TEGRETOL Carbamazepine 200mg Tablet 1's

Epilepsy: Complex or simple partial seizures (with or without loss of consciousness) with or without secondary generalization; Generalized tonic-clonic seizures. Mixed forms of seizures.
Carbamazepine (Tegretol) is suitable for both monotherapy and combination therapy.
Carbamazepine (Tegretol) is usually not effective in absences (petit mal) and myoclonic seizures (see Precautions).
Acute mania and maintenance treatment of bipolar affective disorders to prevent or attenuate recurrence.
Alcohol-withdrawal syndrome.
Idiopathic trigeminal neuralgia and trigeminal neuralgia due to multiple sclerosis (either typical or atypical). Idiopathic glossopharyngeal neuralgia.
Painful diabetic neuropathy.
Diabetes insipidus centralis. Polyuria and polydipsia of neurohormonal origin.

 

Epilepsy: When possible, carbamazepine (Tegretol) should be prescribed as monotherapy.
Treatment should be initiated with a low daily dosage, to be slowly increased until an optimal effect is obtained.
The dose of carbamazepine should be adjusted to the needs of the individual patient to achieve adequate control of seizures. Determination of plasma levels may help in establishing the optimum dosage. In the treatment of epilepsy, the dose of carbamazepine usually requires total plasma-carbamazepine concentrations of about 4 to 12 micrograms/mL (17 to 50 micromoles/litre) (see Precautions).
When carbamazepine (Tegretol) is added to existing antiepileptic therapy, this should be done gradually while maintaining, or if necessary, adapting the dosage of the other antiepileptic(s) (see Interactions and Pharmacology: Pharmacokinetics under Actions).
General target population/Adults: Dosage in Epilepsy: Oral forms: Initially, 100 to 200 mg once or twice daily; the dosage should be slowly raised until - generally at 400 mg 2 to 3 times daily - an optimum response is obtained. In some patients 1600 mg or even 2000 mg daily may be appropriate.
Dosage in Acute mania and maintenance treatment of bipolar affective disorders: Dosage range: about 400 to 1600 mg daily, the usual dosage being 400 to 600 mg daily given in 2 to 3 divided doses. In acute mania, the dosage should be increased rather quickly, whereas small dosage increments are recommended for maintenance therapy of bipolar disorders in order to ensure optimal tolerability.
Dosage in Alcohol-withdrawal syndrome: Average dosage: 200 mg 3 times daily. In severe cases, it can be raised during the first few days (e.g. to 400 mg 3 times daily). At the start of treatment for severe withdrawal manifestations, carbamazepine (Tegretol) should be given in combination with sedative-hypnotic drugs (e.g. clomethiazole, chlordiazepoxide). After the acute stage has abated, carbamazepine (Tegretol) can be continued as monotherapy.
Dosage in Trigeminal neuralgia: The initial dosage of 200 to 400 mg should be slowly raised daily until freedom from pain is achieved (normally at 200 mg 3 to 4 times daily). The dosage should then be gradually reduced to the lowest possible maintenance level. Maximum recommended dose is 1200 mg/day. When pain relief has been obtained, attempts should be made to gradually discontinue therapy, until another attack occurs.
Dosage in Painful diabetic neuropathy: Average dosage: 200 mg 2 to 4 times daily.
Dosage in Diabetes insipidus centralis: Average dosage for adults: 200 mg 2 to 3 times daily. In children the dosage should be reduced proportionally to the child's age and body weight.
