Components:
Method of action:
Treatment option:
Medically reviewed by Kovalenko Svetlana Olegovna, PharmD. Last updated on 29.03.2022
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Zigma is indicated for
- epilepsy (generalised tonic-clonic and partial seizures)
Note: Zigma is not usually effective in absences (petit mal) and myoclonic seizures. Moreover, anecdotal evidence suggests that seizure exacerbation may occur in patients with atypical absences.
- the paroxysmal pain of trigeminal neuralgia
- the prophylaxis of manic-depressive psychosis in patients unresponsive to lithium therapy.
Epilepsy - generalised tonic-clonic and partial seizures.
| Note: | Zigma is not usually effective in absences (petit mal) and myoclonic seizures. Moreover, anecdotal evidence suggests that seizure exacerbation may occur in patients with atypical absences. |
The paroxysmal pain of trigeminal neuralgia.
For the prophylaxis of manic-depressive psychosis in patients unresponsive to lithium therapy.
Posology
Since a given dose of Zigma oral suspension will produce higher peak levels than the same dose in tablet form, it is advisable to start with low doses of the liquid and to increase them slowly so as to avoid adverse effects on the central nervous system such as dizziness and lethargy.
When switching a patient from tablets to liquid the same overall dose may be used but in smaller, more frequent, doses.
Epilepsy
The dose of Zigma 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 Zigma usually requires total plasma-Zigma concentrations of about 4 to 12 micrograms/ml (17 to 50 micromoles/litre) (see warnings and precautions).
Adults
It is advised that with all formulations of Zigma, a gradually increasing dosage scheme is used and this should be adjusted to suit the needs of the individual patient.
Zigma should be taken in a number of divided doses although initially 100-200 mg once to twice daily is recommended. This may be followed by a slow increase until the best response is obtained, often 800-1200 mg daily. In some instances, 1600 mg or even 2000 mg daily may be necessary.
Elderly
Due to the potential for drug interactions, the dosage of Zigma should be selected with caution in elderly patients.
Paediatric population
It is advised that with all formulations of Zigma, a gradually increasing dosage scheme is used and this should be adjusted to suit the needs of the individual patient.
Usual dosage 10-20 mg/kg bodyweight daily in several divided doses.
| Age up to 1 year: 1-5 years: 5-10 years: 10-15 years: 15 years of age: | 100 to 200 mg daily (5-10 ml liquid per day) 200 to 400 mg daily (10-20 ml liquid per day) 400 to 600 mg daily (20-30 ml liquid per day to be taken in divided doses) 600 to 1000 mg daily (30-50 ml liquid per day to be taken in several divided doses) 800 to 1200 mg daily (same as adult dose). |
Maximum recommended dose
| Up to 6 years of age: 6-15 years of age: >15 years of age: | 35 mg/kg/day 1000 mg/day 1200 mg/day. |
Wherever possible anti-epileptic agents should be prescribed as the sole drug anti-epileptic agent but if used in polytherapy, the same incremental dosage pattern is advised.
When Zigma 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 4.5 Interaction with other Medicaments and other forms of Interaction).
Trigeminal neuralgia
Slowly raise the initial dosage of 200-400 mg daily until freedom from pain is achieved (normally at 200 mg 3-4 times daily). In the majority of patients a dosage of 200 mg 3 or 4 times a day is sufficient to maintain a pain free state. In some instances, doses of 1600 mg Zigma daily may be needed. However, once the pain is in remission, the dosage should 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.
Elderly
Dosage in Trigeminal neuralgia
Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of Zigma 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.
For the prophylaxis of manic depressive psychosis in patients unresponsive to lithium therapy
Initial starting dose of 400 mg daily, in divided doses, increasing gradually until symptoms are controlled or a total of 1600 mg given in divided doses is reached. The usual dosage range is 400-600 mg daily, given in divided doses.
Special populations
Renal impairment / Hepatic impairment
No data are available on the pharmacokinetics of Zigma in patients with impaired hepatic or renal function.
Method of administration
Zigma oral suspension is given orally, usually in two or three divided doses. Zigma oral suspension (oral suspension should be shaken before use) may be taken during, after or between meals.
Zigma Liquid is given orally, usually in two or three divided doses.
Zigma Liquid (the liquid should be shaken before use) may be taken during, after or between meals.
Since a given dose of Zigma Liquid will produce higher peak levels than the same dose in tablet form, it is advisable to start with low doses of the liquid and to increase them slowly so as to avoid adverse effects on the central nervous system such as dizziness and lethargy.
When switching a patient from tablets to liquid the same overall dose may be used but in smaller, more frequent, doses.
Epilepsy:
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 warnings and precautions).
Adults: It is advised that with all formulations of Zigma, a gradually increasing dosage scheme is used and this should be adjusted to suit the needs of the individual patient.
Zigma should be taken in a number of divided doses although initially 100-200mg once to twice daily is recommended. This may be followed by a slow increase until the best response is obtained, often 800-1200mg daily. In some instances, 1600mg or even 2000mg daily may be necessary.
Elderly: Due to the potential for drug interactions, the dosage of Zigma should be selected with caution in elderly patients.
Children and adolescents: It is advised that with all formulations of Zigma, a gradually increasing dosage scheme is used and this should be adjusted to suit the needs of the individual patient.
Usual dosage 10-20mg/kg bodyweight daily in several divided doses.
| Age up to 1 year: | 100 to 200mg daily (5-10ml liquid per day). |
| 1-5 years: | 200 to 400mg daily (10-20ml liquid per day). |
| 5-10 years: | 400 to 600mg daily (20-30ml liquid per day to be taken in divided doses). |
| 10-15 years: | 600 to 1000mg daily (30-50ml liquid per day to be taken in several divided doses). |
| >15 years of age: | 800 to 1200mg daily (same as adult dose). |
Maximum recommended dose
Up to 6 years of age: 35mg/kg/day
6-15 years of age: 1000mg/day
>15 years of age: 1200mg/day.
