For medical use
active substance: carbamazepin;
1 tablet contains 400 mg of carbamazepin;
excipients:microcrystalline cellulose, hypromellose, sodium laurylsulfat, povidon (PVP K 30), colloidal silicon dioxide, magnesium stearate.
Pharmaceutical form. Prolonged-action tablets.
Main physicochemical feature:white or nearly white, round, plano-cylinder tablets with “C400” pressing on one side and cruciformthe line on the other one.
Antiepileptic drugs. АТС CodeN03A F01.
As an antiepileptic agentMezacar® SR is effective at partial seizures (simple and complex) with and without secondary generalization; generalized tonic-clonic seizures, as well as combinations of these types of seizures. The mechanism of action of carbamazepine 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 blockade of sodium channels is 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 the drug.
Carbamazepine given as monotherapy to patients with epilepsy (in particular children and adolescents) has been reported to exert a psychotropic action, including a positive effect on symptoms of anxiety and depression as well as a decrease in irritability and aggressiveness. As regards cognitive and psychomotor performance, in some studies equivocal or negative effects, depending also upon dosages administered, were reported. In other studies, a beneficial effect of carbamazepine on attentiveness, cognitive performance/memory was observed.
As a neurotropic agent carbamazepine is effective in a number of neurological disorders, e.g. it prevents paroxysmal attacks of pain in idiopathic and secondary trigeminal neuralgia. In addition, the drug is used for the relief of neurogenic pain in a variety of conditions, including tabes dorsalis, post-traumatic paresthesia, and post-herpetic neuralgia. In alcohol-withdrawal syndrome it raises the convulsion threshold (that is lowered in this state) and improves such withdrawal symptoms, as hyperexcitability, tremor, impaired gait. In diabetes insipidus centralis, the drug reduces the urinary volume and relieves the feeling of thirst.
As a psychotropic agent the drug proved to have clinical efficacy in affective disorders, i.e. as treatment for acute mania as well as for maintenance treatment of (manic-depressive) bipolar affective disorders, (when given either as monotherapy or in combination with neuroleptics, antidepressants, or lithium).
Absorption.Carbamazepine is absorbed almost completely but relatively slowly from the tablets. After a single pill prolonged maximum plasma concentration (Cmax) is achieved in 24 hours. When using prolonged action tablets carbamazepine bioavailability of approximately 15% lower than with immediate-release tablets active ingredient. Bioavailability ranges from 85-100%. Ingestion of food has no significant influence on the rate and extent of carbamazepine absorption.
Steady-state plasma concentrations of carbamazepine are attained within about 1-2 weeks, depending individually upon specific metabolism (liver enzyme systems auto-induction by carbamazepine and hetero-induction by other drugs that are used simultaneously) as well as on pre-treatment status, dosage, and duration of treatment.
The steady-state plasma concentrations of carbamazepine considered as ‘therapeutic range’ vary considerably interindividually: for the majority of patients a range between 4 to 12 µg/ml (17 to 50 µmol/L) has been reported. Concentrations of carbamazepine-10,11-epoxide (pharmacologically active metabolite): about 30% of carbamazepine levels.
Distribution. Assuming complete absorption of carbamazepine, the apparent volume of distribution ranges from 0.8 to 1.9 L/kg. Carbamazepine crosses the placental barrier. Carbamazepine is bound to serum proteins to the extent of 70 to 80%. The concentration of unchanged carbamazepine in cerebrospinal fluid and saliva reflects the non-protein bound portion in the plasma (20 to 30%). Concentrations of carbamazepine in breast milk were found to be equivalent to 25 to 60% of the corresponding plasma levels.
Metabolism. Carbamazepine is metabolized in the liver, where the epoxide pathway 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 the pharmacologically active carbamazepine-10,11 epoxide from carbamazepine. 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 uridine diphosphate glucuronosyltransferase (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 400 mg carbamazepine, 72% is excreted in the urine and 28% in the feces. In the urine, about 2% of the dose is recovered as unchanged drug and about 1% as the pharmacologically active 10, 11-epoxide metabolite.
Pharmacokinetics in special populations.
Children. Owing to enhanced carbamazepine elimination, children may require higher doses of carbamazepine (in mg/kg of body weight) than adults to maintain therapeutic drug concentrations.