Special populations: Renal impairment/Hepatic impairment: No data are available on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal function.
Pediatrics/Children and adolescents: Oral forms: For children aged 4 years or less, a starting dose of 20 to 60 mg/day, increasing by 20 to 60 mg every second day, is recommended. For children over the age of 4 years, therapy may begin with 100 mg/day, increasing at weekly intervals by 100 mg.
Maintenance dosage: 10 to 20 mg/kg body weight daily in divided doses, e.g.: Up to 1 year of age: 100 to 200 mg daily (= 5 to 10 mL 1-2 measures of oral suspension); 1 to 5 years of age: 200 to 400 mg daily (= 10 to 20 mL 2 x 1-2 measures of oral suspension); 6 to 10 years of age: 400 to 600 mg daily (= 20 to 30 mL 2-3 x 2 measures of oral suspension); 11 to 15 years of age: 600 to 1000 mg daily [= 30 to 50 mL 3 x 2-3 measures of oral suspension (plus an extra measure of 5 mL in case of administration of 1000 mg)]; >15 years of age: 800 to 1200 mg daily (same as adult dose).
Maximum recommended dose: Up to 6 years of age: 35 mg/kg/day; 6-15 years of age: 1000 mg/day; >15 years of age: 1200 mg/day.
Dosage in Diabetes insipidus centralis: In children the dosage should be reduced proportionally to the child's age and body weight. Average dosage for adults: 200 mg 2 to 3 times daily.
Geriatric patients (65 years or above): Dosage in Trigeminal neuralgia: Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of carbamazepine (Tegretol) should be selected with caution in elderly patients.
In elderly patients, an initial dose of 100 mg twice daily is recommended. The initial dosage of 100 mg twice daily should be slowly raised daily until freedom from pain is achieved (normally at 200 mg 3 to 4 times daily). The dosage should then be gradually reduced to the lowest possible maintenance level. Maximum recommended dose is 1200 mg/day. When pain relief has been obtained, attempts should be made to gradually discontinue therapy, until another attack occurs.
Method of Administration: The tablets and the oral suspension (to be shaken before use) may be taken during, after, or between meals. Tablets should be taken with a little liquid.
The SR/LA tablets (either whole or, if so prescribed, only half a tablet) should be swallowed unchewed with a little liquid. The oral suspension formulation (one measure = 5 mL = 100 mg; half a measure = 2.5 mL = 50 mg) is particularly suitable for patients who have difficulty in swallowing tablets or need initial careful adjustment of the dosage.
As a result of slow, controlled release of the active substance from the SR/LA tablets, these are designed to be taken in a twice-daily dosage regimen.
Since a given dose of oral suspension will produce higher peak levels than the same dose in tablet form, it is advisable to start with low doses and increase them slowly so as to avoid adverse reactions.
Switching patients from tablets to oral suspension: this should be done by giving the same number of mg per day in smaller, more frequent doses (e.g. oral suspension three times a day (t.i.d.) instead of tablets twice a day (b.i.d)).
Switching patients from conventional tablets to SR/LA tablets: clinical experience shows that in some patients the dosage in the form of SR/LA tablets may need to be increased.
Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of carbamazepine (Tegretol) should be selected with caution in elderly patients.