Wherever possible anti-epileptic agents should be prescribed as the sole drug anti-epileptic agent but if used in polytherapy, the same incremental dosage pattern is advised.
When Zigma 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 4.5 Interaction with other Medicaments and other forms of Interaction).
Trigeminal neuralgia:
Slowly raise the initial dosage of 200-400mg daily until freedom from pain is achieved (normally at 200mg 3-4 times daily). In the majority of patients a dosage of 200mg 3 or 4 times a day is sufficient to maintain a pain free state. In some instances, doses of 1600mg Zigma daily may be needed. However, once the pain is in remission, the dosage should 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.
Elderly:
Dosage in Trigeminal neuralgia
Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of Zigma should be selected with caution in elderly patients.
In elderly patients, an initial dose of 100mg twice daily is recommended. The initial dosage of 100mg twice daily should be slowly raised daily until freedom from pain is achieved (normally at 200mg 3 to 4 times daily). The dosage should then be gradually reduced to the lowest possible maintenance level. Maximum recommended dose is 1200mg/day. When pain relief has been obtained, attempts should be made to gradually discontinue therapy, until another attack occurs.
For the prophylaxis of manic depressive psychosis in patients unresponsive to lithium therapy:
Initial starting dose of 400mg daily, in divided doses, increasing gradually until symptoms are controlled or a total of 1600mg given in divided doses is reached. The usual dosage range is 400-600mg daily, given in divided doses.
Special populations
Renal impairment / Hepatic impairment
No data are available on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal function.
- patients with atrioventricular block, a history of bone marrow depression or a history of hepatic porphyria (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda)
Known hypersensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants) or any other component of the formulation.
Patients with atrioventricular block, a history of bone marrow depression or a history of hepatic porphyrias (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda).
Warnings
Agranulocytosis and aplastic anaemia have been associated with Zigma; however, due to the very low incidence of these conditions, meaningful risk estimates for Zigma 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 anaemia.
Decreased platelet or white blood cell counts occur occasionally to frequently in association with the use of Zigma. Nonetheless, complete pre-treatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline, and periodically thereafter.
Patients and their relatives should be made aware of early toxic signs and symptoms indicative of a potential haematological 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 his physician immediately.
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. However, treatment with Zigma should be discontinued if the patient develops leukopenia which is severe, progressive or accompanied by clinical manifestations, e.g. fever or sore throat. Zigma should also be discontinued if any evidence of significant bone marrow depression appears.
Liver function tests should also be performed before commencing treatment and periodically thereafter, 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 acute liver disease.
Some liver function tests in patients receiving Zigma may be found to be abnormal, particularly gamma glutamyl transferase. This is probably due to hepatic enzyme induction. Enzyme induction may also produce modest elevations in alkaline phosphatase. These enhancements of hepatic metabolising capacity are not an indication for the withdrawal of Zigma.
Severe hepatic reactions to Zigma occur very rarely. The development of signs and symptoms of liver dysfunction or active liver disease should be urgently evaluated and treatment with Zigma suspended pending the outcome of the evaluation.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Zigma.
Therefore patients should be monitored for signs of suicidal ideation and behaviours 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.
Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN: also known as Lyell's syndrome) have been reported very rarely with Zigma. 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 with Zigma. 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, Zigma should be withdrawn at once and alternative therapy should be considered.
Cutaneous reactions
Serious and sometimes fatal cutaneous reactions including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been reported during treatment with Zigma. These reactions are estimated to occur in 1-6 per 10 000 new users in countries with mainly Caucasian populations, but the risk in some Asian countries is estimated to be about 10 times higher.
There is growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated adverse reactions.
HLA-B*1502 allele - in Han Chinese, Thai and other Asian populations
HLA-B*1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing Stevens-Johnson syndrome (SJS) when treated with Zigma. The prevalence of HLA-B*1502 carrier is about 10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screened for this allele before starting treatment with Zigma. If these individuals test positive, Zigma should not be started unless there is no other therapeutic option. Tested patients who are found to be negative for HLA-B*1502 have a low risk of SJS, although the reactions may still very rarely occur.
There are some data that suggest an increased risk of serious Zigma-associated TEN/SJS in other Asian populations. Because of the prevalence of this allele in other Asian populations (e.g. above 15% in the Philippines and Malaysia), testing genetically at risk populations for the presence of HLA-B*1502 may be considered.
The prevalence of the HLA-B*1502 allele is negligible in e.g. European descent, African, Hispanic populations sampled, and in Japanese and Koreans (< 1%).
HLA-A*3101 allele - European descent and Japanese populations
There are some data that suggest HLA-A*3101 is associated with an increased risk of Zigma induced cutaneous adverse drug reactions including SJS, TEN, Drug rash with eosinophilia (DRESS), or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash in people of European descent and the Japanese.
The frequency of the HLA-A*3101 allele varies widely between ethnic populations. HLA-A*3101 allele has a prevalence of 2 to 5% in European populations and about 10% in Japanese population.
The presence of HLA-A*3101 allele may increase the risk for Zigma induced cutaneous reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of Northern European ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%.
There are insufficient data supporting a recommendation for HLA-A*3101 screening before starting Zigma treatment.
If patients of European descent or Japanese origin are known to be positive for HLA-A*3101 allele, the use of Zigma may be considered if the benefits are thought to exceed risks.
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-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from Zigma, such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption).