Elderly. There is no indication of altered pharmacokinetics of carbamazepine in elderly patients as compared with young adults.
Patients with hepatic or renal impairment.No data are available on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal function
complex or simple partial seizures (with or without loss of consciousness) with or without secondary generalization;
generalised tonic-clonic seizures;
mixed forms of seizures
Mezacar® SR is suitable for both monotherapy and combination therapy.
Acute mania; maintenance treatment of bipolar affective disorders to prevent or attenuate recurrence.
Idiopathic trigeminal neuralgia and trigeminal neuralgia in disseminated sclerosis (either typical and atypical).
Idiopathic glossopharyngeal neuralgia.
Hypersensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants) or any other component of the formulation;
A history of bone marrow depression;
A history of hepatic porphyrias (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda);
Combination with monoamine oxidase inhibitors (MAOIs).
Interaction with other medicinal products and other forms of interaction.
Cytochrome Р450 3А4 (CYP3A4) is the main enzyme catalyzing formation of the active metabolite carbamazepine-10,11-epoxide. Co-administration of inhibitors of CYP3A4 may result in increased carbamazepine plasma concentrations which could induce adverse reactions. Co-administration 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 comedications 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.
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 Mezacar®SR should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the drugs described below:
Analgesics, anti-inflammatory drugs: dextropropoxyphene, ibuprofen.
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 anti-convulsants may be recommended in patients treated with voriconazole or itraconazole.
Antihistamines: loratadine, terfenadine.
Antipsychotics: olanzapine, loxapine, quetiapine.
Antivirals: protease inhibitors for HIV treatment (e.g. ritonavir).
Carbonic anhydrase inhibitors: acetazolamide.
Cardiovascular drugs: diltiazem, verapamil.
Gastrointestinal drugs: cimetidine, omeprazole.
Muscle relaxants: oxybutynin, dantrolene.
Platelet aggregation inhibitors: ticlopidine.
Other interactions: grapefruit juice, nicotinamide (in adults, only in high dosage).
Agents that may raise the active metabolite carbamazepine-10,11-epoxide plasma levels.
Since raised plasma active metabolite carbamazepine-10,11-epoxide levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of Mezacar®SRshould be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described below: loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.
Agents that may decrease carbamazepine plasma levels.
The dose of Mezacar®SRmay have to be adjusted when used concomitantly with the substances described below.
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 μg/mL before adding carbamazepine to the treatment) and fosphenytoin, primidone, and, although the data are partly contradictory, possibly also clonazepam.
Antineoplastics: cisplatin or doxorubicin.
Bronchodilatators or anti-asthma drugs: theophylline, aminophylline.
Dermatological drugs: isotretinoin.
Other interactions: herbal preparations containing St John's wort (Hypericum perforatum).
Mefloquine may antagonize anticonvulsant effect of Mezacar® SR. The dosage of Mezacar® SR should be adjusted respectively.
As reported, isotretinoin changes bioavailability and/or clearance of carbamazepine and carbamazepine-10,11-epoxide; carbamazepine plasma concentrations should be monitored.
Effect of Mezacar® SRon plasma levels of concomitant agents.
Carbamazepine may lower the plasma level, diminish or even abolish the activity of certain drugs. The dosage of the following drugs may have to be adjusted to clinical requirement.
Analgesics, anti-inflammatory agents: buprenorphine, methadone, paracetamol (long term administration of carbamazepine and paracetamol (acetaminophen) may be associated with hepatotoxicity), tramadol.
Antibiotics: doxycycline, rifabutin.
Anticoagulants: oral anticoagulants (e.g. warfarin, phenprocoumon, dicoumarol and acenocoumarol).
Antidepressants: bupropion, citalopram, nefazodone, sertraline, trazodone, tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine).
Antiepileptics: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. There have been reported of either increase or decrease of plasma level of phenytoin caused by carbamazepine action and there have been rare reports of an increase in plasma mephenytoin levels.
Antifungals: itraconazole, voriconazole, ketoconazole. 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.
Bronchodilatators 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, quinidine, propranolol, simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine.
Corticosteroids: corticosteroids (e.g. prednisolone, dexamethasone).
Drugs used in erectile dysfunction: tadalafil.
Immunosuppressants: cyclosporin, everolimus, tacrolimus, sirolimus.
