carbatrol causes, or would be expected to cause, decreased levels of, for example, the following drugs, for which monitoring of concentrations or dosage adjustment may be necessary:
(2)Concomitant use of Carbatrol 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.
(3)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.
(4)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.
(5)Warfarin's anticoagulant effect can be reduced in the presence of carbamazepine.
(6)Concomitant use of carbamazepine with rivaroxaban, apixaban, dabigatran, and edoxaban (direct acting oral anticoagulants) is expected to result in decreased plasma concentrations of these anticoagulants that may be insufficient to achieve the intended therapeutic effect. In general, coadministration of carbamazepine with rivaroxaban, apixaban, dabigatran, and edoxaban should be avoided.
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, it is reasonable to expect that a dose increase for the concomitant agent may be necessary.
Carbatrol increases the plasma levels of the following agents. 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, it is reasonable to expect that a dose decrease for the concomitant agent may be necessary.
Carbatrol can increase the concentrations of clomipramine, phenytoin, and primidone. If a patient has been titrated to a stable dosage on one of these agents in this category, and then begins treatment with Carbatrol, it may be necessary to decrease the dose of these drugs.
(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.
Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate of metabolism and the leukopenic activity of cyclophosphamide are reportedly increased by chronic co-administration of CYP3A4 inducers. There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine.
Coadministration of Carbatrol with delavirdine may lead to loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors (see
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.
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, it is reasonable to expect that a dose adjustment may be necessary.
The concomitant use of Carbatrol and other CNS depressants can increase the risk of respiratory depression, profound sedation, hypotension, and syncope. CNS depressants include: alcohol, opioid analgesics, benzodiazepines, tricyclic antidepressants, sedative/hypnotics, anticonvulsants, antipsychotics, antihistamines, anticholinergics, alpha and beta blockers, general anesthetics, muscle relaxants, and illicit CNS depressants. Consider reducing the dose of CNS depressants or Carbatrol when using these drugs concomitantly. Because of its primary CNS effect, caution should be used when Carbatrol is taken with other centrally acting drugs and alcohol.
Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered carbamazepine. Whether or not carbamazepine has the same effect on other nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
Carbatrol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types:
- Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvements than those with other types.
- Generalized tonic-clonic seizures (grand mal).
- 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 (seePRECAUTIONS, General).
Carbatrol is indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia. This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
Carbamazepine should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline 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 Carbatrol 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.
The most severe adverse reactions previously observed with carbamazepine were reported in the hemopoietic system and skin (see
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.
Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to the following:
Carbamazepine is not highly bound to plasma proteins; therefore, administration of Carbatrol to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.
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 include, for example, the following:
Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. Coadministration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations. Accordingly, the dosage of Carbatrol should be adjusted and/or the plasma levels monitored when used concomitantly with loxapine, quetiapine, or valproic acid.
Thus, if a patient has been titrated to a stable dosage of Carbatrol, 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 may be necessary.
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 include, for example, the following:
(1)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, and then begins a course of treatment with one of these CYP3A4 inducers, it is reasonable to expect that a dose increase for Carbatrol may be necessary.
Carbamazepine is a potent inducer of hepatic CYP3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C9/19 and 3A4, through induction of their metabolism. When used concomitantly with Carbatrol, monitoring of concentrations or dosage adjustment of these agents may be necessary:
- When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole dose should be reduced.
- When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended.
- The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus. If patients must be coadministered carbamazepine with temsirolimus, an adjustment of temsirolimus dosage should be considered.
- The use of carbamazepine with lapatinib should generally be avoided. If carbamazepine is started in a patient already taking lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the lapatinib dose should be reduced.
- Concomitant use of carbamazepine with nefazodone results in plasma concentrations of nefazodone and its active metabolite insufficient to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see ).
CONTRAINDICATIONSCarbamazepine 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 Carbatrol 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.
- Monitor concentrations of valproate when Carbatrol is introduced or withdrawn in patients using valproic acid.
In addition, Carbatrol causes, or would be expected to cause, decreased levels of, for example, the following drugs, for which monitoring of concentrations or dosage adjustment may be necessary:
(2)Concomitant use of Carbatrol 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.
(3)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.
(4)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.
(5)Warfarin's anticoagulant effect can be reduced in the presence of carbamazepine.
(6)Concomitant use of carbamazepine with rivaroxaban, apixaban, dabigatran, and edoxaban (direct acting oral anticoagulants) is expected to result in decreased plasma concentrations of these anticoagulants that may be insufficient to achieve the intended therapeutic effect. In general, coadministration of carbamazepine with rivaroxaban, apixaban, dabigatran, and edoxaban should be avoided.
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, it is reasonable to expect that a dose increase for the concomitant agent may be necessary.
Carbatrol increases the plasma levels of the following agents. 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, it is reasonable to expect that a dose decrease for the concomitant agent may be necessary.
Carbatrol can increase the concentrations of clomipramine, phenytoin, and primidone. If a patient has been titrated to a stable dosage on one of these agents in this category, and then begins treatment with Carbatrol, it may be necessary to decrease the dose of these drugs.
(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.
Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate of metabolism and the leukopenic activity of cyclophosphamide are reportedly increased by chronic co-administration of CYP3A4 inducers. There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine.
Coadministration of Carbatrol with delavirdine may lead to loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors (see
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 Carbatrol 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.
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.
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, it is reasonable to expect that a dose adjustment may be necessary.
The concomitant use of Carbatrol and other CNS depressants can increase the risk of respiratory depression, profound sedation, hypotension, and syncope. CNS depressants include: alcohol, opioid analgesics, benzodiazepines, tricyclic antidepressants, sedative/hypnotics, anticonvulsants, antipsychotics, antihistamines, anticholinergics, alpha and beta blockers, general anesthetics, muscle relaxants, and illicit CNS depressants. Consider reducing the dose of CNS depressants or Carbatrol when using these drugs concomitantly. Because of its primary CNS effect, caution should be used when Carbatrol is taken with other centrally acting drugs and alcohol.
Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered carbamazepine. Whether or not carbamazepine has the same effect on other nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.