Hypersensitivity
Zigma may trigger hypersensitivity reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), reactivation of HHV6 associated with DRESS, a delayed multi-organ hypersensitivity disorder with fever, rash, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leukopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts), that may occur in various combinations.
In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Zigma should be withdrawn immediately.
Patients who have exhibited hypersensitivity reactions to Zigma should be informed that 25-30% of these patients may experience hypersensitivity reactions with oxacarbazepine (Trileptal).
Cross-hypersensitivity can occur between Zigma and phenytoin.
Zigma should be used with caution in patients with mixed seizures which include absences, either typical or atypical. In all these conditions, Zigma may exacerbate seizures. In case of exacerbation of seizures, Zigma should be discontinued.
An increase in seizure frequency may occur during switchover from an oral formulation to suppositories.
Dose reduction and withdrawal effects
Abrupt withdrawal of Zigma may precipitate seizures therefore Zigma withdrawal should be gradual. If treatment with Zigma has to be withdrawn abruptly in a patient with epilepsy, the changeover to another anti-epileptic drug should if necessary be effected under the cover of a suitable drug.
Endocrinological effects
Breakthrough bleeding has been reported in women taking Zigma while using hormonal contraceptives. The reliability of hormonal contraceptives may be adversely affected by Zigma and women of childbearing potential should be advised to consider using alternative forms of birth control while taking Zigma.
Patients taking Zigma and requiring hormonal contraception should receive a preparation containing not less than 50 µg oestrogen or use of some alternative non-hormonal method of contraception should be considered.
Monitoring of plasma levels
Although correlations between dosages and plasma levels of Zigma, and between plasma levels and clinical efficacy or tolerability are rather tenuous, monitoring of the plasma levels may be useful in the following conditions: 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
Warnings
Agranulocytosis and aplastic anaemia have been associated with Zigma; however, due to the very low incidence of these conditions, meaningful risk estimates for Zigma 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 anaemia.
Decreased platelet or white blood cell counts occur occasionally to frequently in association with the use of Zigma. Nonetheless, complete pre-treatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline, and periodically thereafter.
Patients and their relatives should be made aware of early toxic signs and symptoms indicative of a potential haematological 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 his physician immediately.
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. However, treatment with Zigma should be discontinued if the patient develops leucopenia which is severe, progressive or accompanied by clinical manifestations, e.g. fever or sore throat. Zigma should also be discontinued if any evidence of significant bone marrow depression appears.
Liver function tests should also be performed before commencing treatment and periodically thereafter, 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 acute liver disease.
Some liver function tests in patients receiving carbamazepine may be found to be abnormal, particularly gamma glutamyl transferase. This is probably due to hepatic enzyme induction. Enzyme induction may also produce modest elevations in alkaline phosphatase. These enhancements of hepatic metabolising capacity are not an indication for the withdrawal of carbamazepine.
Severe hepatic reactions to carbamazepine occur very rarely. The development of signs and symptoms of liver dysfunction or active liver disease should be urgently evaluated and treatment with Zigma suspended pending the outcome of the evaluation.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for carbamazepine.
Therefore patients should be monitored for signs of suicidal ideation and behaviours 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.
Serious dermatological reactions, including toxic epidermal necrolysis (TEN: also known as Lyell's syndrome) and Stevens Johnson syndrome (SJS) have been reported very rarely with Zigma. 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 with Zigma. 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, Zigma should be withdrawn at once and alternative therapy should be considered.
Cutaneous reactions
Serious and sometimes fatal cutaneous reactions including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been reported during treatment with carbamazepine. These reactions are estimated to occur in 1-6 per 10 000 new users in countries with mainly Caucasian populations, but the risk in some Asian countries is estimated to be about 10 times higher.
There is growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated adverse reactions.
HLA-B*1502 allele - in Han Chinese, Thai and other Asian populations
HLA-B*1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing Stevens-Johnson syndrome (SJS) when treated with carbamazepine. The prevalence of HLA-B*1502 carrier is about 10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screened for this allele before starting treatment with carbamazepine. If these individuals test positive, carbamazepine should not be started unless there is no other therapeutic option. Tested patients who are found to be negative for HLA-B*1502 have a low risk of SJS, although the reactions may still very rarely occur.
There are some data that suggest an increased risk of serious carbamazepine-associated TEN/SJS in other Asian populations. Because of the prevalence of this allele in other Asian populations (e.g. above 15% in the Philippines and Malaysia), testing genetically at risk populations for the presence of HLA-B*1502 may be considered.
The prevalence of the HLA-B*1502 allele is negligible in e.g. European descent, African, Hispanic populations sampled, and in Japanese and Koreans (< 1%).
HLA-A*3101 allele - European descent and Japanese populations
There are some data that suggest HLA-A*3101 is associated with an increased risk of carbamazepine induced cutaneous adverse drug reactions including SJS, TEN, Drug rash with eosinophilia (DRESS), or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash in people of European descent and the Japanese.
The frequency of the HLA-A*3101 allele varies widely between ethnic populations. HLA-A*3101 allele has a prevalence of 2 to 5% in European populations and about 10% in Japanese population.
The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of Northern European ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%.
There are insufficient data supporting a recommendation for HLA-A*3101 screening before starting carbamazepine treatment.
If patients of European descent or Japanese origin are known to be positive for HLA-A*3101 allele, the use of carbamazepine may be considered if the benefits are thought to exceed risks.
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-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).
Hypersensitivity
Zigma may trigger hypersensitivity reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), reactivation of HHV6 associated with DRESS, a delayed multi-organ hypersensitivity disorder with fever, rash, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leukopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts), that may occur in various combinations.
In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Zigma should be withdrawn immediately.
Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that 25-30 % of these patients may experience hypersensitivity reactions with oxacarbazepine (Trileptal).
Cross-hypersensitivity can occur between carbamazepine and phenytoin.
Zigma should be used with caution in patients with mixed seizures which include absences, either typical or atypical. In all these conditions, Zigma may exacerbate seizures. In case of exacerbation of seizures, Zigma should be discontinued.
An increase in seizure frequency may occur during switchover from an oral formulation to suppositories.
Zigma liquid 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.
Dose reduction and withdrawal effects:
Abrupt withdrawal of Zigma may precipitate seizures therefore carbamazepine withdrawal should be gradual. If treatment with Zigma has to be withdrawn abruptly in a patient with epilepsy, the changeover to another anti-epileptic drug should if necessary be effected under the cover of a suitable drug.
Endocrinological effects
Breakthrough bleeding has been reported in women taking Zigma while using hormonal contraceptives. The reliability of hormonal contraceptives may be adversely affected by Zigma and women of childbearing potential should be advised to consider using alternative forms of birth control while taking Zigma.
Patients taking Zigma and requiring hormonal contraception should receive a preparation containing not less than 50µg oestrogen or use of some alternative non-hormonal method of contraception should be considered.
Monitoring of plasma levels
Although correlations between dosages 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 conditions: 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
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 reported with Zigma, 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.
Summary of the safety profile
Particularly at the start of treatment with Zigma, 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), as well as 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 the plasma levels and divide the daily dosage into smaller (i.e. 3-4) fractional doses.
Tabulated summary of adverse drug reactions compiled from clinical trials and from spontaneous reports
Adverse drug reactions from clinical trials 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, <1/10), uncommon (>1/1.000, <1/100), rare (>1/10.000, </1.000), very rare (<1/10.000), not known (cannot be estimated from the available data).
| Infections and infestations | |
| Not known**: | reactivation of Human herpesvirus 6 infection |
| Blood and lymphatic system disorders | |
Very common: | leukopenia |
| Common: | thrombocytopenia, eosinophilia |
Rare: | leucocytosis, lymphadenopathy |
Very rare: | agranulocytosis, aplastic anaemia, pancytopenia, aplasia pure red cell, anaemia, anaemia megaloblastic, reticulocytosis, haemolytic anaemia |
| Not known: | bone marrow depression |
| Immune system disorders | |
Rare: | a delayed multi-organ hypersensitivity disorder with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leukopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts) occurring in various combinations. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas, myocardium, colon) |
| Very rare: | anaphylactic reaction, oedema angioedema, hypogammaglobinaemia |
| Not known**: | Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) |
| Endocrine disorders | |
| Common: | oedema, fluid retention, weight increase, hyponatraemia and blood osmolarity decreased due to an antidiuretic hormone (ADH)-like effect, leading in rare cases to water intoxication accompanied by lethargy, vomiting, headache, confusional state, neurological disorders |
| Very rare: | gynaecomastia, galactorrhoea |
| Metabolism and nutrition disorders | |
| Rare: | folate deficiency, decreased appetite |
| Very rare: | porphyria acute (acute intermittent porphyria and variegate porphyria), porphyria non-acute (porphyria cutanea tarda) |
| Psychiatric disorders | |
Rare: | hallucinations (visual or auditory), depression, aggression, agitation, restlessness, confusional state |
Very rare: | activation of psychosis |
| Nervous system disorders | |
| Very common: | ataxia, dizziness, somnolence |
| Common: | diplopia, headache |
| Uncommon: | abnormal involuntary movements (e.g. tremor, asterixis, dystonia, tics), nystagmus |
Rare: | dyskinesia, eye movementdisorder, speech disorders (e.g. dysarthria or slurred speech), choreoathetosis, neuropathy peripheral, paraesthesia, and paresis |
| Very rare: | neuroleptic malignant syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia |
| Not known**: | sedation, memory impairment |
| Eye disorders | |
Common: | accommodation disorders (e.g. blurred vision) |
| Very rare: | lenticular opacities, conjunctivitis |
| Ear and labyrinth disorders | |
Very rare: | hearing disorders, e.g. tinnitus, hyperacusis, hypoacusis, change in pitch perception |
| Cardiac disorders | |
| Rare: | cardiac conduction disorders |
| Very rare: | arrhythmia, atrioventricular block with syncope, bradycardia, cardiac failure congestive, coronary artery disease aggravated |
| Vascular disorders | |
Rare: | hypertension or hypotension |
Very rare: | circulatory collapse, embolism (e.g. pulmonary embolism), thrombophlebitis |
| Respiratory, thoracic and mediastinal disorders | |
| Very rare: | pulmonary hypersensitivity characterised e.g. by fever, dyspnoea, pneumonitis or pneumonia |
| Gastro-intestinal disorders | |
Very common: | nausea, vomiting |
| Common: | dry mouth, with suppositories rectal irritation may occur |
Uncommon: | diarrhoea, constipation |
| Rare: | abdominal pain |
| Very rare: | pancreatitis, glossitis, stomatitis |
| Not known**: | colitis |
| Hepatobiliary disorders | |
Rare: | hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, vanishing bile duct syndrome, jaundice |
Very rare: | hepatic failure, granulomatous liver disease |
| Skin and subcutaneous tissue disorders | |
| Very common: | urticaria, which may be severe dermatitus allergic |
| Uncommon: | dermatitis exfoliative |
| Rare: | systemic lupus erythematosus, pruritus |
| Very rare: | Stevens-Johnson syndrome*, toxic epidermal necrolysis, photosensitivity reaction, erythema multiforme, erythema nodosum, pigmentation disorder, purpura, acne, hyperhydrosis, alopecia, hirsutism. |
| Not known**: | acute generalized exanthematous pustulosis (AGEP)**, lichenoid keratosis, onychomadesis |
| Musculoskeletal, connective tissue and bone disorders | |
| Rare: | muscular weakness |
| Very rare: | bone metabolism disorders (decrease in plasma calcium and blood 25-hydroxy-cholecalciferol) leading to osteomalacia/osteoporosis, arthralgia, myalgia, muscle spasms |
| Not know**: | fracture |
| Renal and urinary disorders | |
| Very rare: | tubulointerstitial nephritis, renal failure, renal impairment (e.g. albuminuria, haematuria, oliguria and blood urea/azotaemia), urinary retention, urinary frequency |
| Reproductive system | |
| Very rare: | sexual disturbances/erecticle dysfunction spermatogenesis abnormal (with decreased sperm count and/or motility) |
| General disorders and administration site conditions | |
| Very common: | fatigue |
| Investigations | |
| Very common: | gamma-glutamyltransferase increased (due to hepatic enzyme induction), usually not clinically relevant |
| Common: | blood alkaline phosphatase increased |
Uncommon: | transaminases increased |
| Very rare: | intraocular pressure increased, blood cholesterol increased, high density lipoprotein increased, blood triglycerides increased. Thyroid function test abnormal: decreased L-Thyroxin (free thyroxine, thyroxine, tri-iodothyronine) and increased blood thyroid stimulating hormone, usually without clinical manifestations, blood prolactin increased |
| Not known**: | bone density decreased. |
*In some Asian countries also reported as rare.