Thyroid agents: levothyroxine.
Other drug interactions: products containing estrogens and/or progesterones (alternative methods of contraception should be considered); buprenorphine, gestrinone, tibolone, toremifene, mianserin, sertraline.
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 Mezacar®SR and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia.
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.
Interactions resulting in a contraindication.
Since carbamazepine is structurally similar to the tricyclic antidepressants, the use of Mezacar® SRis contraindicated in combination with monoamine-oxidase inhibitors (MAOIs); before administering Tegretol MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits.
Interference with serological testing.
Carbamazepine may result in false positive perphenazine concentrations in HPLC (high-performance liquid chromatography) analysis due to interference to determine the concentration of perphenazine.
Carbamazepine and the 10,11-epoxide metabolite may result in false positive tricyclic antidepressant concentration in fluorescence polarized immunoassay method.
MEZACAR® SR should be administered only under medical supervision. MEZACAR® SR should be administered after evaluation of benefit/risk ratio and in close monitoring of patients with cardiac, liver and kidney disorders, side hematologic reactions and other preparations in anamnesis or to patients with interrupted therapy courses by MEZACAR® SRpreparation. Usually the preparation is ineffective in small attacks (petit mal, absence) and myoclonic attacks.
Hematologic effects: The development of agranulocytosis and aplastic anemia is related to the preparation use; nevertheless due to low rate of cases of these states development it is difficult to evaluate a risk in MEZACAR® SRpreparation use. General risk for human, who does not receive therapy, is 4.7 persons/1000000 per year for agranulocytosis development and 2 persons/1000000 per year for aplastic anemia development.
It is periodically observed temporal or steady decrease of number of thrombocyte or white blood cell due to MEZACAR® SRusage. Nevertheless, for the most of theses cases it was proved their temporality and they are not evidence of the development of agranulocytosis and aplastic anemia. Before the therapy and periodically during the therapy it is necessary to make a blood test, including determination of thrombocyte number (and also, probably, reticulocyte number and hemoglobin level).
If during the therapy the number of leucocyte or thrombocyte is significantly decreased and patient’s state should be carefully monitored and blood tests must be constantly done. MEZACAR® SRpreparation use should be discontinued in occurrence of signs of inhibition of bone marrow function.
Patients should be informed about early signs of toxicity and symptoms of possible hematologic disorders, and also about symptoms of dermatological and hepatic reactions. Patients should be warned that in case of appearance of such reactions as fever, angina, skin rash, oral cavity ulcer, easy bruising, petechial hemorrhage or hemorrhagic purpura they must immediately consult a doctor.
Severe dermatological reactions: Severe dermatological reactions, including toxic epidermal necrolysis (TEN or Lyell's syndrome) and Stevens-Johnson syndrome (SJS), occur very rarely during MEZACAR® SRpreparation use. Patients with severe dermatological reactions may need a hospitalization, because these states can threaten their lives and may have a fatal nature. Most of cases of development of SJS/TEN are observed during the first months of the preparation treatment. In development of signs and symptoms, which indicate severe dermatological reactions (for example, SJS, Lyell's syndrome/TEN), MEZACAR® SRpreparation usage should be immediately discontinued and alternative therapy should be administered.
Retrospective studies in patients-Japanese of Khan ethnic group showed an apparent correlation between SJS/TEN skin reactions related to carbamazepin and presence of leukocytic antigen (HLA), allele (HLA)-В*1502 in those patients. The most part of reports about SJS development (they are more frequent “rarely” than “very rarely”) are typical for some countries of Asia (for example, Taiwan, Malaysia and Philippines), where allele (HLA)-В*1502 is prevailed among population. A number of carriers of this allele among Asian population is 15% in Philippines, Thailand, Hong Kong, Malaysia, about 10% – in Taiwan, nearly 4% – in North China, about 2%–4% – in South Asia (including India) and less than 1% – in Japanese and Korea. Allele (HLA)-В*1502 spread is insignificant among European and African population, among American native population and Latin America population.