 

Overdosage

Should be taken with food: Avoid grapefruit juice. SR & LA tab: Swallow whole, do not chew/crush.

Known hypersensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants) or any other component of the formulation.
Patients with atrioventricular block.
Patients with a history of bone-marrow depression.
Patients with a history of hepatic porphyrias (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda).
Use is not recommended in combination with monoamine-oxidase inhibitors (MAOIs) (see Interactions).

Carbamazepine (Tegretol) should be given only under medical supervision. It should be prescribed only after a critical benefit-risk appraisal and under close monitoring in patients with a history of cardiac, hepatic, or renal damage, adverse haematological reactions to other drugs, or interrupted courses of therapy with carbamazepine (Tegretol).
Haematological effects: Agranulocytosis and aplastic anaemia have been associated with carbamazepine (Tegretol); however, due to the very low incidence of these conditions, meaningful risk estimates for carbamazepine (Tegretol) are difficult to obtain. The overall risk in the general untreated population has been estimated at 4.7 persons per million per year for agranulocytosis and 2.0 persons per million per year for aplastic anemia.
Transient or persistent decreased platelet or white blood cell counts occur occasionally to frequently in association with the use of carbamazepine (Tegretol). However, in the majority of cases these effects prove transient and are unlikely to signal the onset of either aplastic anemia or agranulocytosis. Nonetheless, complete pretreatment blood counts, including platelets (and possibly reticulocytes and serum iron), should be obtained at baseline, and periodically thereafter.
If the white blood cell or platelet count is definitely low or decreased during treatment, the patient and the complete blood count should be closely monitored. Carbamazepine (Tegretol) should be discontinued if any evidence of significant bone-marrow depression appears.
Patients should be made aware of early toxic signs and symptoms of a potential hematological problem, as well as symptoms of dermatological or hepatic reactions. If reactions such as fever, sore throat, rash, ulcers in the mouth, easy bruising, petechial or purpuric haemorrhage appear, the patient should be advised to consult the physician immediately.
Serious dermatologic reactions: Serious dermatologic reactions, including toxic epidermal necrolysis (TEN; also known as Lyell's syndrome) and Stevens-Johnson syndrome (SJS), have been reported very rarely with carbamazepine (Tegretol). Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and may be fatal. Most of the SJS/TEN cases appear in the first few months of treatment. These reactions are estimated to occur in 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. If signs and symptoms suggestive of severe skin reactions (e.g. SJS, Lyell's syndrome/TEN) appear, carbamazepine (Tegretol) should be withdrawn at once and alternative therapy should be considered.
Pharmacogenomics: There is growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated adverse reactions.
Association with HLA-B*1502: Retrospective studies in patients of Han Chinese and Thai origin found a strong correlation between SJS/TEN skin reactions associated with carbamazepine and the presence in these patients of the Human Leukocyte Antigene (HLA)-B*1502 allele. The frequency of HLA-B*1502 allele ranges from 2 to 12% in Han Chinese populations and is about 8% in Thai populations. Higher reporting rates of SJS (rare rather than very rare) are reported in some countries in Asia (e.g. Taiwan, Malaysia and the Philippines) in which there is a higher frequency of the HLA-B*1502 allele in the population (e.g. above 15% in the Philippines and some Malaysian populations). Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively. The frequency of the HLA-B*1502 allele is negligible in persons of European descent, African populations, indigenous peoples of the Americas, Hispanic populations sampled and in Japanese (< 1%).
The allele frequencies listed here represent the percentage of chromosomes in the specified population that carry the allele of interest, meaning that the percentage of patients who carry a copy of the allele on at least one of their two chromosomes (i.e., the "carrier frequency") is nearly twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.
Testing for the presence of HLA-B*1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with carbamazepine (Tegretol) (see Information for the Healthcare Professionals as follows). The use of carbamazepine (Tegretol) should be avoided in tested patients who are found to be positive for HLA-B*1502 unless the benefits clearly outweigh the risks. HLA-B*1502 may be a risk factor for the development of SJS/TEN in Chinese patients taking other anti-epileptic drugs (AED) associated with SJS/TEN. Consideration should therefore 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. Screening is not generally recommended in patients from populations in which the prevalence of HLA-B*1502 is low. Screening is generally not recommended for any current users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA-B*1502 status.
The identification of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in these subjects has been shown to decrease the incidence of carbamazepine-induced SJS/TEN.
Association with HLA-A*3101: Human Leukocyte Antigen (HLA)-A*3101 may be a risk factor for the development of cutaneous adverse drug reactions such as SJS, TEN, DRESS, AGEP and maculopapular rash. Retrospective genome-wide studies in Japanese and Northern European populations reported association between severe skin reactions (SJS, TEN, DRESS, AGEP and maculopapular rash) associated with carbamazepine use and the presence of the HLA-A*3101 allele in these patients.