**Additional adverse drug reactions from spontaneous reports (frequency not known)
The following adverse drug reactions have been derived from post-marketing experience with Zigma 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.
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with Zigma. The mechanism by which Zigma affects bone metabolism has not been identified.
There is increasing evidence regarding the association of genetic markers and the occurrence of cutaneous ADRs such as SJS, TEN, DRESS, AGEP and maculopapular rash.4 for further information).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Summary of the safety profile
Particularly at the start of treatment with Zigma, 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), as well as 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 the plasma levels and divide the daily dosage into smaller (i.e. 3-4) fractional doses.
Tabulated summary of adverse drug reactions compiled from clinical trials and from spontaneous reports
Adverse drug reactions from clinical trials 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).
| Blood and lymphatic system disorders | |
| Very common: Common: Rare: Very rare: Not known: | leucopenia. thrombocytopenia, eosinophilia. leucocytosis, lymphadenopathy. agranulocytosis, aplastic anaemia, pancytopenia, aplasia pure red cell, anaemia, anaemia megaloblastic, reticulocytosis, haemolytic anaemia. bone marrow depression. |
| Immune system disorders |
|
| Rare:
Very rare: Not known**: | a delayed multi-organ hypersensitivity disorder with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leucopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts) occurring in various combinations. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas, myocardium, colon). anaphylactic reaction, oedema angioedema, hypogammaglobulinaemia. Drug Rash with Eosinophilia and Systemic Symptoms (DRESS). |
| Infections and infestations | |
| Not known**: | reactivation of Human herpesvirus 6 infection. |
| Endocrine disorders |
|
| Common: Very rare: | Oedema, fluid retention, weight increase, hyponatraemia and blood osmolarity decreased due to an antidiuretic hormone (ADH)-like effect, leading in rare cases to water intoxication accompanied by lethargy, vomiting, headache, confusional state, neurological disorders. galactorrhoea, gynaecomastia. |
| Metabolism and nutrition disorders | |
| Rare: Very rare: | folate deficiency, decreased appetite. porphyria acute (acute intermittent porphyria and variegate porphyria), porphyria non-acute (porphyria cutanea tarda). |
| Psychiatric disorders |
|
| Rare: Very rare: | hallucinations (visual or auditory), depression, aggression, agitation, restlessness, confusional state. activation of psychosis. |
| Nervous system disorders |
|
| Very common: Common: Uncommon: Rare: Very rare: Not known**: | ataxia, dizziness, somnolence. diplopia, headache. abnormal involuntary movements (e.g. tremor, asterixis, dystonia, tics), nystagmus. dyskinesia, eye movementdisorder, speech disorders (e.g. dysarthria or slurred speech), choreoathetosis, neuropathy peripheral, paraesthesia, and paresis. neuroleptic malignant syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia. sedation, memory impairment. |
| Eye disorders |
|
| Common: Very rare: | accommodation disorders (e.g. blurred vision) lenticular opacities, conjunctivitis. |
| Ear and labyrinth disorders |
|
| Very rare: | hearing disorders, e.g. tinnitus, hyperacusis, hypoacusis, change in pitch perception. |
| Cardiac disorders |
|
| Rare: Very rare: | cardiac conduction disorders. arrhythmia, atrioventricular block with syncope, bradycardia, cardiac failure congestive, coronary artery disease aggravated. |
| Vascular disorders | |
| Rare: Very Rare: | hypertension or hypotension. circulatory collapse, embolism (e.g. pulmonary embolism), thrombophlebitis. |
| Respiratory, thoracic and mediastinal disorders |
|
| Very rare:
| pulmonary hypersensitivity characterised e.g. by fever, dyspnoea, pneumonitis or pneumonia. |
| Gastro-intestinal disorders |
|
| Very common: Common: Uncommon: Rare: Very rare: Not known**: | vomiting, nausea. dry mouth, with suppositories rectal irritation may occur. diarrhoea, constipation. abdominal pain. Pancreatitis, glossitis, stomatitis. colitis. |
| Hepatobiliary disorders |
|
| Rare: Very rare: | hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, vanishing bile duct syndrome, jaundice. hepatic failure, granulomatous liver disease. |
| Skin and subcutaneous tissue disorders: |
|
| Very common: Uncommon: Rare: Very rare: Not known**: | urticaria, which may be severe dermatitus allergic,. dermatitis exfoliative. systemic lupus erythematosus, pruritus. Stevens-Johnson syndrome*, toxic epidermal necrolysis, photosensitivity reaction, erythema multiforme, erythema nodosum, pigmentation disorder, purpura, acne, hyperhydrosis, alopecia, hirsutism. Acute Generalized Exanthematous Pustulosis (AGEP)**, lichenoid keratosis, onychomadesis. |
| Musculoskeletal, connective tissue and bone disorders | |
| Rare: Very rare:
Not known**: | muscular weakness. bone metabolism disorders (decrease in plasma calcium and blood 25-hydroxy-cholecalciferol) leading to osteomalacia/osteoporosis, arthralgia, myalgia, muscle spasms. fracture. |
| Renal and urinary disorders |