Before MEZACAR® SRpreparation treatment start it is necessary to make tests on allele (HLA)-В*1502 presence in patients who are considered as genetically belonged to the risk group. If in patient the test on allele (HLA)-В*1502 presence is positive, then it is necessary to avoid MEZACAR® SRpreparation usage with the exception when the benefit of the treatment overweights the risk. Allele (HLA)-В*1502 can be a risk factor of SJS/TEN in patients-Chinese who receive other antiepileptic drugs, which can be associated with SJS/TEN occurrence. Thus, it is necessary to avoid administration of other preparations, which can be associated with SJS/TEN occurrence, in patients who have allele (HLA)-В*1502 if another alternative therapy may be used. Usually it is not recommended to screen genetically patients of nationalities with low allele (HLA)-В*1502. Usually it is not recommended to screen persons who have already taking MEZACAR® SRbecause risk of SJS/TEN occurrence is significantly limited during the first months in spite of allele (HLA)-В*1502 presence in patient’s genes.
Results of genetic screening never should change appropriate clinical supervision and treatment of patient. A lot of Asian patients who have allele (HLA)-В*1502 gene and have the treatment course by MEZACAR® SRpreparation do not have SJS/TEN, but patients of any nationality who do not have allele (HLA)-В*1502 can get SJS/TEN. It has not been studied the role of other possible causative agents such as antiepileptic drug dosage level, complaence, concurrent drugs, influence of other diseases and the level of monitoring of skin disorders in the development and disease incidence of SJS/TEN.
Other dermatological reactions: It is possible a development of easy dermatological reactions both transient and not dangerous to health, for example, isolated macular and maculopapular exanthema. They usually pass in a few days or weeks both in regular dosage and after dose lowering. At the same time patient should be under close supervision for immediate discontinuation of the preparation use in case of reaction worsening during its continuation, because early signs of more serious dermatological reactions may be hardly differentiated from moderate transient reactions.
Allele (HLA)-В*1502 presence in patient is not a risk factor of less serious skin reactions on carbamazepin such as syndrome of hypersensitivity to anticonvulsive drugs or minor rash (maculopapular rash).
Hypersensitivity:MEZACAR® SRcan provoke hypersensitivity reactions development, including multiple hypersensitivity reactions with localization in skin, liver, blood-forming organs and lymphatic system or other organs, together or separately, within systemic reaction.
Patients with hypersensitivity reactions to carbamazepin should be informed that about 25–30% of those patients can have hypersensitivity reactions to carbamazepin.
In carbamazepin usage with phenytoin it is possible a cross hypersensitivity development.
In general, in appearance of signs and symptoms, which indicate hypersensitivity, MEZACAR® SR preparation use should be immediately discontinued.
Attacks: MEZACAR® SRshould be administered with caution to patients with mixed attacks, including absence (typical or non-typical). Under these circumstances the preparation can provoke attacks. In case of attacks provocation MEZACAR® SR preparation use should be immediately discontinued.
Increase of attack rate can be during the transfer from per oral forms of the preparation to suppository.
Liver function: During the preparation therapy it is necessary to evaluate liver function on initial level and periodically evaluate this function during the therapy, especially in patients with hepatic disease in anamnesis and in elderly patients. In acute condition of hepatic dysfunction or in patients with active phase of hepatic disease it is necessary to discontinue the preparation use.
Kidney function: It is recommended to evaluate kidney function and to determine urea nitrogen blood level at the beginning of and during the therapy course.
Anticholinergic effects: MEZACAR® SRhas a moderate anticholinergic activity. Thereby, patients with increased intraocular pressure should be under close supervision during the therapy.
Psychic effects: It is necessary to remember about possibility of latent psychosis activation and in elderly patients – mental constipation and agitation.
Endocrine effects: It was reported about cases of burst bleeding in women who took MEZACAR® SRin combination with hormonal contraceptives. As MEZACAR® SRcan negatively influence on efficacy of hormonal contraceptives women of childbearing age should be recommended to use alternative contraceptive forms during the preparation administration. Due to liver enzymes induction MEZACAR® SRcan be a reason of therapeutical effect of estrogen and/or progesterone preparations (that is it can prevent an effective contraception).
Monitoring of the preparation level in plasma: In spite of that a correlation between dosage and carbamazepin level in plasma and between carbamazepin level in plasma and clinical efficacy and tolerance is unreliable, then monitoring of the preparation level in plasma can be reasonable in the following cases: in sudden attacks rate increasing, in control of patient’s complaence, during pregnancy, in children and adolescent treatment; in suspicion of absorption disorder, in suspected toxicity and in usage of more than one drug.