The frequency of the HLA-A*3101 allele varies widely between ethnic populations and its frequency is about 2 to 5% in European populations and about 10% in the Japanese population. The frequency of this allele is estimated to be less than 5% in the majority of Australian, Asian, African and North American populations with some exceptions within 5-12%. Prevalence above 15% has been estimated in some ethnic groups in South America (Argentina and Brazil), North America (US Navajo and Sioux, and Mexico Sonora Seri) and Southern India (Tamil Nadu) and between 10%-15% in other native ethnicities in these same regions.
The allele frequencies listed here represent the percentage of chromosomes in the specified population that carry the allele of interest, meaning that the percentage of patients who carry a copy of the allele on at least one of their two chromosomes (i.e., the "carrier frequency") is nearly twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.
Testing for the presence of HLA-A*3101 allele should be considered in patients with ancestry in genetically at-risk populations (for example, patients of the Japanese and Caucasian populations, patients who belong to the indigenous populations of the Americas, Hispanic populations, people of southern India, and people of Arabic descent), prior to initiating treatment with carbamazepine (Tegretol) (see Information for the Healthcare Professionals as follows). The use of carbamazepine (Tegretol) should be avoided in patients who are found to be positive for HLA-A* 3101, unless the benefits clearly outweigh the risks. Screening is generally not recommended for any current users, as the risk of SJS/TEN, AGEP, DRESS and maculopapular rash is largely confined to the first few months of therapy, regardless of HLA-A*3101 status.
Limitation of genetic screening: Genetic screening results must never substitute for appropriate clinical vigilance and patient management. Many Asian patients positive for HLA-B*1502 and treated with carbamazepine (Tegretol) will not develop SJS/TEN and patients negative for HLA-B*1502 of any ethnicity can still develop SJS/TEN. Similarly many patients positive for HLA-A*3101 and treated with carbamazepine (Tegretol) will not develop SJS, TEN, DRESS, AGEP or maculopapular rash and patients negative for HLA-A*3101 of any ethnicity can still develop these severe cutaneous adverse reactions. The role of other possible factors in the development of, and morbidity from, these severe cutaneous adverse reactions, such as AED dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied.
Information for the Healthcare Professionals: If testing for the presence of the HLA-B*1502 allele should be performed, high-resolution "HLA-B* 1502 genotyping" 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. Similarly if testing for the presence of the HLA-A*3101 allele should be performed, high-resolution "HLA-A*3101 genotyping" respectively is recommended. The test is positive if either one or two HLA- A*3101 alleles are detected and negative if no HLA- A*3101 alleles are detected.
Other dermatologic reactions: Mild skin reactions, e.g. isolated macular or maculopapular exanthema, can also occur and are mostly transient and not hazardous. They usually disappear within a few days or weeks, either during the continued course of treatment or following a decrease in dosage. However, since it may be difficult to differentiate the early signs of more serious skin reactions from mild transient reactions, the patient should be kept under close surveillance with consideration given to immediately withdrawing the drug should the reaction worsen with continued use.
The HLA-A*3101 allele has been found to be associated with less severe adverse cutaneous reactions from carbamazepine and may predict the risk of these reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption). However, the HLA-B*1502 allele has not been found to predict the risk of these aforementioned skin reactions.
Hypersensitivity: Carbamazepine (Tegretol) may trigger hypersensitivity reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), a delayed multi-organ hypersensitivity disorder with fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts), that may occur in various combinations. Other organs may also be affected (e.g. lungs, kidneys, pancreas, myocardium, colon). (See Adverse Reactions).
The HLA-A*3101 allele has been found to be associated with the occurrence of hypersensitivity syndrome, including maculopapular rash.
Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25 to 30% of these patients may experience hypersensitivity reactions with oxcarbazepine (Trileptal).
Cross-hypersensitivity can occur between carbamazepine and aromatic antiepileptic drugs (e.g. phenytoin, primidone and phenobarbital).
In general, if signs and symptoms suggestive of hypersensitivity reactions occur, carbamazepine (Tegretol) should be withdrawn immediately.
Seizures: Carbamazepine (Tegretol) should be used with caution in patients with mixed seizures which includes absences, either typical or atypical. In all these conditions, carbamazepine (Tegretol) may exacerbate seizures. In the event of exacerbation of seizures, treatment should be discontinued.
Hepatic function: Baseline and periodic evaluations of hepatic function must be performed during treatment, particularly in patients with a history of liver disease and in elderly patients. The drug should be withdrawn immediately in cases of aggravated liver dysfunction or active liver disease.
Renal function: Baseline and periodic complete urinalysis and BUN determinations are recommended.