|
| Very rare: | tubulointerstitial nephritis, renal failure, renal impairment (e.g. albuminuria, haematuria, oliguria and blood urea/ azotaemia), urinary retention, urinary frequency. |
| Reproductive System |
|
| Very rare: | sexual disturbances/erecticle dysfunction spermatogenesis abnormal (with decreased sperm count and/or motility). |
| General disorders and administration site conditions | |
| Very common: | fatigue. |
| Investigations |
|
| Very common: Common: Uncommon: Very rare:
Not known**: | gamma-glutamyltransferase increased (due to hepatic enzyme induction), usually not clinically relevant. blood alkaline phosphatase increased. transaminases increased. intraocular pressure increased, blood cholesterol increased, high density lipoprotein increased, blood triglycerides increased. Thyroid function test abnormal: decreased L-Thyroxin (free thyroxine, thyroxine, tri-iodothyronine) and increased blood thyroid stimulating hormone, usually without clinical manifestations, blood prolactin increased, bone density decreased. |
**Additional adverse drug reactions from spontaneous reports (frequency not known)
The following adverse drug reactions have been derived from post-marketing experience with Zigma 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.
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with carbamazepine. The mechanism by which carbamazepine affects bone metabolism has not been identified.
There is increasing evidence regarding the association of genetic markers and the occurrence of cutaneous ADRs such as SJS, TEN, DRESS, AGEP and maculopapular rash.4 for further information).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Signs and symptoms
Central nervous system: CNS depression; disorientation, depressed level of consciousness, somnolence, agitation, hallucination, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, initially hyperreflexia, later hyporeflexia; convulsions, psychomotor disturbances, myoclonus, hypothermia, mydriasis.
Respiratory system: Respiratory depression, pulmonary oedema.
Cardiovascular system: Tachycardia, hypotension and at times hypertension, conduction disturbance with widening of QRS complex; syncope in association with cardiac arrest.
Gastro-intestinal system: Vomiting, delayed gastric emptying, reduced bowel motility.
Musculoskeletal system: There have been some cases which reported rhabdomyolysis in association with Zigma toxicity.
Renal function: Retention of urine, oliguria or anuria; fluid retention, water intoxication due to ADH-like effect of Zigma.
Laboratory findings: Hyponatraemia, possibly metabolic acidosis, possibly hyperglycaemia, increased muscle creatine phosphokinase.
Treatment
There is no specific antidote.
Management should initially be guided by the patient's clinical condition; admission to hospital. Measurement of the plasma level to confirm Zigma poisoning and to ascertain the size of the overdose.
Evacuation of the stomach, gastric lavage, and administration of activated charcoal. Delay in evacuating the stomach may result in delayed absorption, leading to relapse during recovery from intoxication. Supportive medical care in an intensive care unit with cardiac monitoring and careful correction of electrolyte imbalance.
Special recommendations
Charcoal haemoperfusion has been recommended. Hemodialysis is the effective treatment modality in the management of the Zigma overdose.
Relapse and aggravation of symptomatology on the 2nd and 3rd day after overdose, due to delayed absorption, should be anticipated.
Signs and symptoms
<Central nervous system: CNS depression; disorientation, depressed level of consciousness, somnolence, agitation, hallucination, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, initially hyperreflexia, later hyporeflexia; convulsions, psychomotor disturbances, myoclonus, hypothermia, mydriasis.
Respiratory system: Respiratory depression, pulmonary oedema.
Cardiovascular system: Tachycardia, hypotension and at times hypertension, conduction disturbance with widening of QRS complex; syncope in association with cardiac arrest.
Gastro-intestinal system: Vomiting, delayed gastric emptying, reduced bowel motility.
Musculoskeletal system: There have been some cases which reported rhabdomyolysis in association with carbamazepine toxicity.
Renal function: Retention of urine, oliguria or anuria; fluid retention, water intoxication due to ADH-like effect of carbamazepine.
Laboratory findings: Hyponatraemia, possibly metabolic acidosis, possibly hyperglycaemia, increased muscle creatine phosphokinase.
Treatment
There is no specific antidote.
Management should initially be guided by the patient's clinical condition; admission to hospital.
Measurement of the plasma level to confirm carbamazepine poisoning and to ascertain the size of the overdose.
Evacuation of the stomach, gastric lavage, and administration of activated charcoal. Delay in evacuating the stomach may result in delayed absorption, leading to relapse during recovery from intoxication. Supportive medical care in an intensive care unit with cardiac monitoring and careful correction of electrolyte imbalance.
Special recommendations:
Charcoal haemoperfusion has been recommended. Hemodialysis is the effective treatment modality in the management of the carbamazepine overdose.