Dosage lowering and preparation withdrawal: Sudden MEZACAR® SRwithdrawal can cause attacks. In case of sudden preparation withdrawal in patients with epilepsy a transfer to another antiepileptic drug should be against the background of the therapy by appropriate preparation (for example, diazepam intravenously, through rectum or phenytoin intravenously).
Patient’s transfer from tablets into retard tablets: Clinical experience shows that it can be a necessity of the preparation dose increasing in some patients in usage of retard tablets.
Taking into account drugs interaction and different pharmacokinetics of antiepileptic preparations it is necessary to adjust MEZACAR® SR doses with caution for elderly patients.
Pregnancy and lactation.
In animals oral administration of carbamazepine caused the development of defects.
Offspring of epileptic mothers are known to be more prone to developmental disorders, including malformations. The possibility that carbamazepine, like all major antiepileptic drugs, increases the risk has been reported, although conclusive evidence from controlled studies with carbamazepine monotherapy is lacking. However, there are reports on developmental disorders and malformations, including spina bifida, and also other congenital anomalies e.g. craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving various body systems, have been reported in association with carbamazepine.
Taking these data into consideration.
Pregnant women with epilepsy should be treated with Mezacar® SRwith special care.
If women receiving Mezacar® SRbecome pregnant or plan to become pregnant, or if the problem of initiating treatment with Mezacar® SRarises during pregnancy, the drug's expected benefits must be carefully weighed against its possible hazards, particularly in the first 3 months of pregnancy.
In women of childbearing potential Mezacar® SRshould, wherever possible, be prescribed as monotherapy.
Minimum effective doses should be given and monitoring of plasma levels is recommended.
Patients should be counseled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.
During pregnancy, an effective antiepileptic treatment should not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.
Monitoring and prevention. Folic acid deficiency is known to occur in pregnancy. Antiepileptic drugs have been reported to aggravate folic acid deficiency, therefore folic acid supplementation has been recommended before and during pregnancy
In the neonate. In order to prevent bleeding disorders in the offspring, it has also been recommended that vitamin K1 be given to the mother during the last weeks of pregnancy as well as to the neonate.
There have been a few cases of neonatal seizures and/or respiratory depression, vomiting, diarrhoea and/or decreased feeding associated with maternal carbamazepine and other concomitant anticonvulsant drug use.
Breast-feeding. Carbamazepine passes into the breast milk (about 25 to 60% of plasma concentrations). The benefits of breast-feeding should be weighed against the remote possibility of adverse effects occurring in the infant. Mothers taking Mezacar® SR may breast-feed their infants, provided the infant is observed for possible adverse reactions (e.g. excessive somnolence, allergic skin reaction).
There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.
Effects on the ability to drive and use machines.
The patient's ability to react may be impaired with Mezacar® SR due to the emergence of dizziness and drowsiness, 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.
Administration and dosage.
Mezacar® SRis given orally, usually in one or two divided doses. Prolonged action tablets have dividing line, take them during or after a meal with a necessary number of liquid (eg a glass of water). Prolonged action tablets can be taken after a previous dissolution of in water (in the form of suspension ). Prolonged action of it is preserved after dissolving the tablet in water. Duration of use depends on the testimony and individual reactions of the patient to the drug.
Before deciding to initiate treatment, patients that are potential HLA-B*1502 allele carrier should whenever possible be screened for this allele as it strongly predicts the risk of severe skin reactions.
Initially, the dosage should be low and then slowly raised. The dose should be adjusted to the needs of the individual patient.
Determination of plasma levels may help in establishing the optimum dosage. Especially in case of combination therapy the therapeutic dose should be calculated on the basic determination of plasma carbamazepine and effectiveness.
Adults: the recommended starting dose is 100-200 mg per day. Then slowly increase the dose to achieve optimal effect, often daily dose of 800-1200 mg. Some patients may require dose Mezakar® SR, reaching 1600 mg (4 prolonged action tablets) or even 2000 mg (5 tablets of prolonged action) per day.
Elderly: Due to the potential for drug interactions, the dosage of Mezacar® SR should be selected with caution in elderly patients.
Children: therapy may begin with 100 mg/day, increasing at weekly intervals by 100 mg.