Hyponatremia: Hyponatremia is known to occur with carbamazepine. In patients with pre-existing renal conditions associated with low sodium or in patients treated concomitantly with sodium-lowering medicinal products (e.g. diuretics, medicinal products associated with inappropriate ADH secretion), serum sodium levels should be measured prior to initiating carbamazepine therapy. Thereafter, serum sodium levels should be measured after approximately two weeks and then at monthly intervals for the first three months during therapy, or according to clinical need. These risk factors may apply especially to elderly patients. If hyponatraemia is observed, water restriction is an important counter-measurement if clinically indicated.
Hypothyroidism: Carbamazepine may reduce serum concentrations of thyroid hormones through enzyme induction requiring an increase in dose of thyroid replacement therapy in patients with hypothyroidism. Hence thyroid function monitoring is suggested to adjust the dosage of thyroid replacement therapy.
Anticholinergic effects: Carbamazepine (Tegretol) has shown mild anticholinergic activity. Patients with increased intraocular pressure and urinary retention should therefore be closely observed during therapy (see Adverse Reactions).
Psychiatric effects: The possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
Suicidal ideation and behaviour: Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomized placebo controlled trials of antiepileptic drugs has shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known.
Therefore patients should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Endocrinological effects: Breakthrough bleeding has been reported in women taking carbamazepine (Tegretol) while using hormonal contraceptives. The reliability of hormonal contraceptives may be adversely affected by carbamazepine (Tegretol) and women of childbearing potential should be advised to consider using alternative forms of birth control while taking carbamazepine (Tegretol).
Monitoring of plasma levels: Although correlations between dosage and plasma levels of carbamazepine, and between plasma levels and clinical efficacy or tolerability are rather tenuous, monitoring of the plasma levels may be useful in the following situations: dramatic increase in seizure frequency/verification of patient compliance, during pregnancy, when treating children or adolescents; in suspected absorption disorders; in suspected toxicity when more than one drug is being used (see Interactions).
Dose reduction and withdrawal effects: Abrupt withdrawal may precipitate seizures therefore carbamazepine should be withdrawn gradually over a 6-month period. If treatment has to be withdrawn abruptly in a patient with epilepsy, the switch to the new antiepileptic compound should be made under cover of a suitable drug.
Interactions: Co-administration of inhibitors of CYP3A4 or inhibitors of epoxide hydrolase with carbamazepine can induce adverse reactions (increase of carbamazepine or carbamazepine-10,11 epoxide plasma concentrations respectively). Dosage should be adjusted accordingly and/or the plasma levels monitored.
Co-administration of CYP3A4 inducers with carbamazepine may decrease carbamazepine plasma concentrations and its therapeutic effect, while discontinuation of a CYP3A4 inducer may increase carbamazepine plasma concentrations. The dosage of carbamazepine may have to be adjusted.
Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II enzyme systems in the liver, and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP3A4 by induction of their metabolism (see Interactions).
Female patients of childbearing potential should be warned that the concurrent use of carbamazepine with hormonal contraceptives may render this type of contraceptive ineffective (see Interactions and Use in Pregnancy & Lactation). Alternative non-hormonal forms of contraception are recommended when using carbamazepine.
Falls: Treatment has been associated with ataxia, dizziness, somnolence, hypotension, confusional state, sedation (see Adverse Reactions) which may lead to falls and, consequently fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete risk assessment of fall should be considered recurrently for patients on long-term treatment.
Special excipients: The oral suspension contains parahydroxybenzoates which may cause allergic reactions (possibly delayed). It also contains sorbitol and, therefore, should not be administered to patients with rare hereditary problems of fructose intolerance.
Driving and Using Machines: The patient's ability to react may be impaired by the medical condition resulting in seizures and adverse reactions including dizziness, drowsiness, ataxia, diplopia, impaired accommodation and blurred vision have been reported with carbamazepine (Tegretol), especially at the start of treatment or in connection with dose adjustments. Patients should therefore exercise due caution when driving a vehicle or operating machinery.
Use in Pregnancy: Pregnancy and females of reproductive potential: Carbamazepine may be associated with fetal harm when administered to a pregnant woman (see Use in Pregnancy & Lactation). Carbamazepine (Tegretol) should be used during pregnancy only if the potential benefit justifies the potential risks.
Adequate counselling should be made available to all pregnant women and women of childbearing potential regarding the risks associated with pregnancy due to potential teratogenic risk to the fetus (see Use in Pregnancy & Lactation).
Women of childbearing potential should use effective contraception during treatment with carbamazepine and for 2 weeks after the last dose (see Endocrinological effects and Interactions as previously mentioned and Use in Pregnancy & Lactation).