Relapse and aggravation of symptomatology on the 2nd and 3rd day after overdose, due to delayed absorption, should be anticipated.
Pharmacotherapeutic group: Anti-epileptic, neurotropic and psychotropic agent; ATC Code: N03A FO1. Dibenzazepine derivative.
As an antiepileptic agent its spectrum of activity embraces: partial seizures (simple and complex) with and without secondary generalisation; generalised tonic-clonic seizures, as well as combinations of these types of seizures.
The mechanism of action of Zigma, the active substance of Zigma, has only been partially elucidated. Zigma stabilises hyperexcited nerve membranes, inhibits repetitive neuronal discharges, and reduces synaptic propagation of excitatory impulses. It is conceivable that prevention of repetitive firing of sodium-dependent action potentials in depolarised neurons via use- and voltage-dependent blockade of sodium channels may be its main mechanism of action.
Whereas reduction of glutamate release and stabilisation of neuronal membranes may account for the antiepileptic effects, the depressant effect on dopamine and noradrenaline turnover could be responsible for the antimanic properties of Zigma.
Therapeutic class: Anti-epileptic, neurotropic and psychotropic agent; (ATC Code: N03 AF01). Dibenzazepine derivative.
As an antiepileptic agent its spectrum of activity embraces: partial seizures (simple and complex) with and without secondary generalisation; generalised tonic-clonic seizures, as well as combinations of these types of seizures.
The mechanism of action of carbamazepine, the active substance of Zigma, has only been partially elucidated. Carbamazepine stabilises hyperexcited nerve membranes, inhibits repetitive neuronal discharges, and reduces synaptic propagation of excitatory impulses. It is conceivable that prevention of repetitive firing of sodium-dependent action potentials in depolarised neurons via use- and voltage-dependent blockade of sodium channels may be its main mechanism of action.
Whereas reduction of glutamate release and stabilisation of neuronal membranes may account for the antiepileptic effects, the depressant effect on dopamine and noradrenaline turnover could be responsible for the antimanic properties of carbamazepine.
Absorption
Zigma is absorbed almost completely but relatively slowly from the tablets. The conventional tablets yield mean peak plasma concentrations of the unchanged substance within 12 hours (liquid 2 hours) following single oral doses. With respect to the amount of active substance absorbed, there is no clinically relevant difference between the oral dosage forms. After a single oral dose of 400 mg Zigma (tablets) the mean peak concentration of unchanged Zigma in the plasma is approx. 4.5μg/ml.
The bioavailability of Zigma in various oral formulations has been shown to lie between 85-100%.
Ingestion of food has no significant influence on the rate and extent of absorption, regardless of the dosage form of Zigma.
Steady-state plasma concentrations of Zigma are attained within about 1-2 weeks, depending individually upon auto-induction by Zigma and hetero-induction by other enzyme-inducing drugs, as well as on pre-treatment status, dosage, and duration of treatment.
Different preparations of Zigma may vary in bioavailability; to avoid reduced effect or risk of breakthrough seizures or excessive side effects, it may be prudent to avoid changing the formulation.
Distribution
Zigma is bound to serum proteins to the extent of 70-80%. The concentration of unchanged substance in cerebrospinal fluid and saliva reflects the non-protein bound portion in plasma (20-30%). Concentrations in breast milk were found to be equivalent to 25-60% of the corresponding plasma levels.
Zigma crosses the placental barrier. Assuming complete absorption of Zigma, the apparent volume of distribution ranges from 0.8 to 1.9 l/kg.
Biotransformation
Zigma is metabolised in the liver, where the epoxide pathway of biotransformation is the most important one, yielding the 10, 11-transdiol derivative and its glucuronide as the main metabolites.
Cytochrome P450 3A4 has been identified as the major isoform responsible for the formation of Zigma 10, 11-epoxide from Zigma. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from Zigma-10,11 epoxide. 9-Hydroxy-methyl-
10-carbamoyl acridan is a minor metabolite related to this pathway. After a single oral dose of Zigma about 30% appears in the urine as end-products of the epoxide pathway.
Other important biotransformation pathways for Zigma lead to various monohydroxylated compounds, as well as to the N-glucuronide of Zigma produced by UGT2B7.
Elimination
The elimination half-life of unchanged Zigma averages approx. 36 hours following a single oral dose, whereas after repeated administration it averages only 16-24 hours (auto-induction of the hepatic mono-oxygenase system), depending on the duration of the medication. In patients receiving concomitant treatment with other enzyme-inducing drugs (e.g. phenytoin, phenobarbitone), half-life values averaging 9-10 hours have been found.
The mean elimination half-life of the 10, 11-epoxide metabolite in the plasma is about 6 hours following single oral doses of the epoxide itself.
After administration of a single oral dose of 400 mg Zigma, 72% is excreted in the urine and 28% in the faeces. In the urine, about 2% of the dose is recovered as unchanged drug and about 1% as the pharmacologically active 10, 11-epoxide metabolite.
Characteristics in patients
The steady-state plasma concentrations of Zigma considered as “therapeutic range†vary considerably inter-individually; for the majority of patients a range between 4-12 μg/ml corresponding to 17-50 μmol/l has been reported. Concentrations of Zigma 10, 11-epoxide (pharmacologically active metabolite): about 30% of Zigma levels.
Owing to enhanced Zigma elimination, children may require higher doses of Zigma (in mg/kg) than adults to maintain therapeutic concentrations.
There is no indication of altered pharmacokinetics of Zigma in elderly patients as compared with young adults.
No data are available on the pharmacokinetics of Zigma in patients with impaired hepatic or renal function.