Usual dosage 10-20 mg/kg bodyweight daily taken in several divided doses.
Child age 5 - 10 years old daily dosage 400 - 600 mg.
Child age10 - 15 years old daily dosage 600 - 1000 mg.
For children aged 15 and over the dosage is same as in adults.
Acute mania and maintenance treatment of bipolar affective disorders
Dosage range: about 400 to 1600 mg daily, given in 2 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.
To prevent the development of convulsive seizures in alcohol-withdrawal syndromeMezakar® SR 400mg used only in stationary conditions. The average daily dose - 600 mg (0.5 tablets with prolonged action in the morning and 1 prolonged action tablet in the evening). In severe cases, in first days, the dose may be increased to 1200 mg (1.5 prolonged action tablets tablets in the morning and 1.5 prolonged action evening)
In severe forms of alcohol withdrawal treatment drug combination to begin Mezakar® SR, a sedative-hypnotic drugs (eg, klometiazolom, chlordiazepoxide), following the above instructions for dosage. After completing the acute phase of treatment with Mezakar® SR, can continue as monotherapy.
Idiopathic trigeminal neuralgia and trigeminal neuralgia in disseminated sclerosis (either typical or atypical).Idiopathic glossopharyngeal neuralgia.
The initial dosage is 200 to 400 mg daily (100mg twice daily for elderly). It should be slowly raised daily until freedom from pain is achieved (normally at 400-800 mg 1 to 2 times daily). In some instances, 1600mg of Mezacar® SR daily may be necessary (4 prolonged action tablets). After freedom from pain is achieved the dosage should then be gradually reduced to the lowest possible maintenance level.
Owing to enhanced carbamazepine elimination, children may require higher doses of the drug (in mg/kg of body weight) than adults. Mezacar® SR can be administered in children aged 5 and older.
Symptoms. The presenting signs and symptoms of overdosage usually involve the central nervous, cardiovascular, respiratory systems.
Central nervous system: CNS depression; disorientation, depressed level of consciousness, somnolence, agitation, hallucination, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, initially hyper-reflexia, later hyporeflexia; convulsions, psychomotor disturbances, myoclonus, hypothermia, mydriasis.
Respiratory system: respiratory depression, pulmonary oedema.
Cardiovascular system: tachycardia, hypotension, at times hypertension, conduction disturbance with widening of QRS complex; syncope in association with cardiac arrest, accompanied by loss of consciousness.
Gastrointestinal system: vomiting, delayed gastric emptying, reduced bowel motility.
Musculoskeletal system: There have been some cases which reported rhabdomyolysis in association with carbamazepine toxicity.
Urinary system: retention of urine, oliguria or anuria; fluid retention, water intoxication due to an ADH-like effect of carbamazepine.
Laboratory findings: hyponatremia, possibly metabolic acidosis, hyperglycemia, increased muscle creatine phosphokinase.
Management. 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. If hypotension is observed intravenous administration of dopamine or dobutamine is indicated; in case of arrhythmia the treatment is selected individually; if seizures are observed – administration of benzodiazepines (e.g. diazepam) or other anticonvulsants, e.g. phenobarbital (with caution because of an increased risk of respiratory depression) or paraldehyde; if hyponatremia is observed (water intoxication) - water restriction, slow, careful intravenous infusion of 0,9% sodium chloride solution. These measures may be useful for the prevention of cerebral edema.
Charcoal hemoperfusion has been recommended. Forced diuresis, hemodialysis and peritoneal dialysis are not effective.
Relapse and aggravation of symptomatology on the 2nd and 3rd day after overdose, due to delayed absorption, should be anticipated.
Adverse drug reactions.
Particularly at the start of treatment with Mezacar® SR, or if the initial dosage is too high, or when treating elderly patients, certain types of adverse reaction occur, e.g. CNS adverse reactions; gastrointestinal disturbances, 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 of active substance 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.
Blood and lymphatic system disorders: leukopenia; thrombocytopenia,, eosinophilia, leukocytosis, lymphadenopathy, folic acid deficiency, agranulocytosis, aplastic anemia, pancytopenia, aplasia pure red cell, anemia, anemia megaloblastic, acute intermittent porphyria, variegate porphyria, late cutaneous porphyria, reticulocytosis, hemolytic anemia, bone marrow failure.