 

Use In Pregnancy & Lactation

Summary of the safety profile: Particularly at the start of treatment with carbamazepine (Tegretol), or if the initial dosage is too high, or when treating elderly patients, certain types of adverse reaction occur very commonly or commonly, e.g. CNS adverse reactions (dizziness, headache, ataxia, drowsiness, fatigue, diplopia); gastrointestinal disturbances (nausea, vomiting), and allergic skin reactions.
The dose-related adverse reactions usually abate within a few days, either spontaneously or after a transient dosage reduction. The occurrence of CNS adverse reactions may be a manifestation of relative overdosage or significant fluctuation in plasma levels. In such cases it is advisable to monitor plasma levels.
Tabulated summary of adverse drug reactions compiled from clinical trials and from spontaneous reports: Adverse drug reactions from clinical trials (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Table 1.)

Additional adverse drug reactions from spontaneous reports (frequency not known): The following adverse drug reactions have been derived from post-marketing experience via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness. (See Table 2.)

 

Cytochrome P450 3A4 (CYP3A4) is the main enzyme catalyzing formation of the active metabolite carbamazepine-10,11-epoxide. Coadministration of inhibitors of CYP3A4 may result in increased carbamazepine plasma concentrations which could induce adverse reactions. Coadministration of CYP3A4 inducers might increase the rate of carbamazepine metabolism, thus leading to potential decreases in the carbamazepine serum level and therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may decrease the rate of metabolism of carbamazepine, leading to an increase in carbamazepine plasma levels.
Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II enzyme systems in the liver, and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP3A4 by induction of their metabolism.
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. Co-administration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations.
Interactions resulting in a contraindication: The use of carbamazepine is contraindicated in combination with monoamine-oxidase inhibitors (MAOIs); before administering carbamazepine MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits (see Contraindications).
Agents that may raise carbamazepine plasma levels: Since raised plasma carbamazepine levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of carbamazepine (Tegretol) should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described as follows.
Analgesics, anti-inflammatory drugs: dextropropoxyphene, ibuprofen.
Androgens: danazol.
Antibiotics: macrolide antibiotics (e.g. erythromycin, troleandomycin, josamycin, clarithromycin), ciprofloxacin.
Antidepressants: possibly desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine.
Antiepileptics: stiripentol, vigabatrin.
Antifungals: azoles (e.g. itraconazole, ketoconazole, fluconazole, voriconazole). Alternative anticonvulsants may be recommended in patients treated with voriconazole or itraconazole.
Antihistamines: loratadine, terfenadine.
Antipsychotics: olanzapine.
Antituberculosis: isoniazid.
Antivirals: protease inhibitors for HIV treatment (e.g. ritonavir).
Carbonic anhydrase inhibitors: acetazolamide.
Cardiovascular drugs: diltiazem, verapamil.
Gastrointestinal drugs: possibly cimetidine, omeprazole.
Muscle relaxants: oxybutynin, dantrolene.
Platelet aggregation inhibitors: ticlopidine.
Other interactions: grapefruit juice, nicotinamide (only in high dosage).
Agents that may raise the active metabolite carbamazepine-10,11-epoxide plasma levels: Since raised plasma carbamazepine-10,11-epoxide levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage) should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described as follows: Loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.
Agents that may decrease carbamazepine plasma levels: The dose of carbamazepine (Tegretol) may have to be adjusted when used concomitantly with the substances described as follows: Antiepileptics: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin (to avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine it is recommended to adjust the plasma concentration of phenytoin to 13 micrograms /mL before adding carbamazepine to the treatment) and fosphenytoin, primidone, and, although the data are partly contradictory, possibly also clonazepam.