Absorption
Carbamazepine is absorbed almost completely but relatively slowly from the tablets. The conventional tablets yield mean peak plasma concentrations of the unchanged substance within 12 hours (liquid 2 hours) following single oral doses. With respect to the amount of active substance absorbed, there is no clinically relevant difference between the oral dosage forms. After a single oral dose of 400mg carbamazepine (tablets) the mean peak concentration of unchanged carbamazepine in the plasma is approx. 4.5µg/ml.
The bioavailability of Zigma in various oral formulations has been shown to lie between 85-100%.
Ingestion of food has no significant influence on the rate and extent of absorption, regardless of the dosage form of Zigma.
Steady-state plasma concentrations of carbamazepine are attained within about 1-2 weeks, depending individually upon auto-induction by carbamazepine and hetero-induction by other enzyme-inducing drugs, as well as on pre-treatment status, dosage, and duration of treatment.
Different preparations of carbamazepine may vary in bioavailability; to avoid reduced effect or risk of breakthrough seizures or excessive side effects, it may be prudent to avoid changing the formulation.
Distribution
Carbamazepine is bound to serum proteins to the extent of 70-80%. The concentration of unchanged substance in cerebrospinal fluid and saliva reflects the non-protein bound portion in plasma (20-30%). Concentrations in breast milk were found to be equivalent to 25-60% of the corresponding plasma levels.
Carbamazepine crosses the placental barrier. Assuming complete absorption of carbamazepine, the apparent volume of distribution ranges from 0.8 to 1.9 L/kg.
Biotransformation
Carbamazepine is metabolised in the liver, where the epoxide pathway of biotransformation is the most important one, yielding the 10, 11-transdiol derivative and its glucuronide as the main metabolites.
Cytochrome P450 3A4 has been identified as the major isoform responsible for the formation of carbamazepine 10, 11-epoxide from carbamazepine. 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. 9-Hydroxy-methyl-10-carbamoyl acridan is a minor metabolite related to this pathway. After a single oral dose of carbamazepine about 30% appears in the urine as end-products of the epoxide pathway.
Other important biotransformation pathways for carbamazepine lead to various monohydroxylated compounds, as well as to the N-glucuronide of carbamazepine produced by UGT2B7.
Elimination
The elimination half-life of unchanged carbamazepine averages approx. 36 hours following a single oral dose, whereas after repeated administration it averages only 16-24 hours (auto-induction of the hepatic mono-oxygenase system), depending on the duration of the medication. In patients receiving concomitant treatment with other enzyme-inducing drugs (e.g. phenytoin, phenobarbitone), half-life values averaging 9-10 hours have been found.
The mean elimination half-life of the 10, 11-epoxide metabolite in the plasma is about 6 hours following single oral doses of the epoxide itself.
After administration of a single oral dose of 400mg carbamazepine, 72% is excreted in the urine and 28% in the faeces. In the urine, about 2% of the dose is recovered as unchanged drug and about 1% as the pharmacologically active 10, 11-epoxide metabolite.
Characteristics in patients
The steady-state plasma concentrations of carbamazepine considered as “therapeutic range†vary considerably inter-individually; for the majority of patients a range between 4-12µg/ml corresponding to 17-50µmol/l has been reported. Concentrations of carbamazepine 10, 11-epoxide (pharmacologically active metabolite): about 30% of carbamazepine levels.
Owing to enhanced carbamazepine elimination, children may require higher doses of carbamazepine (in mg/kg) than adults to maintain therapeutic concentrations.
There is no indication of altered pharmacokinetics of carbamazepine in elderly patients as compared with young adults.
No data are available on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal function.
Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, local tolerance, genotoxicity and carcinogenic potential. Reproductive toxicity studies in animals were insufficient to rule out a teratogenic effect of Zigma in humans.
Carcinogenicity
In rats treated with Zigma for two years, there was an increased incidence of hepatocellular tumours in females and benign testicular tumours in males. However, there is no evidence to date that these observations are of any relevance to the therapeutic use of Zigma in humans.
Reproductive toxicity
In animals studies in mice, rats and rabbits oral administration of Zigma during organogenesis led to increased embryo-fetal mortality and fetal growth retardation at daily doses which were associated with maternal toxicity (above 200 mg/kg/day). Zigma was teratogenic in a number of studies, particularly in mice, however showed no or only minor teratogenic potential at doses relevant to humans. In a reproduction study in rats, nursing offspring demonstrated a reduced weight gain at a maternal dosage level of 192 mg/kg/day.
Fertility
In chronic toxicity studies dose related testicular atrophy and aspermatogenesis occurred in rats receiving Zigma. The safety margin for this effect is not known.
Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, local tolerance, genotoxicity and carcinogenic potential. Reproductive toxicity studies in animals were insufficient to rule out a teratogenic effect of carbamazepine in humans.
Carcinogenicity
In rats treated with carbamazepine for two years, there was an increased incidence of hepatocellular tumours in females and benign testicular tumours in males. However, there is no evidence to date that these observations are of any relevance to the therapeutic use of carbamazepine in humans.
Reproductive toxicity
In animals studies in mice, rats and rabbits oral administration of carbamazepine during organogenesis led to increased embryo-fetal mortality and fetal growth retardation at daily doses which were associated with maternal toxicity (above 200mg/kg/day). Carbamazepine was teratogenic in a number of studies, particularly in mice, however showed no or only minor teratogenic potential at doses relevant to humans. In a reproduction study in rats, nursing offspring demonstrated a reduced weight gain at a maternal dosage level of 192 mg/kg/day.
Fertility
In chronic toxicity studies dose related testicular atrophy and aspermatogenesis occurred in rats receiving carbamazepine. The safety margin for this effect is not known.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
None known
No special requirements.
None
However, we will provide data for each active ingredient