Immune system disorders: 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), aseptic meningitis with myoclonus and peripheral eosinophilia, anaphylactic reaction, drug rash with eosinophilia and systemic symptoms (DRESS), oedema angioedema, hypogammaglobulinemia.
Endocrine disorders: oedema, fluid retention, weight increase, hyponatremia 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; increased blood prolactin, accompanied or not accompanied by such reactions as galactorrhoea, gynecomastia; Thyroid function test abnormal: decreased L-Thyroxin (FT4, T4, T3) and increased blood thyroid stimulating hormone, usually without clinical manifestations.
Metabolism and nutrition disorders: folate deficiency, decreased appetite, porphyria acute (acute intermittent porphyria and variegate porphyria), porphyria non-acute (porphyria cutanea tarda).
Psychiatric disorders: hallucinations (visual or auditory), depression, decreased appetite, restlessness, aggression, agitation, confusional state, activation of psychosis.
Nervous system disorders:dizziness, ataxia, somnolence, sedation, memory impairment, headache, diplopia, accommodation disorders (e.g. blurred vision); abnormal involuntary movements (e.g. tremor, dystonia, tics), nystagmus; orofacial dyskinesia, eye movement disorder, speech disorders (e.g. dysarthria or slurred speech), choreoathetosis, neuropathy peripheral, paraesthesia, paresis; taste disorders, neuroleptic malignant syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia.
Eye disorders: accommodation disorders (e.g. blurred vision), lenticular opacities, conjunctivitis, increased intraocular pressure.
Ear and labyrinth disorders:hearing disorders, e.g. tinnitus, hyperacusis, hypoacusis, change in pitch perception.
Cardiac and vascular disorders: cardiac conduction disorders; hypertension or hypotension; bradycardia, arrhythmia, atrioventricular block with syncope, circulatory collapse, cardiac failure congestive, recrudescence of coronary artery disease, thrombophlebitis, thrombembolia (e.g. pulmonary embolism).
Respiratory, thoracic and mediastinal disorders: pulmonary hypersensitivity characterized e.g. by fever, dyspnoea, pneumonitis or pneumonia.
Gastrointestinal disorders:nausea, vomiting, dry mouth, diarrhoea or constipation, abdominal pain, glossitis, stomatitis, pancreatitis, colitis.
Hepatobiliary disorders:gamma-glutamyltransferase increased (due to hepatic enzyme induction, usually not clinically relevant), blood alkaline phosphatase increased, transaminases increased, hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, vanishing bile duct syndrome, jaundice, granulomatous hepatitis, hepatic failure.
Skin and subcutaneous tissue disorders:dermatitis allergic, urticaria (which may be severe), dermatitis exfoliative, erythroderma, systemic lupus erythematosus, lupuslike syndrome, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity reaction, erythema multiforme and nodular, pigmentation disorder, purpura, acne, hyperhydrosis, alopecia, hirsutism, Acute Generalized Exanthematous Pustulosis (AGEP), lichenoid keratosis, onychomadesis.
Musculoskeletal, connective tissue and bone disorders: muscular weakness,arthralgia, myalgia, muscle spasms, bone metabolism disorders (decrease in plasma calcium and blood 25-hydroxy-cholecalciferol, leading to osteomalacia and osteoporosis), fractures, bone mineral density decreased.
Renal and urinary disorders:tubulointerstitial nephritis, renal failure, renal impairment (e.g. albuminuria, hematuria, oliguria, and blood urea increased/azotemia), urinary frequency, urinary retention.
Reproductive system: sexual dysfunction, impotence, erectile dysfunction, spermatogenesis abnormal (with decreased sperm count and/or motility).
General disorders: fatigue.
Deviations in laboratory and instrumental examinations: intraocular pressure increased, blood cholesterol increased, high density lipoprotein increased, blood triglycerides increased.
Infections and infestations: reactivation of human herpesvirus (HHV-4).
Shelf life. 2 years.
Store below 25°C.
Keep it out of reach of children.
There are 10 tablets in a blister; there are 5 blisters in a carton pack.
Conditions of supply:
Kusum Healthcare PVT LTD.
SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.
1 tablet contains carbamazepin 400 mg; аntiepileptic drugs.
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