Antineoplastics: cisplatin or doxorubicin.
Antituberculosis: rifampicin.
Bronchodilatators or anti-asthma drugs: theophylline, aminophylline.
Dermatological drugs: isotretinoin.
Other interactions: herbal preparations containing St John's wort (Hypericum perforatum).
Effect of carbamazepine (Tegretol) on plasma levels of concomitant agents: Carbamazepine may lower the plasma level, or diminish - or even abolish - the activity of certain drugs. The dosage of the following drugs may have to be adjusted to clinical requirements: Analgesics, anti-inflammatory agents: buprenorphine, methadone, paracetamol (long term administration of carbamazepine and paracetamol (acetaminophen) may be associated with hepatotoxicity), phenazone (antipyrine), tramadol.
Antibiotics: doxycycline, rifabutin.
Anticoagulants: oral anticoagulants (e.g. warfarin, phenprocoumon, dicoumarol, acenocoumarol, rivaroxaban, dabigatran, apixaban, edoxaban).
Antidepressants: bupropion, citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine).
Antiemetics: aprepitant.
Antiepileptics: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, eslicarbazepine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. To avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine it is recommended to adjust the plasma concentration of phenytoin to 13 micrograms/mL before adding carbamazepine to the treatment. There have been rare reports of an increase in plasma mephenytoin levels.
Antifungals: itraconazole, voriconazole. Alternative anti-convulsants may be recommended in patients treated with voriconazole or itraconazole.
Antihelmintics: praziquantel, albendazole.
Antineoplastics: imatinib, cyclophosphamide, lapatinib, temsirolimus.
Antipsychotics: clozapine, haloperidol and bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, paliperidone.
Antivirals: protease inhibitors for HIV treatment (e.g. indinavir, ritonavir, saquinavir).
Anxiolytics: alprazolam, midazolam.
Bronchodilators or anti-asthma drugs: theophylline.
Contraceptives: hormonal contraceptives (alternative contraceptive methods should be considered).
Cardiovascular drugs: calcium channel blockers (dihydropyridine group) e.g. felodipine, digoxin, simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine.
Corticosteroids: corticosteroids (e.g. prednisolone, dexamethasone).
Drugs used in erectile dysfunction: tadalafil.
Immunosuppressants: ciclosporin, everolimus, tacrolimus, sirolimus.
Thyroid agents: levothyroxine.
Other drug interactions: products containing oestrogens and/or progesterones.
Combinations that require specific consideration: Concomitant use of carbamazepine and levetiracetam has been reported to increase carbamazepine-induced toxicity.
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.
Combined use of carbamazepine and lithium or metoclopramide on the one hand, and carbamazepine and neuroleptics (haloperidol, thioridazine) on the other, may lead to increased neurological adverse reactions (with the latter combination even in the presence of 'therapeutic plasma levels').
Concomitant medication with some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatraemia.
Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g. pancuronium). Their dosage may need to be raised, and patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected.
Carbamazepine, like other psychoactive drugs, may reduce alcohol tolerance. It is therefore advisable for the patient to abstain from alcohol.
Concomitant use of carbamazepine with direct acting oral anti-coagulants (rivaroxaban, dabigatran, apixaban, and edoxaban) may lead to reduced plasma concentrations of direct acting oral anticoagulants, which carries the risk of thrombosis. Therefore, if a concomitant use is necessary, close monitoring of signs and symptoms of thrombosis is recommended.
Interference with serological testing: Carbamazepine may result in false positive perphenazine concentrations in HPLC analysis due to interference.
Carbamazepine and the 10,11-epoxide metabolite may result in false positive tricyclic antidepressant concentration in fluorescence polarized immunoassay method.

 

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Anticonvulsants / Drugs for Neuropathic Pain